砷是廣泛存在的環境毒物，其暴露會增加人類癌病的形成，包括肺癌、皮膚癌、膀胱癌等的發生。砷的致癌性與其造成基因體損傷，抑制DNA修補，妨礙細胞週期運轉以及干擾細胞分裂有極高的關係。砷對哺乳類細胞會迅速誘發訊號傳遞路徑，然而如何藉由活化之訊號分子來調整適宜的細胞反應有待深入研究。本篇論文探討人類細胞在砷的處理下，誘發之生長素活化激酶(mitogen-activated protein kinases; MAPKs)是否參與細胞損傷反應系統來影響細胞週期運轉、核酸切除修補(nucleotide excision repair; NER)、細胞毒性與基因毒性。我們首先探討砷化鈉對生長中的人類肺癌細胞株CL3誘發ERK、JNK和p38三個MAPKs訊號分子與它們的交互作用以及細胞效應。砷在約六成細胞致死劑量下(50 □M, 3 h)能持久性地活化ERK、JNK與p38，抑制NER修補效率，並且誘發微核產生。砷暴露時，抑制ERK訊號會加強JNK活化的強度，反之，額外加強MKK1-ERK訊號則降低JNK活化的強度。抑制JNK或p38訊號並不影響另二個MAPKs被砷活化的強度。此結果顯示砷誘發ERK活化會負調控JNK，而p38活化與ERK或JNK之間沒有交互作用。抑制ERK活化時會加強砷之細胞毒性。雖然抑制JNK不影響，但同時抑制ERK及JNK活化會顯著地協力加強之。相反地，抑制p38活化會降低砷之細胞毒性。抑制ERK或p38訊號時均可減少砷誘發微核產生，而抑制JNK則不影響之。有趣地，砷減弱之NER修補效率可因抑制ERK活化而顯著地回復，但抑制JNK或p38活化並不影響之。加強MKK1-ERK訊號可以提升內生性NER修補效率，此時砷仍能抑制NER修補，然而加強此訊號也能緩和砷抑制NER修補的情形，暗示ERK訊號具有正反調控NER修補效率的雙重作用。綜合上述推論，砷暴露過的CL3細胞中，活化之p38訊號加強細胞與基因毒性，ERK訊號提供細胞存活但參與抑制NER修補及加強基因毒性，而JNK訊號協力地參與ERK媒介之細胞存活。我們也發現對G1期細胞而言，砷誘發的細胞毒性雖比較不敏感，但仍會引起NER修補抑制並產生相對高量的微核，且也能持久性誘發ERK和p38訊號。經過砷處理之G1細胞，抑制ERK活化會加強細胞毒性，然而也會緩和NER修補抑制的情形並降低微核產生，但抑制p38活化並不影響之。砷(50 □M, 3 h)造成G1期細胞週期運轉停滯約12小時，降低cyclin D1、cyclin E與cyclin A蛋白量，減少G1 cyclin-Cdk激酶活性。同時也降低Skp2蛋白量伴隨著p21Cip1與p27Kip1的增加。抑制ERK訊號會延長砷對G1期造成細胞週期運轉停滯，增加細胞凋亡，且加強砷降低cyclin D1蛋白量與其激酶活性的能力。綜合上述推論，砷暴露過的G1期細胞產生之ERK訊號可降低細胞凋亡並促使cyclin D1蛋白重新生成以拮抗G1期暫停，然而此訊號也參與抑制NER修補並加強微核產生，因此提供ERK訊號可能參與砷的致癌性之分子證據。進而探討砷是否啟動G2細胞週期之監控反應以及p38或ERK活化的角色。利用aphidicolin同步化方法得到G2初期或G2末期之CL3細胞。砷處理G2初期細胞會顯著地使G2期運轉停滯，並降低cyclin B1的含量和Cdk1的激酶活性。相反地，砷對G2末期細胞卻造成cyclin B1含量的累積，顯示cyclin B1對砷的敏感性受細胞週期影響。在砷處理過之G2初期細胞cyclin B1蛋白被修飾上polyubiquitin之後，藉由26S proteasome路徑來造成蛋白降解；此時也伴隨著p38與ERK訊號之活化。抑制p38活化顯著地減緩砷誘發cyclin B1的ubiquitination及降解的能力並回復Cdk1的激酶活性；相對地，額外表現MKK3/6-p38會加強砷促使cyclin B1降解的能力。砷暴露下，抑制p38活化會顯著地回復G2初期細胞進入有絲分裂期，減少細胞凋亡及提高細胞存活；相對地，抑制ERK活化雖不影響砷造成之G2細胞週期停滯及cyclin B1降解，但會加強G2初期細胞進行凋亡並增加細胞毒性。抑制p38或ERK活化均會減低砷對G2細胞誘發之微核。綜合上述推論，砷活化p38訊號會連結G2細胞週期停滯與細胞凋亡，而ERK訊號使細胞存活，然而這兩個訊號都會造成基因體的不穩定性。本論文闡述之證據顯示砷誘發之各MAPKs參與細胞損傷反應以及它們在癌化過程扮演的不同角色。

Arsenic, a widely distributed natural toxicant, is highly associated with increased risk for human cancers of the lung, skin, bladder, and other internal organs. Arsenic carcinogenicity has been associated with its ability to cause genomic injury, inhibit DNA repair processes, perturb cell cycle progression, and impede cell division. Many signal transduction pathways are quickly activated upon exposing mammalian cells to arsenic, however, the mechanism that appropriate cellular responses regulated by these activated signals remains to be elucidated. In this thesis, we investigated whether mitogen-activated protein kinases (MAPKs) serves as a part of the cellular damage-response network to regulate cell cycle progression, nucleotide excision repair (NER), cytotoxicity, and genotoxicity in arsenite-treated human cells. We began to explore the ability of sodium arsenite in activating three members of MAPKs, i.e., ERK, JNK, and p38, and their cross-talks and cellular effects in asynchronous CL3 human non-small-cell lung carcinoma cells. Arsenite at doses causing ~60% cytotoxicity (50 □M, 3 h) activated sustained-ERK, -JNK, and -p38, inhibited NER-repair synthesis, and induced micronucleus formation. Upon arsenite exposure, suppression of ERK activation further enhanced JNK activity; conversely, forced expression of MKK1-ERK attenuated JNK activity. Inhibition of JNK or p38 did not affect the ability of arsenite to elicit the other two MAPKs. The results suggest that ERK down-regulates JNK activation, while p38 does not crosstalk with ERK and JNK in arsenite-treated cells. Suppression of ERK activation enhanced arsenite cytotoxicity. Inhibition of JNK did not affect arsenite cytotoxicity, yet co-inhibition of ERK and JNK synergistically enhanced it. Conversely, suppression of p38 reduced arsenite cytotoxicity. Suppression of either ERK or p38, but not JNK, decreased arsenite-induced micronucleus formation. Intriguingly, suppression of ERK activation rescued the NER synthesis inhibition after arsenite, while suppression of JNK or p38 could not. Forced expression of MKK1-ERK markedly elevated the endogenous NER synthesis, which could be suppressed by arsenite. However, the arsenite-elicited NER inhibition was recovered by reinforcing the MKK1-ERK signal. The results suggest that ERK signal exhibits dual roles in regulating NER synthesis. Thus, under arsenite exposure of exponential growing CL3 cells, p38 activation contributed to genomic instability and cell death, ERK activation played a part in NER synthesis inhibition, genomic instability, and survival, and JNK synergistically contributed to ERK-mediated survival.Furthermore, we found that G1 was the most insensitive phase to arsenite cytotoxicity, yet it was highly susceptible to arsenite in NER synthesis inhibition, micronucleus induction, and the activation of sustained-ERK and -p38 signals. In the arsenite-treated G1-enriched cells, suppression of ERK activation further enhanced cytotoxicity, yet recovered NER synthesis activity and lowered the micronucleus induction. In contrast, suppression of p38 did not show such effects on the arsenite-induced cytotoxicity and micronucleus induction. Arsenite (50 □M, 3 h) delayed the progression of G1-enriched cells for at least 12 h, partly via down-regulation of cyclin D1, cyclin E, and cyclin A protein levels, and Cdk4-, cyclin E-, cyclin A-, and Cdk2-associated kinase activities. Moreover, arsenite efficiently decreased Skp2, an activating subunit of the SCF ubiquitin ligase, and increased p21Cip1 and p27Kip1 protein levels in G1-enriched CL3 cells. Suppression of ERK activation further enhanced the G1 delay and sub-G1 populations and the decrease in cyclin D1 protein and cyclin D1-associated kinase activity. Thus, after arsenite exposure of the G1-enriched cells the sustained-ERK signal counteracted apoptosis and participated in recovery from the G1 delay via increase in cyclin D1 re-synthesis, yet the signal also mediated in NER inhibition and micronucleus formation, which may lead to carcinogenesis. We next explored whether arsenite induces the G2-checkpoint responses and roles of the activated-ERK and -p38 signals. Using the aphidicolin protocol, CL3 cells were synchronized in early-G2 and late-G2 phases. Exposing the early-G2 cells to arsenite markedly retarded the G2 progression, and decreased cyclin B1 protein level and Cdk1 kinase activity. In contrast, cyclin B1 protein level was accumulated in arsenite-treated late-G2 cells, indicating cyclin B1 exhibits distinct cell cycle-dependent sensitivity to arsenite. Cyclin B1 was polyubiquitinated and subsequently degraded via 26S proteasome in arsenite-treated early-G2 cells, which was accompanied by activation of p38 and ERK. Under arsenite, knockdown p38□ expression or inhibiting p38 activation lowered the cyclin B1 ubiquitination/degradation and rescued the Cdk1 kinase activity, while forced expression of MKK3/6-p38 exhibited opposing effects. Inactivation of p38 allowed G2-to-M progression, reduced sub-G1 population, and increased cell viability in the arsenite-treated early-G2 cells. By contrast, blockage of ERK activation though did not affect the G2 delay and cyclin B1 proteolysis, markedly enhanced sub-G1 population and decreased cell viability caused by arsenite. Inactivation of either p38 or ERK in early-G2 cells decreased the arsenite-induced micronucleus. Together, the results suggest that under arsenite p38 triggers cyclin B1 degradation and connects G2 arrest and apoptosis, while ERK contributes to survival; yet, both signals may confer genomic instability. The findings obtained in this thesis have provided evidence to indicate that each MAPKs plays distinct roles in cellular damage responses after arsenite, which would contribute to carcinogenesis.

Abbott, D.W. and Holt, J.T. (1999) Mitogen-activated protein kinase kinase 2 activation is essential for progression through the G2/M checkpoint arrest in cells exposed to ionizing radiation. J Biol Chem, 274, 2732-2742.
Achanzar, W.E., Brambila, E.M., Diwan, B.A., Webber, M.M. and Waalkes, M.P. (2002) Inorganic arsenite-induced malignant transformation of human prostate epithelial cells. J Natl Cancer Inst, 94, 1888-1891.
Alblas, J., Slager-Davidov, R., Steenbergh, P.H., Sussenbach, J.S. and van der Burg, B. (1998) The role of MAP kinase in TPA-mediated cell cycle arrest of human breast cancer cells. Oncogene, 16, 131-139.
Alessi, D.R., Cuenda, A., Cohen, P., Dudley, D.T. and Saltiel, A.R. (1995) PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem, 270, 27489-27494.
Ambrosino, C. and Nebreda, A.R. (2001) Cell cycle regulation by p38 MAP kinases. Biol Cell, 93, 47-51.
Andrew, A.S., Karagas, M.R. and Hamilton, J.W. (2003a) Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water. Int J Cancer, 104, 263-268.
Andrew, A.S., Warren, A.J., Barchowsky, A., Temple, K.A., Klei, L., Soucy, N.V., O'Hara, K.A. and Hamilton, J.W. (2003b) Genomic and proteomic profiling of responses to toxic metals in human lung cells. Environ Health Perspect, 111, 825-835.
Asmuss, M., Mullenders, L.H., Eker, A. and Hartwig, A. (2000) Differential effects of toxic metal compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair. Carcinogenesis, 21, 2097-2104.
Bagui, T.K., Mohapatra, S., Haura, E. and Pledger, W.J. (2003) p27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes. Mol Cell Biol, 23, 7285-7290.
Balmanno, K. and Cook, S.J. (1999) Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. Oncogene, 18, 3085-3097.
Bashir, T., Dorrello, N.V., Amador, V., Guardavaccaro, D. and Pagano, M. (2004) Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature, 428, 190-193.
Bassermann, F., von Klitzing, C., Munch, S., Bai, R.Y., Kawaguchi, H., Morris, S.W., Peschel, C. and Duyster, J. (2005) NIPA defines an SCF-type mammalian E3 ligase that regulates mitotic entry. Cell, 122, 45-57.
Basu, A., Mahata, J., Gupta, S. and Giri, A.K. (2001) Genetic toxicology of a paradoxical human carcinogen, arsenic: a review. Mutat Res, 488, 171-194.
Bates, M.N., Smith, A.H. and Hopenhayn-Rich, C. (1992) Arsenic ingestion and internal cancers: a review. Am J Epidemiol, 135, 462-476.
Bau, D.T., Gurr, J.R. and Jan, K.Y. (2001) Nitric oxide is involved in arsenite inhibition of pyrimidine dimer excision. Carcinogenesis, 22, 709-716.
Bau, D.T., Wang, T.S., Chung, C.H., Wang, A.S. and Jan, K.Y. (2002) Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite. Environ Health Perspect, 110 Suppl 5, 753-756.
Bebien, M., Salinas, S., Becamel, C., Richard, V., Linares, L. and Hipskind, R.A. (2003) Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF. Oncogene, 22, 1836-1847.
Benbrahim-Tallaa, L., Waterland, R.A., Styblo, M., Achanzar, W.E., Webber, M.M. and Waalkes, M.P. (2005) Molecular events associated with arsenic-induced malignant transformation of human prostatic epithelial cells: aberrant genomic DNA methylation and K-ras oncogene activation. Toxicol Appl Pharmacol, 206, 288-298.
Bennett, B.L., Sasaki, D.T., Murray, B.W., O'Leary, E.C., Sakata, S.T., Xu, W., Leisten, J.C., Motiwala, A., Pierce, S., Satoh, Y., Bhagwat, S.S., Manning, A.M. and Anderson, D.W. (2001) SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A, 98, 13681-13686.
Berry, L.D. and Gould, K.L. (1996) Regulation of Cdc2 activity by phosphorylation at T14/Y15. Prog Cell Cycle Res, 2, 99-105.
Bessho, T., Sancar, A., Thompson, L.H. and Thelen, M.P. (1997) Reconstitution of human excision nuclease with recombinant XPF-ERCC1 complex. J Biol Chem, 272, 3833-3837.
Boldt, S., Weidle, U.H. and Kolch, W. (2002) The role of MAPK pathways in the action of chemotherapeutic drugs. Carcinogenesis, 23, 1831-1838.
Bootsma, D., Kreamer, K.H., Cleaver, J.E., and Hoeijmakers, J.H. (1998) Nucleotide excision repair syndromes: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. In Vogelsteain, B.a.K., K.W. (ed.), Genetic Basis of Human Cancer. MvGraw-Hill, New York, pp. 254-257.
Bornstein, G., Bloom, J., Sitry-Shevah, D., Nakayama, K., Pagano, M. and Hershko, A. (2003) Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem, 278, 25752-25757.
Bost, F., McKay, R., Dean, N. and Mercola, D. (1997) The JUN kinase/stress-activated protein kinase pathway is required for epidermal growth factor stimulation of growth of human A549 lung carcinoma cells. J Biol Chem, 272, 33422-33429.
Brancho, D., Tanaka, N., Jaeschke, A., Ventura, J.J., Kelkar, N., Tanaka, Y., Kyuuma, M., Takeshita, T., Flavell, R.A. and Davis, R.J. (2003) Mechanism of p38 MAP kinase activation in vivo. Genes Dev, 17, 1969-1978.
Brooks, C.L. and Gu, W. (2006) p53 ubiquitination: Mdm2 and beyond. Mol Cell, 21, 307-315.
Bulavin, D.V., Demidov, O.N., Saito, S., Kauraniemi, P., Phillips, C., Amundson, S.A., Ambrosino, C., Sauter, G., Nebreda, A.R., Anderson, C.W., Kallioniemi, A., Fornace, A.J., Jr. and Appella, E. (2002) Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet, 31, 210-215.
Bulavin, D.V., Higashimoto, Y., Popoff, I.J., Gaarde, W.A., Basrur, V., Potapova, O., Appella, E. and Fornace, A.J., Jr. (2001) Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature, 411, 102-107.
Bulavin, D.V., Saito, S., Hollander, M.C., Sakaguchi, K., Anderson, C.W., Appella, E. and Fornace, A.J., Jr. (1999) Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. Embo J, 18, 6845-6854.
Busino, L., Donzelli, M., Chiesa, M., Guardavaccaro, D., Ganoth, D., Dorrello, N.V., Hershko, A., Pagano, M. and Draetta, G.F. (2003) Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Nature, 426, 87-91.
Canman, C.E., Lim, D.S., Cimprich, K.A., Taya, Y., Tamai, K., Sakaguchi, K., Appella, E., Kastan, M.B. and Siliciano, J.D. (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science, 281, 1677-1679.
Cardozo, T. and Pagano, M. (2004) The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol, 5, 739-751.
Carrano, A.C., Eytan, E., Hershko, A. and Pagano, M. (1999) SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol, 1, 193-199.
Casanovas, O., Miro, F., Estanyol, J.M., Itarte, E., Agell, N. and Bachs, O. (2000) Osmotic stress regulates the stability of cyclin D1 in a p38SAPK2-dependent manner. J Biol Chem, 275, 35091-35097.
Cavigelli, M., Li, W.W., Lin, A., Su, B., Yoshioka, K. and Karin, M. (1996) The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase. Embo J, 15, 6269-6279.
Chao, J.I. and Yang, J.L. (2001) Opposite roles of ERK and p38 mitogen-activated protein kinases in cadmium-induced genotoxicity and mitotic arrest. Chem Res Toxicol, 14, 1193-1202.
Chen, C.J., Chen, C.W., Wu, M.M. and Kuo, T.L. (1992) Cancer potential in liver, lung, bladder and kidney due to ingested inorganic arsenic in drinking water. Br J Cancer, 66, 888-892.
Chen, C.J., Chuang, Y.C., Lin, T.M. and Wu, H.Y. (1985) Malignant neoplasms among residents of a blackfoot disease-endemic area in Taiwan: high-arsenic artesian well water and cancers. Cancer Res, 45, 5895-5899.
Chen, C.J., Hsueh, Y.M., Lai, M.S., Shyu, M.P., Chen, S.Y., Wu, M.M., Kuo, T.L. and Tai, T.Y. (1995) Increased prevalence of hypertension and long-term arsenic exposure. Hypertension, 25, 53-60.
Chen, C.J. and Wang, C.J. (1990) Ecological correlation between arsenic level in well water and age-adjusted mortality from malignant neoplasms. Cancer Res, 50, 5470-5474.
Chen, F., Lu, Y., Zhang, Z., Vallyathan, V., Ding, M., Castranova, V. and Shi, X. (2001a) Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite. J Biol Chem, 276, 11414-11419.
Chen, F., Zhang, Z., Bower, J., Lu, Y., Leonard, S.S., Ding, M., Castranova, V., Piwnica-Worms, H. and Shi, X. (2002) Arsenite-induced Cdc25C degradation is through the KEN-box and ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A, 99, 1990-1995.
Chen, F., Zhang, Z., Leonard, S.S. and Shi, X. (2001b) Contrasting roles of NF-kappaB and JNK in arsenite-induced p53- independent expression of GADD45alpha. Oncogene, 20, 3585-3589.
Chen, H., Liu, J., Merrick, B.A. and Waalkes, M.P. (2001) Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology. Mol Carcinog, 30, 79-87.
Chen, K.L. and Wu, H.Y. (1962) Epidemiologic studies on blackfoot disease. 2. A study of source of drinking water in relation to the disease. J Formos Med Assoc, 61, 611-618.
Chen, L., Shinde, U., Ortolan, T.G. and Madura, K. (2001) Ubiquitin-associated (UBA) domains in Rad23 bind ubiquitin and promote inhibition of multi-ubiquitin chain assembly. EMBO Rep, 2, 933-938.
Chen, N., Nomura, M., She, Q.B., Ma, W.Y., Bode, A.M., Wang, L., Flavell, R.A. and Dong, Z. (2001) Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice. Cancer Res, 61, 3908-3912.
Chen, W., Martindale, J.L., Holbrook, N.J. and Liu, Y. (1998) Tumor promoter arsenite activates extracellular signal-regulated kinase through a signaling pathway mediated by epidermal growth factor receptor and Shc. Mol Cell Biol, 18, 5178-5188.
Chen, X., Zhang, Y., Douglas, L. and Zhou, P. (2001) UV-damaged DNA-binding proteins are targets of CUL-4A-mediated ubiquitination and degradation. J Biol Chem, 276, 48175-48182.
Cheng, M., Sexl, V., Sherr, C.J. and Roussel, M.F. (1998) Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc Natl Acad Sci U S A, 95, 1091-1096.
Chien, C.W., Chiang, M.C., Ho, I.C. and Lee, T.C. (2004) Association of chromosomal alterations with arsenite-induced tumorigenicity of human HaCaT keratinocytes in nude mice. Environ Health Perspect, 112, 1704-1710.
Chien, Y.H., Bau, D.T. and Jan, K.Y. (2004) Nitric oxide inhibits DNA-adduct excision in nucleotide excision repair. Free Radic Biol Med, 36, 1011-1017.
Chiou, H.Y., Chiou, S.T., Hsu, Y.H., Chou, Y.L., Tseng, C.H., Wei, M.L. and Chen, C.J. (2001) Incidence of transitional cell carcinoma and arsenic in drinking water: a follow-up study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan. Am J Epidemiol, 153, 411-418.
Chiou, H.Y., Hsueh, Y.M., Liaw, K.F., Horng, S.F., Chiang, M.H., Pu, Y.S., Lin, J.S., Huang, C.H. and Chen, C.J. (1995) Incidence of internal cancers and ingested inorganic arsenic: a seven- year follow-up study in Taiwan. Cancer Res, 55, 1296-1300.
Chuang, S.M., Wang, I.C. and Yang, J.L. (2000) Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium. Carcinogenesis, 21, 1423-1432.
Cleaver, J.E. (2005) Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer, 5, 564-573.
Clute, P. and Pines, J. (1999) Temporal and spatial control of cyclin B1 destruction in metaphase. Nat Cell Biol, 1, 82-87.
Coleman, M.L., Marshall, C.J. and Olson, M.F. (2003) Ras promotes p21(Waf1/Cip1) protein stability via a cyclin D1-imposed block in proteasome-mediated degradation. Embo J, 22, 2036-2046.
Corbit, K.C., Trakul, N., Eves, E.M., Diaz, B., Marshall, M. and Rosner, M.R. (2003) Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J Biol Chem, 278, 13061-13068.
de Laat, W.L., Jaspers, N.G. and Hoeijmakers, J.H. (1999) Molecular mechanism of nucleotide excision repair. Genes Dev, 13, 768-785.
Delavaine, L. and La Thangue, N.B. (1999) Control of E2F activity by p21Waf1/Cip1. Oncogene, 18, 5381-5392.
Derijard, B., Hibi, M., Wu, I.H., Barrett, T., Su, B., Deng, T., Karin, M. and Davis, R.J. (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell, 76, 1025-1037.
Diehl, N.L., Enslen, H., Fortner, K.A., Merritt, C., Stetson, N., Charland, C., Flavell, R.A., Davis, R.J. and Rincon, M. (2000) Activation of the p38 mitogen-activated protein kinase pathway arrests cell cycle progression and differentiation of immature thymocytes in vivo. J Exp Med, 191, 321-334.
Ding, W., Hudson, L.G. and Liu, K.J. (2005) Inorganic arsenic compounds cause oxidative damage to DNA and protein by inducing ROS and RNS generation in human keratinocytes. Mol Cell Biochem, 279, 105-112.
Dmitrieva, N.I., Bulavin, D.V., Fornace, A.J., Jr. and Burg, M.B. (2002) Rapid activation of G2/M checkpoint after hypertonic stress in renal inner medullary epithelial (IME) cells is protective and requires p38 kinase. Proc Natl Acad Sci U S A, 99, 184-189.
Dobrowolski, S., Harter, M. and Stacey, D.W. (1994) Cellular ras activity is required for passage through multiple points of the G0/G1 phase in BALB/c 3T3 cells. Mol Cell Biol, 14, 5441-5449.
Dong, J.T. and Luo, X.M. (1993) Arsenic-induced DNA-strand breaks associated with DNA-protein crosslinks in human fetal lung fibroblasts. Mutat Res, 302, 97-102.
Donzelli, M. and Draetta, G.F. (2003) Regulating mammalian checkpoints through Cdc25 inactivation. EMBO Rep, 4, 671-677.
Dudley, D.T., Pang, L., Decker, S.J., Bridges, A.J. and Saltiel, A.R. (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A, 92, 7686-7689.
Ebisuya, M., Kondoh, K. and Nishida, E. (2005) The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity. J Cell Sci, 118, 2997-3002.
Elledge, S.J. (1996) Cell cycle checkpoints: preventing an identity crisis. Science, 274, 1664-1672.
Engelman, J.A., Lisanti, M.P. and Scherer, P.E. (1998) Specific inhibitors of p38 mitogen-activated protein kinase block 3T3-L1 adipogenesis. J Biol Chem, 273, 32111-32120.
English, J., Pearson, G., Wilsbacher, J., Swantek, J., Karandikar, M., Xu, S. and Cobb, M.H. (1999) New insights into the control of MAP kinase pathways. Exp Cell Res, 253, 255-270.
EPA. (2001) National primary drinking water regulations. Arsenic and clarification to compliance and new source contaminants monitoring. In Environmental Protection Agency, Final rule, (ed.), Federal Regist., Vol. 66, pp. 6975-7066.
Ezhevsky, S.A., Ho, A., Becker-Hapak, M., Davis, P.K. and Dowdy, S.F. (2001) Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo. Mol Cell Biol, 21, 4773-4784.
Falck, J., Mailand, N., Syljuasen, R.G., Bartek, J. and Lukas, J. (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature, 410, 842-847.
Favata, M.F., Horiuchi, K.Y., Manos, E.J., Daulerio, A.J., Stradley, D.A., Feeser, W.S., Van Dyk, D.E., Pitts, W.J., Earl, R.A., Hobbs, F., Copeland, R.A., Magolda, R.L., Scherle, P.A. and Trzaskos, J.M. (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem, 273, 18623-18632.
Fenech, M. (1993) The cytokinesis-block micronucleus technique: a detailed description of the method and its application to genotoxicity studies in human populations. Mutat Res, 285, 35-44.
Florea, A.M., Yamoah, E.N. and Dopp, E. (2005) Intracellular calcium disturbances induced by arsenic and its methylated derivatives in relation to genomic damage and apoptosis induction. Environ Health Perspect, 113, 659-664.
Ford, J.M. and Hanawalt, P.C. (1997) Expression of wild-type p53 is required for efficient global genomic nucleotide excision repair in UV-irradiated human fibroblasts. J Biol Chem, 272, 28073-28080.
Friedberg, E.C. (2001) How nucleotide excision repair protects against cancer. Nat Rev Cancer, 1, 22-33.
Friedberg, E.C. (2003) DNA damage and repair. Nature, 421, 436-440.
Fukasawa, K. and Vande Woude, G.F. (1997) Synergy between the Mos/mitogen-activated protein kinase pathway and loss of p53 function in transformation and chromosome instability. Mol Cell Biol, 17, 506-518.
Gioeli, D., Mandell, J.W., Petroni, G.R., Frierson, H.F., Jr. and Weber, M.J. (1999) Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res, 59, 279-284.
Glotzer, M., Murray, A.W. and Kirschner, M.W. (1991) Cyclin is degraded by the ubiquitin pathway. Nature, 349, 132-138.
Goss, V.L., Cross, J.V., Ma, K., Qian, Y., Mola, P.W. and Templeton, D.J. (2003) SAPK/JNK regulates cdc2/cyclin B kinase through phosphorylation and inhibition of cdc25c. Cell Signal, 15, 709-718.
Greenberg, A.K., Basu, S., Hu, J., Yie, T.A., Tchou-Wong, K.M., Rom, W.N. and Lee, T.C. (2002) Selective p38 activation in human non-small cell lung cancer. Am J Respir Cell Mol Biol, 26, 558-564.
Groisman, R., Polanowska, J., Kuraoka, I., Sawada, J., Saijo, M., Drapkin, R., Kisselev, A.F., Tanaka, K. and Nakatani, Y. (2003) The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell, 113, 357-367.
Guardavaccaro, D., Kudo, Y., Boulaire, J., Barchi, M., Busino, L., Donzelli, M., Margottin-Goguet, F., Jackson, P.K., Yamasaki, L. and Pagano, M. (2003) Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Dev Cell, 4, 799-812.
Gurr, J.R., Lin, Y.C., Ho, I.C., Jan, K.Y. and Lee, T.C. (1993) Induction of chromatid breaks and tetraploidy in Chinese hamster ovary cells by treatment with sodium arsenite during the G2 phase. Mutat Res, 319, 135-142.
Gurr, J.R., Liu, F., Lynn, S. and Jan, K.Y. (1998) Calcium-dependent nitric oxide production is involved in arsenite-induced micronuclei. Mutat Res, 416, 137-148.
Gurr, J.R., Yih, L.H., Samikkannu, T., Bau, D.T., Lin, S.Y. and Jan, K.Y. (2003) Nitric oxide production by arsenite. Mutat Res, 533, 173-182.
Haas, S. and Kaina, B. (1995) c-Fos is involved in the cellular defence against the genotoxic effect of UV radiation. Carcinogenesis, 16, 985-991.
Hagting, A., Jackman, M., Simpson, K. and Pines, J. (1999) Translocation of cyclin B1 to the nucleus at prophase requires a phosphorylation-dependent nuclear import signal. Curr Biol, 9, 680-689.
Hamadeh, H.K., Trouba, K.J., Amin, R.P., Afshari, C.A. and Germolec, D. (2002) Coordination of altered DNA repair and damage pathways in arsenite-exposed keratinocytes. Toxicol Sci, 69, 306-316.
Hamdi, M., Kool, J., Cornelissen-Steijger, P., Carlotti, F., Popeijus, H.E., van der Burgt, C., Janssen, J.M., Yasui, A., Hoeben, R.C., Terleth, C., Mullenders, L.H. and van Dam, H. (2005) DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1. Oncogene, 24, 7135-7144.
Han, J., Lee, J.D., Bibbs, L. and Ulevitch, R.J. (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science, 265, 808-811.
Hanks, S.K. and Hunter, T. (1995) Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. Faseb J, 9, 576-596.
Harbour, J.W., Luo, R.X., Dei Santi, A., Postigo, A.A. and Dean, D.C. (1999) Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell, 98, 859-869.
Hardwick, J.C., van den Brink, G.R., Offerhaus, G.J., van Deventer, S.J. and Peppelenbosch, M.P. (2001) NF-kappaB, p38 MAPK and JNK are highly expressed and active in the stroma of human colonic adenomatous polyps. Oncogene, 20, 819-827.
Hartwig, A., Groblinghoff, U.D., Beyersmann, D., Natarajan, A.T., Filon, R. and Mullenders, L.H. (1997) Interaction of arsenic(III) with nucleotide excision repair in UV-irradiated human fibroblasts. Carcinogenesis, 18, 399-405.
Hartwig, A., Pelzer, A., Asmuss, M. and Burkle, A. (2003) Very low concentrations of arsenite suppress poly(ADP-ribosyl)ation in mammalian cells. Int J Cancer, 104, 1-6.
Hayakawa, J., Depatie, C., Ohmichi, M. and Mercola, D. (2003) The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair. J Biol Chem, 278, 20582-20592.
Hayakawa, J., Mittal, S., Wang, Y., Korkmaz, K.S., Adamson, E., English, C., Ohmichi, M., McClelland, M. and Mercola, D. (2004) Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress. Mol Cell, 16, 521-535.
Hayne, C., Tzivion, G. and Luo, Z. (2000) Raf-1/MEK/MAPK pathway is necessary for the G2/M transition induced by nocodazole. J Biol Chem, 275, 31876-31882.
He, Z., Cho, Y.Y., Liu, G., Ma, W.Y., Bode, A.M. and Dong, Z. (2003) p38 Mitogen-activated protein kinase regulation of JB6 Cl41 cell transformation promoted by epidermal growth factor. J Biol Chem, 278, 26435-26442.
Hei, T.K., Liu, S.X. and Waldren, C. (1998) Mutagenicity of arsenic in mammalian cells: role of reactive oxygen species. Proc Natl Acad Sci U S A, 95, 8103-8107.
Hernandez-Zavala, A., Cordova, E., Del Razo, L.M., Cebrian, M.E. and Garrido, E. (2005) Effects of arsenite on cell cycle progression in a human bladder cancer cell line. Toxicology, 207, 49-57.
Hess, M.T., Schwitter, U., Petretta, M., Giese, B. and Naegeli, H. (1997) Bipartite substrate discrimination by human nucleotide excision repair. Proc Natl Acad Sci U S A, 94, 6664-6669.
Hirose, Y., Katayama, M., Stokoe, D., Haas-Kogan, D.A., Berger, M.S. and Pieper, R.O. (2003) The p38 mitogen-activated protein kinase pathway links the DNA mismatch repair system to the G2 checkpoint and to resistance to chemotherapeutic DNA-methylating agents. Mol Cell Biol, 23, 8306-8315.
Hoeijmakers, J.H. (2001) Genome maintenance mechanisms for preventing cancer. Nature, 411, 366-374.
Hoffmann, I., Clarke, P.R., Marcote, M.J., Karsenti, E. and Draetta, G. (1993) Phosphorylation and activation of human cdc25-C by cdc2--cyclin B and its involvement in the self-amplification of MPF at mitosis. Embo J, 12, 53-63.
Hoshino, R., Chatani, Y., Yamori, T., Tsuruo, T., Oka, H., Yoshida, O., Shimada, Y., Ari-i, S., Wada, H., Fujimoto, J. and Kohno, M. (1999) Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene, 18, 813-822.
Hsu, Y.H., Li, S.Y., Chiou, H.Y., Yeh, P.M., Liou, J.C., Hsueh, Y.M., Chang, S.H. and Chen, C.J. (1997) Spontaneous and induced sister chromatid exchanges and delayed cell proliferation in peripheral lymphocytes of Bowen's disease patients and matched controls of arseniasis-hyperendemic villages in Taiwan. Mutat Res, 386, 241-251.
Hu, E., Kim, J.B., Sarraf, P. and Spiegelman, B.M. (1996) Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science, 274, 2100-2103.
Hu, Y., Su, L. and Snow, E.T. (1998) Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes. Mutat Res, 408, 203-218.
Huang, C., Bode, A.M., Chen, N.Y., Ma, W.Y., Li, J., Nomura, M. and Dong, Z. (2001a) Transactivation of AP-1 in AP-1-luciferase reporter transgenic mice by arsenite and arsenate. Anticancer Res, 21, 261-267.
Huang, C., Ke, Q., Costa, M. and Shi, X. (2004) Molecular mechanisms of arsenic carcinogenesis. Mol Cell Biochem, 255, 57-66.
Huang, C., Li, J., Ding, M., Wang, L., Shi, X., Castranova, V., Vallyathan, V., Ju, G. and Costa, M. (2001b) Arsenic-induced NFkappaB transactivation through Erks- and JNKs-dependent pathways in mouse epidermal JB6 cells. Mol Cell Biochem, 222, 29-34.
Huang, C., Ma, W.Y., Li, J. and Dong, Z. (1999a) Arsenic induces apoptosis through a c-Jun NH2-terminal kinase-dependent, p53-independent pathway. Cancer Res, 59, 3053-3058.
Huang, C., Ma, W.Y., Li, J., Goranson, A. and Dong, Z. (1999b) Requirement of Erk, but not JNK, for arsenite-induced cell transformation. J Biol Chem, 274, 14595-14601.
Huang, J.C., Svoboda, D.L., Reardon, J.T. and Sancar, A. (1992) Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5' and the 6th phosphodiester bond 3' to the photodimer. Proc Natl Acad Sci U S A, 89, 3664-3668.
Huang, R.N., Ho, I.C., Yih, L.H. and Lee, T.C. (1995) Sodium arsenite induces chromosome endoreduplication and inhibits protein phosphatase activity in human fibroblasts. Environ Mol Mutagen, 25, 188-196.
Huang, R.Y., Jan, K.Y. and Lee, T.C. (1987) Posttreatment with sodium arsenite is coclastogenic in log phase but not in stationary phase. Hum Genet, 75, 159-162.
Huang, R.Y., Lee, T.C. and Jan, K.Y. (1986) Cycloheximide suppresses the enhancing effect of sodium arsenite on the clastogenicity of ethyl methanesulphonate. Mutagenesis, 1, 467-470.
Huang, S., Huang, C.F. and Lee, T. (2000) Induction of mitosis-mediated apoptosis by sodium arsenite in HeLa S3 cells. Biochem Pharmacol, 60, 771-780.
Huang, S., Jiang, Y., Li, Z., Nishida, E., Mathias, P., Lin, S., Ulevitch, R.J., Nemerow, G.R. and Han, J. (1997) Apoptosis signaling pathway in T cells is composed of ICE/Ced-3 family proteases and MAP kinase kinase 6b. Immunity, 6, 739-749.
Huang, S.C. and Lee, T.C. (1998) Arsenite inhibits mitotic division and perturbs spindle dynamics in HeLa S3 cells. Carcinogenesis, 19, 889-896.
Huang, T.T. and D'Andrea, A.D. (2006) Regulation of DNA repair by ubiquitylation. Nat Rev Mol Cell Biol, 7, 323-334.
Hyun Park, W., Hee Cho, Y., Won Jung, C., Oh Park, J., Kim, K., Hyuck Im, Y., Lee, M.H., Ki Kang, W. and Park, K. (2003) Arsenic trioxide inhibits the growth of A498 renal cell carcinoma cells via cell cycle arrest or apoptosis. Biochem Biophys Res Commun, 300, 230-235.
IARC. (1980) Carcinogenesis of arsenic and arsenic compounds. In IARC Monographs on Evaluation of Carcinogenic Risks to Humans. IARC, Lyon, pp. 37-141.
IARC. (1987) Arsenic and arsenic compounds. In Overall Evaluation of Carcinogenicity: An Updating of IARC Monographs. IARC, Lyon, pp. 100-106.
Ip, Y.T. and Davis, R.J. (1998) Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. Curr Opin Cell Biol, 10, 205-219.
Isagawa, T., Takahashi, M., Kato, T., Jr., Mukai, H. and Ono, Y. (2005) Involvement of protein kinase PKN1 in G2/M delay caused by arsenite. Mol Carcinog, 43, 1-12.
Ivanov, V.N. and Hei, T.K. (2004) Arsenite treatment sensitizes human melanomas to apoptosis via TNF -mediated pathway. J Biol Chem.
Jha, A.N., Noditi, M., Nilsson, R. and Natarajan, A.T. (1992) Genotoxic effects of sodium arsenite on human cells. Mutat Res, 284, 215-221.
Jin, J., Shirogane, T., Xu, L., Nalepa, G., Qin, J., Elledge, S.J. and Harper, J.W. (2003) SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev, 17, 3062-3074.
Jin, P., Hardy, S. and Morgan, D.O. (1998) Nuclear localization of cyclin B1 controls mitotic entry after DNA damage. J Cell Biol, 141, 875-885.
Johnson, D.G. and Walker, C.L. (1999) Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol, 39, 295-312.
Jung, D.K., Bae, G.U., Kim, Y.K., Han, S.H., Choi, W.S., Kang, H., Seo, D.W., Lee, H.Y., Cho, E.J., Lee, H.W. and Han, J.W. (2003) Hydrogen peroxide mediates arsenite activation of p70(s6k) and extracellular signal-regulated kinase. Exp Cell Res, 290, 144-154.
Juo, P., Kuo, C.J., Reynolds, S.E., Konz, R.F., Raingeaud, J., Davis, R.J., Biemann, H.P. and Blenis, J. (1997) Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases. Mol Cell Biol, 17, 24-35.
Kaina, B., Haas, S. and Kappes, H. (1997) A general role for c-Fos in cellular protection against DNA-damaging carcinogens and cytostatic drugs. Cancer Res, 57, 2721-2731.
Kanemori, Y., Uto, K. and Sagata, N. (2005) Beta-TrCP recognizes a previously undescribed nonphosphorylated destruction motif in Cdc25A and Cdc25B phosphatases. Proc Natl Acad Sci U S A, 102, 6279-6284.
Kang, Y.H., Yi, M.J., Kim, M.J., Park, M.T., Bae, S., Kang, C.M., Cho, C.K., Park, I.C., Park, M.J., Rhee, C.H., Hong, S.I., Chung, H.Y., Lee, Y.S. and Lee, S.J. (2004) Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: reactive oxygen species-mediated poly(ADP-ribose) polymerase-1 activation signals apoptosis-inducing factor release from mitochondria. Cancer Res, 64, 8960-8967.
Kastan, M.B. and Bartek, J. (2004) Cell-cycle checkpoints and cancer. Nature, 432, 316-323.
Kietzmann, T., Samoylenko, A. and Immenschuh, S. (2003) Transcriptional regulation of heme oxygenase-1 gene expression by MAP kinases of the JNK and p38 pathways in primary cultures of rat hepatocytes. J Biol Chem, 278, 17927-17936.
Kim, J.Y., Choi, J.A., Kim, T.H., Yoo, Y.D., Kim, J.I., Lee, Y.J., Yoo, S.Y., Cho, C.K., Lee, Y.S. and Lee, S.J. (2002) Involvement of p38 mitogen-activated protein kinase in the cell growth inhibition by sodium arsenite. J Cell Physiol, 190, 29-37.
King, R.W., Deshaies, R.J., Peters, J.M. and Kirschner, M.W. (1996) How proteolysis drives the cell cycle. Science, 274, 1652-1659.
King, R.W., Peters, J.M., Tugendreich, S., Rolfe, M., Hieter, P. and Kirschner, M.W. (1995) A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell, 81, 279-288.
Kitagawa, D., Tanemura, S., Ohata, S., Shimizu, N., Seo, J., Nishitai, G., Watanabe, T., Nakagawa, K., Kishimoto, H., Wada, T., Tezuka, T., Yamamoto, T., Nishina, H. and Katada, T. (2002) Activation of extracellular signal-regulated kinase by ultraviolet is mediated through Src-dependent epidermal growth factor receptor phosphorylation. Its implication in an anti-apoptotic function. J Biol Chem, 277, 366-371.
Ko, J.C., Wang, Y.T. and Yang, J.L. (2004) Dual and opposing roles of ERK in regulating G(1) and S-G(2)/M delays in A549 cells caused by hyperoxia. Exp Cell Res, 297, 472-483.
Kolch, W. (2000) Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem J, 351 Pt 2, 289-305.
Kolch, W. (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol, 6, 827-837.
Kyriakis, J.M. and Avruch, J. (1990) pp54 microtubule-associated protein 2 kinase. A novel serine/threonine protein kinase regulated by phosphorylation and stimulated by poly-L-lysine. J Biol Chem, 265, 17355-17363.
Kyriakis, J.M. and Avruch, J. (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev, 81, 807-869.
Ladha, M.H., Lee, K.Y., Upton, T.M., Reed, M.F. and Ewen, M.E. (1998) Regulation of exit from quiescence by p27 and cyclin D1-CDK4. Mol Cell Biol, 18, 6605-6615.
Lai, M.S., Hsueh, Y.M., Chen, C.J., Shyu, M.P., Chen, S.Y., Kuo, T.L., Wu, M.M. and Tai, T.Y. (1994) Ingested inorganic arsenic and prevalence of diabetes mellitus. Am J Epidemiol, 139, 484-492.
Lakin, N.D., Hann, B.C. and Jackson, S.P. (1999) The ataxia-telangiectasia related protein ATR mediates DNA-dependent phosphorylation of p53. Oncogene, 18, 3989-3995.
Lamy, F., Wilkin, F., Baptist, M., Posada, J., Roger, P.P. and Dumont, J.E. (1993) Phosphorylation of mitogen-activated protein kinases is involved in the epidermal growth factor and phorbol ester, but not in the thyrotropin/cAMP, thyroid mitogenic pathway. J Biol Chem, 268, 8398-8401.
Landolph, J.R. (1994) Molecular mechanisms of transformation of C3H/10T1/2 C1 8 mouse embryo cells and diploid human fibroblasts by carcinogenic metal compounds. Environ Health Perspect, 102 Suppl 3, 119-125.
Lange-Carter, C.A., Pleiman, C.M., Gardner, A.M., Blumer, K.J. and Johnson, G.L. (1993) A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science, 260, 315-319.
Lau, A.T., Li, M., Xie, R., He, Q.Y. and Chiu, J.F. (2004) Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. Carcinogenesis, 25, 21-28.
Lavoie, J.N., L'Allemain, G., Brunet, A., Muller, R. and Pouyssegur, J. (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem, 271, 20608-20616.
Le Page, F., Kwoh, E.E., Avrutskaya, A., Gentil, A., Leadon, S.A., Sarasin, A. and Cooper, P.K. (2000) Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome. Cell, 101, 159-171.
Lee-Chen, S.F., Gurr, J.R., Lin, I.B. and Jan, K.Y. (1993) Arsenite enhances DNA double-strand breaks and cell killing of methyl methanesulfonate-treated cells by inhibiting the excision of alkali-labile sites. Mutat Res, 294, 21-28.
Lee-Chen, S.F., Yu, C.T. and Jan, K.Y. (1992) Effect of arsenite on the DNA repair of UV-irradiated Chinese hamster ovary cells. Mutagenesis, 7, 51-55.
Lee-Kwon, W., Park, D. and Bernier, M. (1998) Involvement of the Ras/extracellular signal-regulated kinase signalling pathway in the regulation of ERCC-1 mRNA levels by insulin. Biochem J, 331 ( Pt 2), 591-597.
Lee, J.C., Laydon, J.T., McDonnell, P.C., Gallagher, T.F., Kumar, S., Green, D., McNulty, D., Blumenthal, M.J., Heys, J.R., Landvatter, S.W. and et al. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature, 372, 739-746.
Lee, K.B. and Sharp, P.A. (2004) Transcription-dependent polyubiquitination of RNA polymerase II requires lysine 63 of ubiquitin. Biochemistry, 43, 15223-15229.
Lee, T.C., Huang, R.Y. and Jan, K.Y. (1985a) Sodium arsenite enhances the cytotoxicity, clastogenicity, and 6-thioguanine-resistant mutagenicity of ultraviolet light in Chinese hamster ovary cells. Mutat Res, 148, 83-89.
Lee, T.C., Kao, S.L. and Yih, L.H. (1991) Suppression of sodium arsenite-potentiated cytotoxicity of ultraviolet light by cycloheximide in Chinese hamster ovary cells. Arch Toxicol, 65, 640-645.
Lee, T.C., Lee, K.C., Tzeng, Y.J., Huang, R.Y. and Jan, K.Y. (1986a) Sodium arsenite potentiates the clastogenicity and mutagenicity of DNA crosslinking agents. Environ Mutagen, 8, 119-128.
Lee, T.C., Oshimura, M. and Barrett, J.C. (1985b) Comparison of arsenic-induced cell transformation, cytotoxicity, mutation and cytogenetic effects in Syrian hamster embryo cells in culture. Carcinogenesis, 6, 1421-1426.
Lee, T.C., Tanaka, N., Lamb, P.W., Gilmer, T.M. and Barrett, J.C. (1988) Induction of gene amplification by arsenic. Science, 241, 79-81.
Lee, T.C., Tzeng, S.F., Chang, W.J., Lin, Y.C. and Jan, K.Y. (1986b) Post-treatments with sodium arsenite during G2 enhance the frequency of chromosomal aberrations induced by S-dependent clastogens. Mutat Res, 163, 263-269.
Lewis, T.S., Hunt, J.B., Aveline, L.D., Jonscher, K.R., Louie, D.F., Yeh, J.M., Nahreini, T.S., Resing, K.A. and Ahn, N.G. (2000) Identification of novel MAP kinase pathway signaling targets by functional proteomics and mass spectrometry. Mol Cell, 6, 1343-1354.
Li, J., Gorospe, M., Barnes, J. and Liu, Y. (2003) Tumor promoter arsenite stimulates histone H3 phosphoacetylation of proto-oncogenes c-fos and c-jun chromatin in human diploid fibroblasts. J Biol Chem, 278, 13183-13191.
Li, J., Meyer, A.N. and Donoghue, D.J. (1997) Nuclear localization of cyclin B1 mediates its biological activity and is regulated by phosphorylation. Proc Natl Acad Sci U S A, 94, 502-507.
Li, J.H. and Rossman, T.G. (1989a) Inhibition of DNA ligase activity by arsenite: a possible mechanism of its comutagenesis. Mol Toxicol, 2, 1-9.
Li, J.H. and Rossman, T.G. (1989b) Mechanism of comutagenesis of sodium arsenite with n-methyl-n-nitrosourea. Biol Trace Elem Res, 21, 373-381.
Li, S.P., Junttila, M.R., Han, J., Kahari, V.M. and Westermarck, J. (2003) p38 Mitogen-activated protein kinase pathway suppresses cell survival by inducing dephosphorylation of mitogen-activated protein/extracellular signal-regulated kinase kinase1,2. Cancer Res, 63, 3473-3477.
Li, X., Ding, X. and Adrian, T.E. (2003) Arsenic trioxide induces apoptosis in pancreatic cancer cells via changes in cell cycle, caspase activation, and GADD expression. Pancreas, 27, 174-179.
Lin, Y.W., Chuang, S.M. and Yang, J.L. (2003) Persistent activation of ERK1/2 by lead acetate increases nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity. Carcinogenesis, 24, 53-61.
Lin, Y.W. and Yang, J.L. (2006) Cooperation of ERK and SCFSkp2 for MKP-1 destruction provides a positive feedback regulation of proliferating signaling. J Biol Chem, 281, 915-926.
Lindahl, T. (2000) Suppression of spontaneous mutagenesis in human cells by DNA base excision-repair. Mutat Res, 462, 129-135.
Lindahl, T. and Wood, R.D. (1999) Quality control by DNA repair. Science, 286, 1897-1905.
Liu, F. and Jan, K.Y. (2000) DNA damage in arsenite- and cadmium-treated bovine aortic endothelial cells. Free Radic Biol Med, 28, 55-63.
Liu, J., Kadiiska, M.B., Liu, Y., Lu, T., Qu, W. and Waalkes, M.P. (2001) Stress-related gene expression in mice treated with inorganic arsenicals. Toxicol Sci, 61, 314-320.
Liu, L., Trimarchi, J.R., Navarro, P., Blasco, M.A. and Keefe, D.L. (2003) Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability, and apoptosis. J Biol Chem, 278, 31998-32004.
Liu, X., Yan, S., Zhou, T., Terada, Y. and Erikson, R.L. (2004) The MAP kinase pathway is required for entry into mitosis and cell survival. Oncogene, 23, 763-776.
Liu, Y., Guyton, K.Z., Gorospe, M., Xu, Q., Lee, J.C. and Holbrook, N.J. (1996) Differential activation of ERK, JNK/SAPK and P38/CSBP/RK map kinase family members during the cellular response to arsenite. Free Radic Biol Med, 21, 771-781.
Liu, Y.C. and Huang, H. (1996) Lowering extracellular calcium content protects cells from arsenite-induced killing and micronuclei formation. Mutagenesis, 11, 75-78.
Liu, Y.C. and Huang, H. (1997) Involvement of calcium-dependent protein kinase C in arsenite-induced genotoxicity in Chinese hamster ovary cells. J Cell Biochem, 64, 423-433.
Liu, Z.G., Hsu, H., Goeddel, D.V. and Karin, M. (1996) Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell, 87, 565-576.
Ludwig, S., Hoffmeyer, A., Goebeler, M., Kilian, K., Hafner, H., Neufeld, B., Han, J. and Rapp, U.R. (1998) The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38-dependent pathway. J Biol Chem, 273, 1917-1922.
Lukas, C., Sorensen, C.S., Kramer, E., Santoni-Rugiu, E., Lindeneg, C., Peters, J.M., Bartek, J. and Lukas, J. (1999) Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex. Nature, 401, 815-818.
Lundberg, A.S. and Weinberg, R.A. (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol, 18, 753-761.
Lundberg, A.S. and Weinberg, R.A. (1999) Control of the cell cycle and apoptosis. Eur J Cancer, 35, 1886-1894.
Lynn, S., Gurr, J.R., Lai, H.T. and Jan, K.Y. (2000) NADH oxidase activation is involved in arsenite-induced oxidative DNA damage in human vascular smooth muscle cells. Circ Res, 86, 514-519.
Lynn, S., Lai, H.T., Gurr, J.R. and Jan, K.Y. (1997) Arsenite retards DNA break rejoining by inhibiting DNA ligation. Mutagenesis, 12, 353-358.
Lynn, S., Shiung, J.N., Gurr, J.R. and Jan, K.Y. (1998) Arsenite stimulates poly(ADP-ribosylation) by generation of nitric oxide. Free Radic Biol Med, 24, 442-449.
MacCorkle, R.A. and Tan, T.H. (2004) Inhibition of JNK2 disrupts anaphase and produces aneuploidy in mammalian cells. J Biol Chem, 279, 40112-40121.
Mailand, N., Falck, J., Lukas, C., Syljuasen, R.G., Welcker, M., Bartek, J. and Lukas, J. (2000) Rapid destruction of human Cdc25A in response to DNA damage. Science, 288, 1425-1429.
Mailand, N., Podtelejnikov, A.V., Groth, A., Mann, M., Bartek, J. and Lukas, J. (2002) Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability. Embo J, 21, 5911-5920.
Manke, I.A., Nguyen, A., Lim, D., Stewart, M.Q., Elia, A.E. and Yaffe, M.B. (2005) MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell, 17, 37-48.
Mansour, S.J., Candia, J.M., Gloor, K.K. and Ahn, N.G. (1996) Constitutively active mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 mediate similar transcriptional and morphological responses. Cell Growth Differ, 7, 243-250.
Mansour, S.J., Matten, W.T., Hermann, A.S., Candia, J.M., Rong, S., Fukasawa, K., Vande Woude, G.F. and Ahn, N.G. (1994) Transformation of mammalian cells by constitutively active MAP kinase kinase. Science, 265, 966-970.
Margottin-Goguet, F., Hsu, J.Y., Loktev, A., Hsieh, H.M., Reimann, J.D. and Jackson, P.K. (2003) Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev Cell, 4, 813-826.
Marrero, M.B., Schieffer, B., Li, B., Sun, J., Harp, J.B. and Ling, B.N. (1997) Role of Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades in angiotensin II- and platelet-derived growth factor-induced vascular smooth muscle cell proliferation. J Biol Chem, 272, 24684-24690.
Marshall, C.J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell, 80, 179-185.
Matsuoka, S., Rotman, G., Ogawa, A., Shiloh, Y., Tamai, K. and Elledge, S.J. (2000) Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci U S A, 97, 10389-10394.
Matsusaka, T. and Pines, J. (2004) Chfr acts with the p38 stress kinases to block entry to mitosis in mammalian cells. J Cell Biol, 166, 507-516.
Maya, R., Balass, M., Kim, S.T., Shkedy, D., Leal, J.F., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., Kastan, M.B., Katzir, E. and Oren, M. (2001) ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Genes Dev, 15, 1067-1077.
McCabe, M.J., Jr., Singh, K.P., Reddy, S.A., Chelladurai, B., Pounds, J.G., Reiners, J.J., Jr. and States, J.C. (2000) Sensitivity of myelomonocytic leukemia cells to arsenite-induced cell cycle disruption, apoptosis, and enhanced differentiation is dependent on the inter-relationship between arsenic concentration, duration of treatment, and cell cycle phase. J Pharmacol Exp Ther, 295, 724-733.
McCollum, G., Keng, P.C., States, J.C. and McCabe, M.J., Jr. (2005) Arsenite delays progression through each cell cycle phase and induces apoptosis following G2/M arrest in U937 myeloid leukemia cells. J Pharmacol Exp Ther, 313, 877-887.
Meriin, A.B., Yaglom, J.A., Gabai, V.L., Zon, L., Ganiatsas, S., Mosser, D.D. and Sherman, M.Y. (1999) Protein-damaging stresses activate c-Jun N-terminal kinase via inhibition of its dephosphorylation: a novel pathway controlled by HSP72. Mol Cell Biol, 19, 2547-2555.
Mikhailov, A., Shinohara, M. and Rieder, C.L. (2004) Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway. J Cell Biol, 166, 517-526.
Miller, W.H., Jr., Schipper, H.M., Lee, J.S., Singer, J. and Waxman, S. (2002) Mechanisms of action of arsenic trioxide. Cancer Res, 62, 3893-3903.
Mingo-Sion, A.M., Marietta, P.M., Koller, E., Wolf, D.M. and Van Den Berg, C.L. (2004) Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells. Oncogene, 23, 596-604.
Moberg, K., Starz, M.A. and Lees, J.A. (1996) E2F-4 switches from p130 to p107 and pRB in response to cell cycle reentry. Mol Cell Biol, 16, 1436-1449.
Molinari, M., Mercurio, C., Dominguez, J., Goubin, F. and Draetta, G.F. (2000) Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis. EMBO Rep, 1, 71-79.
Molnar, A., Theodoras, A.M., Zon, L.I. and Kyriakis, J.M. (1997) Cdc42Hs, but not Rac1, inhibits serum-stimulated cell cycle progression at G1/S through a mechanism requiring p38/RK. J Biol Chem, 272, 13229-13235.
Moore, L.E., Smith, A.H., Eng, C., Kalman, D., DeVries, S., Bhargava, V., Chew, K., Moore, D., 2nd, Ferreccio, C., Rey, O.A. and Waldman, F.M. (2002) Arsenic-related chromosomal alterations in bladder cancer. J Natl Cancer Inst, 94, 1688-1696.
Morgan, D.O. (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol, 13, 261-291.
Morooka, T. and Nishida, E. (1998) Requirement of p38 mitogen-activated protein kinase for neuronal differentiation in PC12 cells. J Biol Chem, 273, 24285-24288.
Morton, W.E. and Dunnette, D.A. (1994) Health Effects of Environmental Arsenic. In Nriagu, J.O. (ed.), Arsenic in the Environment, Part II: Human Health and Ecosystem Effects. John Wiley& Sons, Inc., New York, pp. 17-34.
Mu, D., Hsu, D.S. and Sancar, A. (1996) Reaction mechanism of human DNA repair excision nuclease. J Biol Chem, 271, 8285-8294.
Mure, K., Uddin, A.N., Lopez, L.C., Styblo, M. and Rossman, T.G. (2003) Arsenite induces delayed mutagenesis and transformation in human osteosarcoma cells at extremely low concentrations. Environ Mol Mutagen, 41, 322-331.
Murphy, L.O., MacKeigan, J.P. and Blenis, J. (2004) A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol Cell Biol, 24, 144-153.
Murphy, L.O., Smith, S., Chen, R.H., Fingar, D.C. and Blenis, J. (2002) Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol, 4, 556-564.
Murray, A.W. (2004) Recycling the cell cycle: cyclins revisited. Cell, 116, 221-234.
Namgung, U. and Xia, Z. (2001) Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. Toxicol Appl Pharmacol, 174, 130-138.
Naqvi, S.M., Vaishnavi, C. and Singh, H. (1994) Toxicity and Metabolism of Arsenic in Vertebrates. In Nriagu, J.O. (ed.), Arsenic in the Environment, Part II: Human Health and Ecosystem Effects. John Wiley& Sons, Inc., New York, pp. 55-92.
Nebreda, A.R. and Porras, A. (2000) p38 MAP kinases: beyond the stress response. Trends Biochem Sci, 25, 257-260.
Niida, H. and Nakanishi, M. (2006) DNA damage checkpoints in mammals. Mutagenesis, 21, 3-9.
Nilsson, I. and Hoffmann, I. (2000) Cell cycle regulation by the Cdc25 phosphatase family. Prog Cell Cycle Res, 4, 107-114.
Nishina, H., Fischer, K.D., Radvanyi, L., Shahinian, A., Hakem, R., Rubie, E.A., Bernstein, A., Mak, T.W., Woodgett, J.R. and Penninger, J.M. (1997) Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3. Nature, 385, 350-353.
Nordstrom, D.K. (2002) Public health. Worldwide occurrences of arsenic in ground water. Science, 296, 2143-2145.
Okui, T. and Fujiwara, Y. (1986) Inhibition of human excision DNA repair by inorganic arsenic and the co-mutagenic effect in V79 Chinese hamster cells. Mutat Res, 172, 69-76.
Ouyang, W., Ma, Q., Li, J., Zhang, D., Liu, Z.G., Rustgi, A.K. and Huang, C. (2005) Cyclin D1 induction through IkappaB kinase beta/nuclear factor-kappaB pathway is responsible for arsenite-induced increased cell cycle G1-S phase transition in human keratinocytes. Cancer Res, 65, 9287-9293.
Pagano, M. (1997) Cell cycle regulation by the ubiquitin pathway. Faseb J, 11, 1067-1075.
Pagano, M., Pepperkok, R., Lukas, J., Baldin, V., Ansorge, W., Bartek, J. and Draetta, G. (1993) Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts. J Cell Biol, 121, 101-111.
Pagano, M., Pepperkok, R., Verde, F., Ansorge, W. and Draetta, G. (1992) Cyclin A is required at two points in the human cell cycle. Embo J, 11, 961-971.
Pages, G., Lenormand, P., L'Allemain, G., Chambard, J.C., Meloche, S. and Pouyssegur, J. (1993) Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A, 90, 8319-8323.
Pardee, A.B. (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci U S A, 71, 1286-1290.
Pardo, O.E., Arcaro, A., Salerno, G., Raguz, S., Downward, J. and Seckl, M.J. (2002) Fibroblast growth factor-2 induces translational regulation of Bcl-XL and Bcl-2 via a MEK-dependent pathway: correlation with resistance to etoposide-induced apoptosis. J Biol Chem, 277, 12040-12046.
Park, J.G., Yuk, Y., Rhim, H., Yi, S.Y. and Yoo, Y.S. (2002) Role of p38 MAPK in the regulation of apoptosis signaling induced by TNF-alpha in differentiated PC12 cells. J Biochem Mol Biol, 35, 267-272.
Peng, C.Y., Graves, P.R., Thoma, R.S., Wu, Z., Shaw, A.S. and Piwnica-Worms, H. (1997) Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science, 277, 1501-1505.
Peter, M., Le Peuch, C., Labbe, J.C., Meyer, A.N., Donoghue, D.J. and Doree, M. (2002) Initial activation of cyclin-B1-cdc2 kinase requires phosphorylation of cyclin B1. EMBO Rep, 3, 551-556.
Peters, J.M. (2002) The anaphase-promoting complex: proteolysis in mitosis and beyond. Mol Cell, 9, 931-943.
Pham, C.D., Arlinghaus, R.B., Zheng, C.F., Guan, K.L. and Singh, B. (1995) Characterization of MEK1 phosphorylation by the v-Mos protein. Oncogene, 10, 1683-1688.
Pines, J. (1999) Four-dimensional control of the cell cycle. Nat Cell Biol, 1, E73-79.
Pines, J. and Hunter, T. (1989) Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2. Cell, 58, 833-846.
Porras, A., Zuluaga, S., Black, E., Valladares, A., Alvarez, A.M., Ambrosino, C., Benito, M. and Nebreda, A.R. (2004) P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol Biol Cell, 15, 922-933.
Porter, A.C., Fanger, G.R. and Vaillancourt, R.R. (1999) Signal transduction pathways regulated by arsenate and arsenite. Oncogene, 18, 7794-7802.
Potapova, O., Gorospe, M., Bost, F., Dean, N.M., Gaarde, W.A., Mercola, D. and Holbrook, N.J. (2000a) c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells. J Biol Chem, 275, 24767-24775.
Potapova, O., Gorospe, M., Dougherty, R.H., Dean, N.M., Gaarde, W.A. and Holbrook, N.J. (2000b) Inhibition of c-Jun N-terminal kinase 2 expression suppresses growth and induces apoptosis of human tumor cells in a p53-dependent manner. Mol Cell Biol, 20, 1713-1722.
Qu, W., Bortner, C.D., Sakurai, T., Hobson, M.J. and Waalkes, M.P. (2002) Acquisition of apoptotic resistance in arsenic-induced malignant transformation: role of the JNK signal transduction pathway. Carcinogenesis, 23, 151-159.
Raitano, A.B., Halpern, J.R., Hambuch, T.M. and Sawyers, C.L. (1995) The Bcr-Abl leukemia oncogene activates Jun kinase and requires Jun for transformation. Proc Natl Acad Sci U S A, 92, 11746-11750.
Roberts, E.C., Shapiro, P.S., Nahreini, T.S., Pages, G., Pouyssegur, J. and Ahn, N.G. (2002) Distinct cell cycle timing requirements for extracellular signal-regulated kinase and phosphoinositide 3-kinase signaling pathways in somatic cell mitosis. Mol Cell Biol, 22, 7226-7241.
Roovers, K. and Assoian, R.K. (2000) Integrating the MAP kinase signal into the G1 phase cell cycle machinery. Bioessays, 22, 818-826.
Rossman, T.G., Stone, D., Molina, M. and Troll, W. (1980) Absence of arsenite mutagenicity in E coli and Chinese hamster cells. Environ Mutagen, 2, 371-379.
Roulston, A., Reinhard, C., Amiri, P. and Williams, L.T. (1998) Early activation of c-Jun N-terminal kinase and p38 kinase regulate cell survival in response to tumor necrosis factor alpha. J Biol Chem, 273, 10232-10239.
Rouse, J., Cohen, P., Trigon, S., Morange, M., Alonso-Llamazares, A., Zamanillo, D., Hunt, T. and Nebreda, A.R. (1994) A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell, 78, 1027-1037.
Roux, P.P. and Blenis, J. (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev, 68, 320-344.
Saavedra, H.I., Fukasawa, K., Conn, C.W. and Stambrook, P.J. (1999) MAPK mediates RAS-induced chromosome instability. J Biol Chem, 274, 38083-38090.
Saavedra, H.I., Knauf, J.A., Shirokawa, J.M., Wang, J., Ouyang, B., Elisei, R., Stambrook, P.J. and Fagin, J.A. (2000) The RAS oncogene induces genomic instability in thyroid PCCL3 cells via the MAPK pathway. Oncogene, 19, 3948-3954.
Sanchez-Prieto, R., Rojas, J.M., Taya, Y. and Gutkind, J.S. (2000) A role for the p38 mitogen-acitvated protein kinase pathway in the transcriptional activation of p53 on genotoxic stress by chemotherapeutic agents. Cancer Res, 60, 2464-2472.
Sanchez, Y., Wong, C., Thoma, R.S., Richman, R., Wu, Z., Piwnica-Worms, H. and Elledge, S.J. (1997) Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science, 277, 1497-1501.
Schauber, C., Chen, L., Tongaonkar, P., Vega, I., Lambertson, D., Potts, W. and Madura, K. (1998) Rad23 links DNA repair to the ubiquitin/proteasome pathway. Nature, 391, 715-718.
Schonwasser, D.C., Marais, R.M., Marshall, C.J. and Parker, P.J. (1998) Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol, 18, 790-798.
Schulze, A., Zerfass, K., Spitkovsky, D., Middendorp, S., Berges, J., Helin, K., Jansen-Durr, P. and Henglein, B. (1995) Cell cycle regulation of the cyclin A gene promoter is mediated by a variant E2F site. Proc Natl Acad Sci U S A, 92, 11264-11268.
Sebolt-Leopold, J.S., Dudley, D.T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R.C., Tecle, H., Barrett, S.D., Bridges, A., Przybranowski, S., Leopold, W.R. and Saltiel, A.R. (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med, 5, 810-816.
Sebolt-Leopold, J.S. and Herrera, R. (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer, 4, 937-947.
Seimiya, H., Mashima, T., Toho, M. and Tsuruo, T. (1997) c-Jun NH2-terminal kinase-mediated activation of interleukin-1beta converting enzyme/CED-3-like protease during anticancer drug-induced apoptosis. J Biol Chem, 272, 4631-4636.
Shapiro, P.S., Vaisberg, E., Hunt, A.J., Tolwinski, N.S., Whalen, A.M., McIntosh, J.R. and Ahn, N.G. (1998) Activation of the MKK/ERK pathway during somatic cell mitosis: direct interactions of active ERK with kinetochores and regulation of the mitotic 3F3/2 phosphoantigen. J Cell Biol, 142, 1533-1545.
Sherr, C.J. and Roberts, J.M. (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev, 13, 1501-1512.
Shi, H., Shi, X. and Liu, K.J. (2004) Oxidative mechanism of arsenic toxicity and carcinogenesis. Mol Cell Biochem, 255, 67-78.
Shiloh, Y. (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer, 3, 155-168.
Shiyanov, P., Bagchi, S., Adami, G., Kokontis, J., Hay, N., Arroyo, M., Morozov, A. and Raychaudhuri, P. (1996) p21 Disrupts the interaction between cdk2 and the E2F-p130 complex. Mol Cell Biol, 16, 737-744.
Simeonova, P.P., Wang, S., Hulderman, T. and Luster, M.I. (2002) c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic. Role in carcinogenesis. J Biol Chem, 277, 2945-2950.
Simeonova, P.P., Wang, S., Toriuma, W., Kommineni, V., Matheson, J., Unimye, N., Kayama, F., Harki, D., Ding, M., Vallyathan, V. and Luster, M.I. (2000) Arsenic mediates cell proliferation and gene expression in the bladder epithelium: association with activating protein-1 transactivation. Cancer Res, 60, 3445-3453.
Smith, A.H., Hopenhayn-Rich, C., Bates, M.N., Goeden, H.M., Hertz-Picciotto, I., Duggan, H.M., Wood, R., Kosnett, M.J. and Smith, M.T. (1992) Cancer risks from arsenic in drinking water. Environ Health Perspect, 97, 259-267.
Solomon, M.J., Glotzer, M., Lee, T.H., Philippe, M. and Kirschner, M.W. (1990) Cyclin activation of p34cdc2. Cell, 63, 1013-1024.
Sorensen, C.S., Syljuasen, R.G., Falck, J., Schroeder, T., Ronnstrand, L., Khanna, K.K., Zhou, B.B., Bartek, J. and Lukas, J. (2003) Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell, 3, 247-258.
Souza, K., Maddock, D.A., Zhang, Q., Chen, J., Chiu, C., Mehta, S. and Wan, Y. (2001) Arsenite activation of P13K/AKT cell survival pathway is mediated by p38 in cultured human keratinocytes. Mol Med, 7, 767-772.
Summers, M.K., Bothos, J. and Halazonetis, T.D. (2005) The CHFR mitotic checkpoint protein delays cell cycle progression by excluding Cyclin B1 from the nucleus. Oncogene, 24, 2589-2598.
Sutterluty, H., Chatelain, E., Marti, A., Wirbelauer, C., Senften, M., Muller, U. and Krek, W. (1999) p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol, 1, 207-214.
Tadlock, L. and Patel, T. (2001) Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line. Hepatology, 33, 43-51.
Takenaka, K., Moriguchi, T. and Nishida, E. (1998) Activation of the protein kinase p38 in the spindle assembly checkpoint and mitotic arrest. Science, 280, 599-602.
Tamemoto, H., Kadowaki, T., Tobe, K., Ueki, K., Izumi, T., Chatani, Y., Kohno, M., Kasuga, M., Yazaki, Y. and Akanuma, Y. (1992) Biphasic activation of two mitogen-activated protein kinases during the cell cycle in mammalian cells. J Biol Chem, 267, 20293-20297.
Tan, T. and Chu, G. (2002) p53 Binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice. Mol Cell Biol, 22, 3247-3254.
Tang, D., Wu, D., Hirao, A., Lahti, J.M., Liu, L., Mazza, B., Kidd, V.J., Mak, T.W. and Ingram, A.J. (2002) ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem, 277, 12710-12717.
Timofeev, O., Lee, T.Y. and Bulavin, D.V. (2005) A subtle change in p38 MAPK activity is sufficient to suppress in vivo tumorigenesis. Cell Cycle, 4, 118-120.
Toyoshima-Morimoto, F., Taniguchi, E. and Nishida, E. (2002) Plk1 promotes nuclear translocation of human Cdc25C during prophase. EMBO Rep, 3, 341-348.
Toyoshima, F., Moriguchi, T., Wada, A., Fukuda, M. and Nishida, E. (1998) Nuclear export of cyclin B1 and its possible role in the DNA damage-induced G2 checkpoint. Embo J, 17, 2728-2735.
Traverse, S., Gomez, N., Paterson, H., Marshall, C. and Cohen, P. (1992) Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem J, 288 ( Pt 2), 351-355.
Troppmair, J., Bruder, J.T., Munoz, H., Lloyd, P.A., Kyriakis, J., Banerjee, P., Avruch, J. and Rapp, U.R. (1994) Mitogen-activated protein kinase/extracellular signal-regulated protein kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13-acetate requires Raf and is necessary for transformation. J Biol Chem, 269, 7030-7035.
Tsuchiya, T., Tanaka-Kagawa, T., Jinno, H., Tokunaga, H., Sakimoto, K., Ando, M. and Umeda, M. (2005) Inorganic arsenic compounds and methylated metabolites induce morphological transformation in two-stage BALB/c 3T3 cell assay and inhibit metabolic cooperation in V79 cell assay. Toxicol Sci, 84, 344-351.
Vega, L., Gonsebatt, M.E. and Ostrosky-Wegman, P. (1995) Aneugenic effect of sodium arsenite on human lymphocytes in vitro: an individual susceptibility effect detected. Mutat Res, 334, 365-373.
Vodermaier, H.C. (2004) APC/C and SCF: controlling each other and the cell cycle. Curr Biol, 14, R787-796.
Wada, T. and Penninger, J.M. (2004) Mitogen-activated protein kinases in apoptosis regulation. Oncogene, 23, 2838-2849.
Walsh, S., Margolis, S.S. and Kornbluth, S. (2003) Phosphorylation of the cyclin b1 cytoplasmic retention sequence by mitogen-activated protein kinase and Plx. Mol Cancer Res, 1, 280-289.
Wang, T.S., Hsu, T.Y., Chung, C.H., Wang, A.S., Bau, D.T. and Jan, K.Y. (2001) Arsenite induces oxidative DNA adducts and DNA-protein cross-links in mammalian cells. Free Radic Biol Med, 31, 321-330.
Wang, T.S. and Huang, H. (1994) Active oxygen species are involved in the induction of micronuclei by arsenite in XRS-5 cells. Mutagenesis, 9, 253-257.
Wang, T.S., Shu, Y.F., Liu, Y.C., Jan, K.Y. and Huang, H. (1997) Glutathione peroxidase and catalase modulate the genotoxicity of arsenite. Toxicology, 121, 229-237.
Wang, X., Martindale, J.L., Liu, Y. and Holbrook, N.J. (1998) The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J, 333 ( Pt 2), 291-300.
Wang, X., McGowan, C.H., Zhao, M., He, L., Downey, J.S., Fearns, C., Wang, Y., Huang, S. and Han, J. (2000) Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol, 20, 4543-4552.
Wasch, R. and Engelbert, D. (2005) Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells. Oncogene, 24, 1-10.
Weber, J.D., Raben, D.M., Phillips, P.J. and Baldassare, J.J. (1997) Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem J, 326 ( Pt 1), 61-68.
Wei, W., Ayad, N.G., Wan, Y., Zhang, G.J., Kirschner, M.W. and Kaelin, W.G., Jr. (2004) Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature, 428, 194-198.
Wen, W.N., Lieu, T.L., Chang, H.J., Wuu, S.W., Yau, M.L. and Jan, K.Y. (1981) Baseline and sodium arsenite-induced sister chromatid exchanges in cultured lymphocytes from patients with Blackfoot disease and healthy persons. Hum Genet, 59, 201-203.
Westermarck, J., Li, S.P., Kallunki, T., Han, J. and Kahari, V.M. (2001) p38 mitogen-activated protein kinase-dependent activation of protein phosphatases 1 and 2A inhibits MEK1 and MEK2 activity and collagenase 1 (MMP-1) gene expression. Mol Cell Biol, 21, 2373-2383.
Whalen, A.M., Galasinski, S.C., Shapiro, P.S., Nahreini, T.S. and Ahn, N.G. (1997) Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase. Mol Cell Biol, 17, 1947-1958.
Wiencke, J.K., Yager, J.W., Varkonyi, A., Hultner, M. and Lutze, L.H. (1997) Study of arsenic mutagenesis using the plasmid shuttle vector pZ189 propagated in DNA repair proficient human cells. Mutat Res, 386, 335-344.
Wilkinson, M.G. and Millar, J.B. (2000) Control of the eukaryotic cell cycle by MAP kinase signaling pathways. Faseb J, 14, 2147-2157.
Wisdom, R., Johnson, R.S. and Moore, C. (1999) c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms. Embo J, 18, 188-197.
Wright, J.H., Munar, E., Jameson, D.R., Andreassen, P.R., Margolis, R.L., Seger, R. and Krebs, E.G. (1999) Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts. Proc Natl Acad Sci U S A, 96, 11335-11340.
Wu, D., Chen, B., Parihar, K., He, L., Fan, C., Zhang, J., Liu, L., Gillis, A., Bruce, A., Kapoor, A. and Tang, D. (2006) ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function. Oncogene, 25, 1153-1164.
Xia, Z., Dickens, M., Raingeaud, J., Davis, R.J. and Greenberg, M.E. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science, 270, 1326-1331.
Yacoub, A., McKinstry, R., Hinman, D., Chung, T., Dent, P. and Hagan, M.P. (2003) Epidermal growth factor and ionizing radiation up-regulate the DNA repair genes XRCC1 and ERCC1 in DU145 and LNCaP prostate carcinoma through MAPK signaling. Radiat Res, 159, 439-452.
Yacoub, A., Park, J.S., Qiao, L., Dent, P. and Hagan, M.P. (2001) MAPK dependence of DNA damage repair: ionizing radiation and the induction of expression of the DNA repair genes XRCC1 and ERCC1 in DU145 human prostate carcinoma cells in a MEK1/2 dependent fashion. Int J Radiat Biol, 77, 1067-1078.
Yager, J.W. and Wiencke, J.K. (1997) Inhibition of poly(ADP-ribose) polymerase by arsenite. Mutat Res, 386, 345-351.
Yamasaki, L. and Pagano, M. (2004) Cell cycle, proteolysis and cancer. Curr Opin Cell Biol, 16, 623-628.
Yang, J.L., Chen, M.F., Wu, C.W. and Lee, T.C. (1992) Posttreatment with sodium arsenite alters the mutational spectrum induced by ultraviolet light irradiation in Chinese hamster ovary cells. Environ Mol Mutagen, 20, 156-164.
Yang, Y.M., Bost, F., Charbono, W., Dean, N., McKay, R., Rhim, J.S., Depatie, C. and Mercola, D. (2003) C-Jun NH(2)-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma. Clin Cancer Res, 9, 391-401.
Yih, L.H., Ho, I.C. and Lee, T.C. (1997) Sodium arsenite disturbs mitosis and induces chromosome loss in human fibroblasts. Cancer Res, 57, 5051-5059.
Yih, L.H., Hsueh, S.W., Luu, W.S., Chiu, T.H. and Lee, T.C. (2005) Arsenite induces prominent mitotic arrest via inhibition of G2 checkpoint activation in CGL-2 cells. Carcinogenesis, 26, 53-63.
Yih, L.H. and Lee, T.C. (1999) Effects of exposure protocols on induction of kinetochore-plus and -minus micronuclei by arsenite in diploid human fibroblasts. Mutat Res, 440, 75-82.
Yih, L.H. and Lee, T.C. (2000) Arsenite induces p53 accumulation through an ATM-dependent pathway in human fibroblasts. Cancer Res, 60, 6346-6352.
Yih, L.H. and Lee, T.C. (2003) Induction of C-anaphase and diplochromosome through dysregulation of spindle assembly checkpoint by sodium arsenite in human fibroblasts. Cancer Res, 63, 6680-6688.
Yih, L.H., Peck, K. and Lee, T.C. (2002) Changes in gene expression profiles of human fibroblasts in response to sodium arsenite treatment. Carcinogenesis, 23, 867-876.
Yih, L.H., Tseng, Y.Y., Wu, Y.C. and Lee, T.C. (2006) Induction of centrosome amplification during arsenite-induced mitotic arrest in CGL-2 cells. Cancer Res, 66, 2098-2106.
Young, P.R., McLaughlin, M.M., Kumar, S., Kassis, S., Doyle, M.L., McNulty, D., Gallagher, T.F., Fisher, S., McDonnell, P.C., Carr, S.A., Huddleston, M.J., Seibel, G., Porter, T.G., Livi, G.P., Adams, J.L. and Lee, J.C. (1997) Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site. J Biol Chem, 272, 12116-12121.
Yuan, J., Eckerdt, F., Bereiter-Hahn, J., Kurunci-Csacsko, E., Kaufmann, M. and Strebhardt, K. (2002) Cooperative phosphorylation including the activity of polo-like kinase 1 regulates the subcellular localization of cyclin B1. Oncogene, 21, 8282-8292.
Zanke, B.W., Boudreau, K., Rubie, E., Winnett, E., Tibbles, L.A., Zon, L., Kyriakis, J., Liu, F.F. and Woodgett, J.R. (1996) The stress-activated protein kinase pathway mediates cell death following injury induced by cis-platinum, UV irradiation or heat. Curr Biol, 6, 606-613.
Zecevic, M., Catling, A.D., Eblen, S.T., Renzi, L., Hittle, J.C., Yen, T.J., Gorbsky, G.J. and Weber, M.J. (1998) Active MAP kinase in mitosis: localization at kinetochores and association with the motor protein CENP-E. J Cell Biol, 142, 1547-1558.
Zetser, A., Gredinger, E. and Bengal, E. (1999) p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation. Participation of the Mef2c transcription factor. J Biol Chem, 274, 5193-5200.
Zetterberg, A., Larsson, O. and Wiman, K.G. (1995) What is the restriction point? Curr Opin Cell Biol, 7, 835-842.
Zhao, C.Q., Young, M.R., Diwan, B.A., Coogan, T.P. and Waalkes, M.P. (1997) Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci U S A, 94, 10907-10912.
Zhao, H., Watkins, J.L. and Piwnica-Worms, H. (2002) Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc Natl Acad Sci U S A, 99, 14795-14800.
Zhao, S., Tsuchida, T., Kawakami, K., Shi, C. and Kawamoto, K. (2002) Effect of As2O3 on cell cycle progression and cyclins D1 and B1 expression in two glioblastoma cell lines differing in p53 status. Int J Oncol, 21, 49-55.
Zhou, B.B. and Elledge, S.J. (2000) The DNA damage response: putting checkpoints in perspective. Nature, 408, 433-439.
Zhu, J., Chen, Z., Lallemand-Breitenbach, V. and de The, H. (2002) How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer, 2, 705-713.