當細胞遭受基因傷害時，會啟動檢查控制機制，此機制可透過ATR/ATM- p53-p21(Waf1/Cip1) 訊息傳遞路徑來達成，進而保護基因的完整性。而中國倉鼠卵巢細胞中因缺乏p21蛋白質的表現，故當細胞遭受紫外線傷害時，無法將細胞停滯於G1期中。進一步的研究中發現，紫外線照射過的細胞於24小時後會出現大量的細胞凋亡，且其週期蛋白激酶(Cdk2)在紫外線照射後，活性明顯的上升，而且此活性的增加與細胞凋亡的情形是具有相關性的。此外，過度活化的Cdk2會造成Rb蛋白質的過度磷酸化，進而活化E2F蛋白。而紫外線造成的細胞凋亡也會被Cdk2的抑制劑－roscovitine所抑制。另一方面，在進行紫外線照射實驗時給予不同的抗氧化物，發現抗氧化物並無法減低紫外線造成的細胞凋亡。因此我們推論活性氧分子似乎並不參與紫外線造成的細胞凋亡。但是在進行pyrrolidine dithiocarbamate(PDTC)這類的抗氧化物質處理中，我卻發現到PDTC可以透過抑制Cdk2活性，來抑制細胞的生長與減少細胞的凋亡。因此我假設不正常活化的Cdk2會使細胞藉由Rb/E2F活化路徑，走向細胞凋亡。實驗結果中我發現，p53雖然因為紫外線照射而大量產生，但是其下游因子－Bax蛋白卻沒有增加。緊接著利用siRNA減少內源性 p53 的表現，其結果並無法阻止紫外線所造成的細胞凋亡。而實際上我卻發現到p53於中國倉鼠卵巢細胞的核酸修復中，扮演著一個相當重要的角色。總而言之，於此研究的結果中我推論出，不正常活化的Cdk2會使得細胞藉由Rb/E2F路徑，但非p53，以促使細胞進入紫外線所造成的細胞凋亡。另一方面，我更證明出p53直接參與核酸的修補。

DNA damage checkpoint control which involves the pathway of ATR/ATM- p53-p21(Waf1/Cip1) provides a mechanism to protect the genomic integrity. Chinese hamster ovary cells (CHO-K1) which cannot express p21 fail to arrest at G1 phase following UVC irradiation. The UV-irradiated CHO-K1 cells exhibit substantial apoptosis at 24 h after irradiation. Activities of cyclin-dependent kinases especially, Cdk2 are found elevated following the irradiation. The elevation of Cdk2 activity correlates with the increase of UV-induced apoptosis. Further, the increase in Cdk2 activity causes hyperphosphorylation of retinoblastoma (Rb) protein, which consequently activates E2F protein. Moreover, the UV-induced apoptosis was suppressed by roscovitine, a small-molecule Cdk2 inhibitor. On the other hand, the reactive oxygen species (ROS) seems not to be involved in UVC-induced apoptosis, which was proved by pretreatment with different kinds of antioxidant except pyrrolidine dithiocarbamate (PDTC). The PDTC reduces cell proliferation, and its inhibition of UV-induced apoptosis is likely to due to the inhibition of Cdk2 activity. Thus, we hypothesize that deregulation of Cdk2 may lead to apoptosis via the Rb/E2F-mediated pathway. Besides, p53 is induced in UV-irradiated CHO-K1 cells, but the expression of pro-apoptotic Bax protein, a downstream effector of p53, is not elevated. Further study indicates decrease of endogenous p53 by p53 specific siRNA cannot suppress UV-induced apoptosis. In fact, p53 plays an important role in excision of UV-induced DNA adducts. Taken together, my study demonstrates that deregulation of Cdk2 via Rb/E2F and p53-independent pathway induces apoptosis in UV-irradiated cells. Furthermore, p53 is involved in early stage of nucleotide excision repair.

Abello, P.A., Fidler, S.A., Bulkley, G.B. and Buchman, T.G. (1994) Antioxidants modulate induction of programmed endothelial cell death (apoptosis) by endotoxin. Arch Surg, 129, 134-140; discussion 140-131.
Adachi, S., Ito, H., Tamamori-Adachi, M., Ono, Y., Nozato, T., Abe, S., Ikeda, M., Marumo, F. and Hiroe, M. (2001) Cyclin A/cdk2 activation is involved in hypoxia-induced apoptosis in cardiomyocytes. Circ Res, 88, 408-414.
Adimoolam, S. and Ford, J.M. (2002) p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene. Proc Natl Acad Sci U S A, 99, 12985-12990.
Adimoolam, S. and Ford, J.M. (2003) p53 and regulation of DNA damage recognition during nucleotide excision repair. DNA Repair (Amst), 2, 947-954.
Agarwal, M.L., Taylor, W.R., Chernov, M.V., Chernova, O.B. and Stark, G.R. (1998) The p53 network. J Biol Chem, 273, 1-4.
Ames, B.N. (1983) Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science, 221, 1256-1264.
Ames, B.N. and Gold, L.S. (1991) Endogenous mutagens and the causes of aging and cancer. Mutat Res, 250, 3-16.
Aoki, M., Nata, T., Morishita, R., Matsushita, H., Nakagami, H., Yamamoto, K., Yamazaki, K., Nakabayashi, M., Ogihara, T. and Kaneda, Y. (2001) Endothelial apoptosis induced by oxidative stress through activation of NF-kappaB: antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension, 38, 48-55.
Ashcroft, M. and Vousden, K.H. (1999) Regulation of p53 stability. Oncogene, 18, 7637-7643.
Bargonetti, J. and Manfredi, J.J. (2002) Multiple roles of the tumor suppressor p53. Curr Opin Oncol, 14, 86-91.
Bender, K., Blattner, C., Knebel, A., Iordanov, M., Herrlich, P. and Rahmsdorf, H.J. (1997) UV-induced signal transduction. J Photochem Photobiol B, 37, 1-17.
Benhar, M., Engelberg, D. and Levitzki, A. (2002) ROS, stress-activated kinases and stress signaling in cancer. EMBO Rep, 3, 420-425.
Bergstein, T., Henis, Y. and Cavari, B.Z. (1979) Investigations on the photosynthetic sulfur bacterium Chlorobium phaeobacteroides causing seasonal blooms in Lake Kinneret. Can J Microbiol, 25, 999-1007.
Beswick, R.A., Zhang, H., Marable, D., Catravas, J.D., Hill, W.D. and Webb, R.C. (2001) Long-term antioxidant administration attenuates mineralocorticoid hypertension and renal inflammatory response. Hypertension, 37, 781-786.
Blattner, C., Sparks, A. and Lane, D. (1999) Transcription factor E2F-1 is upregulated in response to DNA damage in a manner analogous to that of p53. Mol Cell Biol, 19, 3704-3713.
Boldin, M.P., Goncharov, T.M., Goltsev, Y.V. and Wallach, D. (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell, 85, 803-815.
Bossy-Wetzel, E., Newmeyer, D.D. and Green, D.R. (1998) Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. Embo J, 17, 37-49.
Breeden, L.L. (2003) Periodic transcription: a cycle within a cycle. Curr Biol, 13, R31-38.
Breen, A.P. and Murphy, J.A. (1995) Reactions of oxyl radicals with DNA. Free Radic Biol Med, 18, 1033-1077.
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J.P., Sedivy, J.M., Kinzler, K.W. and Vogelstein, B. (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science, 282, 1497-1501.
Buttitta, F., Marchetti, A., Gadducci, A., Pellegrini, S., Morganti, M., Carnicelli, V., Cosio, S., Gagetti, O., Genazzani, A.R. and Bevilacqua, G. (1997) p53 alterations are predictive of chemoresistance and aggressiveness in ovarian carcinomas: a molecular and immunohistochemical study. Br J Cancer, 75, 230-235.
Buttke, T.M., McCubrey, J.A. and Owen, T.C. (1993) Use of an aqueous soluble tetrazolium/formazan assay to measure viability and proliferation of lymphokine-dependent cell lines. J Immunol Methods, 157, 233-240.
Cadet, J., Berger, M., Douki, T., Morin, B., Raoul, S., Ravanat, J.L. and Spinelli, S. (1997) Effects of UV and visible radiation on DNA-final base damage. Biol Chem, 378, 1275-1286.
Cadet, J., Sage, E. and Douki, T. (2005) Ultraviolet radiation-mediated damage to cellular DNA. Mutat Res, 571, 3-17.
Chan, W.H., Wu, C.C. and Yu, J.S. (2003) Curcumin inhibits UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermoid carcinoma A431 cells. J Cell Biochem, 90, 327-338.
Chao, T.I., Henke, A., Reichelt, W., Eberhardt, W., Reinhardt-Maelicke, S. and Reichenbach, A. (1994) Three distinct types of voltage-dependent K+ channels are expressed by Muller (glial) cells of the rabbit retina. Pflugers Arch, 426, 51-60.
Chen, D., Peng, F., Cui, Q.C., Daniel, K.G., Orlu, S., Liu, J. and Dou, Q.P. (2005) Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis. Front Biosci, 10, 2932-2939.
Chen, M. and Wang, J. (2002) Initiator caspases in apoptosis signaling pathways. Apoptosis, 7, 313-319.
Cheng, A.C., Huang, T.C., Lai, C.S. and Pan, M.H. (2005) Induction of apoptosis by luteolin through cleavage of Bcl-2 family in human leukemia HL-60 cells. Eur J Pharmacol, 509, 1-10.
Clingen, P.H., Arlett, C.F., Cole, J., Waugh, A.P., Lowe, J.E., Harcourt, S.A., Hermanova, N., Roza, L., Mori, T., Nikaido, O. and et al. (1995) Correlation of UVC and UVB cytotoxicity with the induction of specific photoproducts in T-lymphocytes and fibroblasts from normal human donors. Photochem Photobiol, 61, 163-170.
Collins, A.R., Downes, C.S. and Johnson, R.T. (1980) Cell cycle-related variations in UV damage and repair capacity in Chinese hamster (CHO-K1) cells. J Cell Physiol, 103, 179-191.
Cooke, M.S., Evans, M.D., Dizdaroglu, M. and Lunec, J. (2003) Oxidative DNA damage: mechanisms, mutation, and disease. Faseb J, 17, 1195-1214.
DeGregori, J., Leone, G., Miron, A., Jakoi, L. and Nevins, J.R. (1997) Distinct roles for E2F proteins in cell growth control and apoptosis. Proc Natl Acad Sci U S A, 94, 7245-7250.
Demarcq, C., Bunch, R.T., Creswell, D. and Eastman, A. (1994) The role of cell cycle progression in cisplatin-induced apoptosis in Chinese hamster ovary cells. Cell Growth Differ, 5, 983-993.
Devary, Y., Gottlieb, R.A., Smeal, T. and Karin, M. (1992) The mammalian ultraviolet response is triggered by activation of Src tyrosine kinases. Cell, 71, 1081-1091.
Diffey, B.L. (2002) Sources and measurement of ultraviolet radiation. Methods, 28, 4-13.
Dizdaroglu, M., Jaruga, P., Birincioglu, M. and Rodriguez, H. (2002) Free radical-induced damage to DNA: mechanisms and measurement. Free Radic Biol Med, 32, 1102-1115.
Dong, Y.B., Yang, H.L., Elliott, M.J., Liu, T.J., Stilwell, A., Atienza, C., Jr. and McMasters, K.M. (1999) Adenovirus-mediated E2F-1 gene transfer efficiently induces apoptosis in melanoma cells. Cancer, 86, 2021-2033.
Dong, Y.B., Yang, H.L., Elliott, M.J. and McMasters, K.M. (2002) Adenovirus-mediated E2F-1 gene transfer sensitizes melanoma cells to apoptosis induced by topoisomerase II inhibitors. Cancer Res, 62, 1776-1783.
Du, J., Suzuki, H., Nagase, F., Akhand, A.A., Ma, X.Y., Yokoyama, T., Miyata, T. and Nakashima, I. (2001) Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process. Free Radic Biol Med, 31, 469-478.
Du, M.Q., Carmichael, P.L. and Phillips, D.H. (1994) Induction of activating mutations in the human c-Ha-ras-1 proto-oncogene by oxygen free radicals. Mol Carcinog, 11, 170-175.
Dulic, V., Kaufmann, W.K., Wilson, S.J., Tlsty, T.D., Lees, E., Harper, J.W., Elledge, S.J. and Reed, S.I. (1994) p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell, 76, 1013-1023.
El Eter, E., Hagar, H.H., Al-Tuwaijiri, A. and Arafa, M. (2005) Nuclear factor-kappaB inhibition by pyrrolidinedithiocarbamate attenuates gastric ischemia-reperfusion injury in rats. Can J Physiol Pharmacol, 83, 483-492.
el-Deiry, W.S. (1998) Regulation of p53 downstream genes. Semin Cancer Biol, 8, 345-357.
Elliott, M.J., Dong, Y.B., Yang, H. and McMasters, K.M. (2001) E2F-1 up-regulates c-Myc and p14(ARF) and induces apoptosis in colon cancer cells. Clin Cancer Res, 7, 3590-3597.
Ellis, R.E., Yuan, J.Y. and Horvitz, H.R. (1991) Mechanisms and functions of cell death. Annu Rev Cell Biol, 7, 663-698.
Eveno, E., Bourre, F., Quilliet, X., Chevallier-Lagente, O., Roza, L., Eker, A.P., Kleijer, W.J., Nikaido, O., Stefanini, M., Hoeijmakers, J.H. and et al. (1995) Different removal of ultraviolet photoproducts in genetically related xeroderma pigmentosum and trichothiodystrophy diseases. Cancer Res, 55, 4325-4332.
Fan, J. and Bertino, J.R. (1997) Functional roles of E2F in cell cycle regulation. Oncogene, 14, 1191-1200.
Floyd, R.A. (1990) The role of 8-hydroxyguanine in carcinogenesis. Carcinogenesis, 11, 1447-1450.
Ford, J.M. and Hanawalt, P.C. (1995) Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc Natl Acad Sci U S A, 92, 8876-8880.
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.
Fortin, A., Cregan, S.P., MacLaurin, J.G., Kushwaha, N., Hickman, E.S., Thompson, C.S., Hakim, A., Albert, P.R., Cecconi, F., Helin, K., Park, D.S. and Slack, R.S. (2001) APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. J Cell Biol, 155, 207-216.
Gil-Gomez, G., Berns, A. and Brady, H.J. (1998) A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. Embo J, 17, 7209-7218.
Gottlieb, T.M. and Oren, M. (1998) p53 and apoptosis. Semin Cancer Biol, 8, 359-368.
Gu, Y., Turck, C.W. and Morgan, D.O. (1993) Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit. Nature, 366, 707-710.
Gupta, S., Purcell, N.H., Lin, A. and Sen, S. (2002) Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy. J Cell Biol, 159, 1019-1028.
Guyton, K.Z. and Kensler, T.W. (1993) Oxidative mechanisms in carcinogenesis. Br Med Bull, 49, 523-544.
Hakem, A., Sasaki, T., Kozieradzki, I. and Penninger, J.M. (1999) The cyclin-dependent kinase Cdk2 regulates thymocyte apoptosis. J Exp Med, 189, 957-968.
Halliwell, B. (1999) Oxygen and nitrogen are pro-carcinogens. Damage to DNA by reactive oxygen, chlorine and nitrogen species: measurement, mechanism and the effects of nutrition. Mutat Res, 443, 37-52.
Han, S. and Sidell, N. (2003) RU486-induced growth inhibition of human endometrial cells involves the nuclear factor-kappa B signaling pathway. J Clin Endocrinol Metab, 88, 713-719.
Hanawalt, P.C. (2002) Subpathways of nucleotide excision repair and their regulation. Oncogene, 21, 8949-8956.
Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K. and Elledge, S.J. (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell, 75, 805-816.
Haupt, Y., Maya, R., Kazaz, A. and Oren, M. (1997) Mdm2 promotes the rapid degradation of p53. Nature, 387, 296-299.
Hayashi, Y., Kondo, T., Zhao, Q.L., Ogawa, R., Cui, Z.G., Feril, L.B., Jr., Teranishi, H. and Kasuya, M. (2004) Signal transduction of p53-independent apoptotic pathway induced by hexavalent chromium in U937 cells. Toxicol Appl Pharmacol, 197, 96-106.
Heinrichs, S. and Deppert, W. (2003) Apoptosis or growth arrest: modulation of the cellular response to p53 by proliferative signals. Oncogene, 22, 555-571.
Hermeking, H., Lengauer, C., Polyak, K., He, T.C., Zhang, L., Thiagalingam, S., Kinzler, K.W. and Vogelstein, B. (1997) 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression. Mol Cell, 1, 3-11.
Hirao, A., Kong, Y.Y., Matsuoka, S., Wakeham, A., Ruland, J., Yoshida, H., Liu, D., Elledge, S.J. and Mak, T.W. (2000) DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science, 287, 1824-1827.
Hiromura, K., Pippin, J.W., Blonski, M.J., Roberts, J.M. and Shankland, S.J. (2002) The subcellular localization of cyclin dependent kinase 2 determines the fate of mesangial cells: role in apoptosis and proliferation. Oncogene, 21, 1750-1758.
Hiromura, K., Pippin, J.W., Fero, M.L., Roberts, J.M. and Shankland, S.J. (1999) Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1). J Clin Invest, 103, 597-604.
Ho, F.M., Lin, W.W., Chen, B.C., Chao, C.M., Yang, C.R., Lin, L.Y., Lai, C.C., Liu, S.H. and Liau, C.S. (2006) High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-kappaB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway. Cell Signal, 18, 391-399.
Hockenbery, D.M., Oltvai, Z.N., Yin, X.M., Milliman, C.L. and Korsmeyer, S.J. (1993) Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell, 75, 241-251.
Honda, R., Tanaka, H. and Yasuda, H. (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett, 420, 25-27.
Hupp, T.R., Meek, D.W., Midgley, C.A. and Lane, D.P. (1992) Regulation of the specific DNA binding function of p53. Cell, 71, 875-886.
Hwang, B.J., Ford, J.M., Hanawalt, P.C. and Chu, G. (1999) Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc Natl Acad Sci U S A, 96, 424-428.
Ichihashi, M., Ueda, M., Budiyanto, A., Bito, T., Oka, M., Fukunaga, M., Tsuru, K. and Horikawa, T. (2003) UV-induced skin damage. Toxicology, 189, 21-39.
Inoshita, S., Terada, Y., Nakashima, O., Kuwahara, M., Sasaki, S. and Marumo, F. (1999) Regulation of the G1/S transition phase in mesangial cells by E2F1. Kidney Int, 56, 1238-1241.
Irwin, M., Marin, M.C., Phillips, A.C., Seelan, R.S., Smith, D.I., Liu, W., Flores, E.R., Tsai, K.Y., Jacks, T., Vousden, K.H. and Kaelin, W.G., Jr. (2000) Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature, 407, 645-648.
Jankowiak, R., Lin, C.H., Zamzow, D., Roberts, K.P., Li, K.M. and Small, G.J. (1999) Spectral and conformational analysis of deoxyadenosine adducts derived from syn- and anti-Dibenzo[a,l]pyrene diol epoxides: fluorescence studies. Chem Res Toxicol, 12, 768-777.
Jaruga, P., Theruvathu, J., Dizdaroglu, M. and Brooks, P.J. (2004) Complete release of (5'S)-8,5'-cyclo-2'-deoxyadenosine from dinucleotides, oligodeoxynucleotides and DNA, and direct comparison of its levels in cellular DNA with other oxidatively induced DNA lesions. Nucleic Acids Res, 32, e87.
Kane, D.J., Sarafian, T.A., Anton, R., Hahn, H., Gralla, E.B., Valentine, J.S., Ord, T. and Bredesen, D.E. (1993) Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science, 262, 1274-1277.
Kaustov, L., Yi, G.S., Ayed, A., Bochkareva, E., Bochkarev, A. and Arrowsmith, C.H. (2006) p53 transcriptional activation domain: a molecular chameleon? Cell Cycle, 5, 489-494.
Kerr, J.F., Wyllie, A.H. and Currie, A.R. (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer, 26, 239-257.
Kim, C.H., Kim, J.H., Hsu, C.Y. and Ahn, Y.S. (1999) Zinc is required in pyrrolidine dithiocarbamate inhibition of NF-kappaB activation. FEBS Lett, 449, 28-32.
Klein, J.A. and Ackerman, S.L. (2003) Oxidative stress, cell cycle, and neurodegeneration. J Clin Invest, 111, 785-793.
Ko, L.J. and Prives, C. (1996) p53: puzzle and paradigm. Genes Dev, 10, 1054-1072.
Koc, M., Nad'ova, Z., Truksa, J., Ehrlichova, M. and Kovar, J. (2005) Iron deprivation induces apoptosis via mitochondrial changes related to Bax translocation. Apoptosis, 10, 381-393.
Kondo, S., Barnett, G.H., Hara, H., Morimura, T. and Takeuchi, J. (1995) MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis. Oncogene, 10, 2001-2006.
Kook, S., Shim, S.R., Choi, S.J., Ahnn, J., Kim, J.I., Eom, S.H., Jung, Y.K., Paik, S.G. and Song, W.K. (2000) Caspase-mediated cleavage of p130cas in etoposide-induced apoptotic Rat-1 cells. Mol Biol Cell, 11, 929-939.
Kothakota, S., Azuma, T., Reinhard, C., Klippel, A., Tang, J., Chu, K., McGarry, T.J., Kirschner, M.W., Koths, K., Kwiatkowski, D.J. and Williams, L.T. (1997) Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis. Science, 278, 294-298.
Kubbutat, M.H., Jones, S.N. and Vousden, K.H. (1997) Regulation of p53 stability by Mdm2. Nature, 387, 299-303.
Kubbutat, M.H., Ludwig, R.L., Ashcroft, M. and Vousden, K.H. (1998) Regulation of Mdm2-directed degradation by the C terminus of p53. Mol Cell Biol, 18, 5690-5698.
Kulms, D. and Schwarz, T. (2002) Molecular mechanisms involved in UV-induced apoptotic cell death. Skin Pharmacol Appl Skin Physiol, 15, 342-347.
Lee, H., Larner, J.M. and Hamlin, J.L. (1997) Cloning and characterization of Chinese hamster p53 cDNA. Gene, 184, 177-183.
Leveillard, T., Andera, L., Bissonnette, N., Schaeffer, L., Bracco, L., Egly, J.M. and Wasylyk, B. (1996) Functional interactions between p53 and the TFIIH complex are affected by tumour-associated mutations. Embo J, 15, 1615-1624.
Levine, A.J. (1997) p53, the cellular gatekeeper for growth and division. Cell, 88, 323-331.
Levkau, B., Koyama, H., Raines, E.W., Clurman, B.E., Herren, B., Orth, K., Roberts, J.M. and Ross, R. (1998) Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade. Mol Cell, 1, 553-563.
Li, H., Zhu, H., Xu, C.J. and Yuan, J. (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell, 94, 491-501.
Li, Q., Yu, Y.Y., Zhu, Z.G., Ji, Y.B., Zhang, Y., Liu, B.Y., Chen, X.H. and Lin, Y.Z. (2005) Effect of NF-kappaB constitutive activation on proliferation and apoptosis of gastric cancer cell lines. Eur Surg Res, 37, 105-110.
Li, W., Xia, J. and Sun, G.Y. (1999) Cytokine induction of iNOS and sPLA2 in immortalized astrocytes (DITNC): response to genistein and pyrrolidine dithiocarbamate. J Interferon Cytokine Res, 19, 121-127.
Liao, C.B., Chang, Y.C., Kao, C.W., Taniga, E.S., Li, H., Tzang, B.S. and Liu, Y.C. (2006) Deregulation of cyclin-dependent kinase 2 activity correlates with UVC-induced apoptosis in Chinese hamster ovary cells. J Cell Biochem, 97, 824-835.
Lin, K.W., Nam, S.Y., Toh, W.H., Dulloo, I. and Sabapathy, K. (2004) Multiple stress signals induce p73beta accumulation. Neoplasia, 6, 546-557.
Lin, W.C., Lin, F.T. and Nevins, J.R. (2001) Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev, 15, 1833-1844.
Loft, S. and Poulsen, H.E. (1996) Cancer risk and oxidative DNA damage in man. J Mol Med, 74, 297-312.
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.
Macleod, K.F., Hu, Y. and Jacks, T. (1996) Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. Embo J, 15, 6178-6188.
Malaguarnera, L., Pilastro, M.R., Vicari, L., Dimarco, R., Manzella, L., Palumbo, G. and Messina, A. (2005) Pyrrolidinedithiocarbamate induces apoptosis in human acute myelogenous leukemic cells affecting NF-kappaB activity. Cancer Invest, 23, 404-412.
Matsumura, Y. and Ananthaswamy, H.N. (2004) Toxic effects of ultraviolet radiation on the skin. Toxicol Appl Pharmacol, 195, 298-308.
Meijer, L., Borgne, A., Mulner, O., Chong, J.P., Blow, J.J., Inagaki, N., Inagaki, M., Delcros, J.G. and Moulinoux, J.P. (1997) Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem, 243, 527-536.
Meyer, M., Schreck, R. and Baeuerle, P.A. (1993) H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. Embo J, 12, 2005-2015.
Michieli, P., Chedid, M., Lin, D., Pierce, J.H., Mercer, W.E. and Givol, D. (1994) Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res, 54, 3391-3395.
Mitchell, D.L. (1988) The relative cytotoxicity of (6-4) photoproducts and cyclobutane dimers in mammalian cells. Photochem Photobiol, 48, 51-57.
Mitchell, D.L., Haipek, C.A. and Clarkson, J.M. (1985) (6-4)Photoproducts are removed from the DNA of UV-irradiated mammalian cells more efficiently than cyclobutane pyrimidine dimers. Mutat Res, 143, 109-112.
Morgenbesser, S.D., Williams, B.O., Jacks, T. and DePinho, R.A. (1994) p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature, 371, 72-74.
Moroni, M.C., Hickman, E.S., Lazzerini Denchi, E., Caprara, G., Colli, E., Cecconi, F., Muller, H. and Helin, K. (2001) Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol, 3, 552-558.
Mowat, M.R. (1998) p53 in tumor progression: life, death, and everything. Adv Cancer Res, 74, 25-48.
Muller, D.N., Dechend, R., Mervaala, E.M., Park, J.K., Schmidt, F., Fiebeler, A., Theuer, J., Breu, V., Ganten, D., Haller, H. and Luft, F.C. (2000) NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension, 35, 193-201.
Nakanishi, M., Adami, G.R., Robetorye, R.S., Noda, A., Venable, S.F., Dimitrov, D., Pereira-Smith, O.M. and Smith, J.R. (1995) Exit from G0 and entry into the cell cycle of cells expressing p21Sdi1 antisense RNA. Proc Natl Acad Sci U S A, 92, 4352-4356.
Nathens, A.B., Bitar, R., Davreux, C., Bujard, M., Marshall, J.C., Dackiw, A.P., Watson, R.W. and Rotstein, O.D. (1997) Pyrrolidine dithiocarbamate attenuates endotoxin-induced acute lung injury. Am J Respir Cell Mol Biol, 17, 608-616.
Niculescu, A.B., 3rd, Chen, X., Smeets, M., Hengst, L., Prives, C. and Reed, S.I. (1998) Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol, 18, 629-643.
Nigg, E.A. (1995) Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. Bioessays, 17, 471-480.
Nishiwaki, Y., Kobayashi, N., Imoto, K., Iwamoto, T.A., Yamamoto, A., Katsumi, S., Shirai, T., Sugiura, S., Nakamura, Y., Sarasin, A., Miyagawa, S. and Mori, T. (2004) Trichothiodystrophy fibroblasts are deficient in the repair of ultraviolet-induced cyclobutane pyrimidine dimers and (6-4)photoproducts. J Invest Dermatol, 122, 526-532.
Nyberg, K.A., Michelson, R.J., Putnam, C.W. and Weinert, T.A. (2002) Toward maintaining the genome: DNA damage and replication checkpoints. Annu Rev Genet, 36, 617-656.
Ogryzko, V.V., Wong, P. and Howard, B.H. (1997) WAF1 retards S-phase progression primarily by inhibition of cyclin-dependent kinases. Mol Cell Biol, 17, 4877-4882.
Oren, M. (1999) Regulation of the p53 tumor suppressor protein. J Biol Chem, 274, 36031-36034.
Orren, D.K., Petersen, L.N. and Bohr, V.A. (1995) A UV-responsive G2 checkpoint in rodent cells. Mol Cell Biol, 15, 3722-3730.
Owen-Schaub, L.B., Zhang, W., Cusack, J.C., Angelo, L.S., Santee, S.M., Fujiwara, T., Roth, J.A., Deisseroth, A.B., Zhang, W.W., Kruzel, E. and et al. (1995) Wild-type human p53 and a temperature-sensitive mutant induce Fas/APO-1 expression. Mol Cell Biol, 15, 3032-3040.
Pappa, A., Chen, C., Koutalos, Y., Townsend, A.J. and Vasiliou, V. (2003) Aldh3a1 protects human corneal epithelial cells from ultraviolet- and 4-hydroxy-2-nonenal-induced oxidative damage. Free Radic Biol Med, 34, 1178-1189.
Pelicano, H., Carney, D. and Huang, P. (2004) ROS stress in cancer cells and therapeutic implications. Drug Resist Updat, 7, 97-110.
Petersen, L.N., Stevnsner, T. and Bohr, V.A. (1995) DNA repair in a UV resistant Chinese hamster ovary cell line. Carcinogenesis, 16, 3075-3081.
Pfeifer, G.P., You, Y.H. and Besaratinia, A. (2005) Mutations induced by ultraviolet light. Mutat Res, 571, 19-31.
Polyak, K., Lee, M.H., Erdjument-Bromage, H., Koff, A., Roberts, J.M., Tempst, P. and Massague, J. (1994) Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell, 78, 59-66.
Prives, C. (1998) Signaling to p53: breaking the MDM2-p53 circuit. Cell, 95, 5-8.
Rangan, G.K., Wang, Y., Tay, Y.C. and Harris, D.C. (2001) Early administration of PDTC in adriamycin nephropathy: effect on proteinuria, cortical tubulointerstitial injury, and NF-kappaB activation. Ren Fail, 23, 773-780.
Rothstein, J.D., Bristol, L.A., Hosler, B., Brown, R.H., Jr. and Kuncl, R.W. (1994) Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. Proc Natl Acad Sci U S A, 91, 4155-4159.
Rudel, T. and Bokoch, G.M. (1997) Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science, 276, 1571-1574.
Sachsenmaier, C., Radler-Pohl, A., Zinck, R., Nordheim, A., Herrlich, P. and Rahmsdorf, H.J. (1994) Involvement of growth factor receptors in the mammalian UVC response. Cell, 78, 963-972.
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.
Scandalios, J.G. (2002) The rise of ROS. Trends Biochem Sci, 27, 483-486.
Scharffetter-Kochanek, K., Wlaschek, M., Brenneisen, P., Schauen, M., Blaudschun, R. and Wenk, J. (1997) UV-induced reactive oxygen species in photocarcinogenesis and photoaging. Biol Chem, 378, 1247-1257.
Schreck, R., Meier, B., Mannel, D.N., Droge, W. and Baeuerle, P.A. (1992) Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med, 175, 1181-1194.
Schwarz, T. (1998) UV light affects cell membrane and cytoplasmic targets. J Photochem Photobiol B, 44, 91-96.
Sherr, C.J. (1996) Cancer cell cycles. Science, 274, 1672-1677.
Sherr, C.J. and Weber, J.D. (2000) The ARF/p53 pathway. Curr Opin Genet Dev, 10, 94-99.
Siliciano, J.D., Canman, C.E., Taya, Y., Sakaguchi, K., Appella, E. and Kastan, M.B. (1997) DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev, 11, 3471-3481.
Simic, M.G. and Bergtold, D.S. (1991) Dietary modulation of DNA damage in human. Mutat Res, 250, 17-24.
Slee, E.A., Harte, M.T., Kluck, R.M., Wolf, B.B., Casiano, C.A., Newmeyer, D.D., Wang, H.G., Reed, J.C., Nicholson, D.W., Alnemri, E.S., Green, D.R. and Martin, S.J. (1999) Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol, 144, 281-292.
Smith, M.L., Chen, I.T., Zhan, Q., O'Connor, P.M. and Fornace, A.J., Jr. (1995) Involvement of the p53 tumor suppressor in repair of u.v.-type DNA damage. Oncogene, 10, 1053-1059.
Smith, M.L. and Fornace, A.J., Jr. (1997) p53-mediated protective responses to UV irradiation. Proc Natl Acad Sci U S A, 94, 12255-12257.
Taimen, P. and Kallajoki, M. (2003) NuMA and nuclear lamins behave differently in Fas-mediated apoptosis. J Cell Sci, 116, 571-583.
Tang, H.L., Le, A.H. and Lung, H.L. (2006) The increase in mitochondrial association with actin precedes Bax translocation in apoptosis. Biochem J, 396, 1-5.
Taniguchi, K., Kohsaka, H., Inoue, N., Terada, Y., Ito, H., Hirokawa, K. and Miyasaka, N. (1999) Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis. Nat Med, 5, 760-767.
Taylor, W.R. and Stark, G.R. (2001) Regulation of the G2/M transition by p53. Oncogene, 20, 1803-1815.
Tewari, M., Quan, L.T., O'Rourke, K., Desnoyers, S., Zeng, Z., Beidler, D.R., Poirier, G.G., Salvesen, G.S. and Dixit, V.M. (1995) Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell, 81, 801-809.
Therrien, J.P., Drouin, R., Baril, C. and Drobetsky, E.A. (1999) Human cells compromised for p53 function exhibit defective global and transcription-coupled nucleotide excision repair, whereas cells compromised for pRb function are defective only in global repair. Proc Natl Acad Sci U S A, 96, 15038-15043.
Thornberry, N.A. and Lazebnik, Y. (1998) Caspases: enemies within. Science, 281, 1312-1316.
Tikhomirov, O. and Carpenter, G. (2005) Bax activation and translocation to mitochondria mediate EGF-induced programmed cell death. J Cell Sci, 118, 5681-5690.
Tornaletti, S. and Pfeifer, G.P. (1996) UV damage and repair mechanisms in mammalian cells. Bioessays, 18, 221-228.
Tsai, K.Y., Hu, Y., Macleod, K.F., Crowley, D., Yamasaki, L. and Jacks, T. (1998) Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell, 2, 293-304.
Tyers, M. and Jorgensen, P. (2000) Proteolysis and the cell cycle: with this RING I do thee destroy. Curr Opin Genet Dev, 10, 54-64.
Tzang, B.S., Chiang, Y.J., Lan, H.C., Liao, C.B. and Liu, Y.C. (2002) Tuning up or down the UV-induced apoptosis in Chinese hamster ovary cells with cell cycle inhibitors. Photochem Photobiol, 75, 662-667.
Tzang, B.S., Lai, Y.C., Hsu, M., Chang, H.W., Chang, C.C., Huang, P.C. and Liu, Y.C. (1999a) Function and sequence analyses of tumor suppressor gene p53 of CHO.K1 cells. DNA Cell Biol, 18, 315-321.
Tzang, B.S., Lai, Y.C. and Liu, Y.C. (1999b) UV-induced but P53 independent apoptotic death in CHO.K1 cells is promoted by M phase inhibitors. In Vitro Cell Dev Biol Anim, 35, 17-18.
Vermes, I., Haanen, C., Steffens-Nakken, H. and Reutelingsperger, C. (1995) A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods, 184, 39-51.
Vogelstein, B., Lane, D. and Levine, A.J. (2000) Surfing the p53 network. Nature, 408, 307-310.
Wang, A.S., Ramanathan, B., Chien, Y.H., Goparaju, C.M. and Jan, K.Y. (2005) Comet assay with nuclear extract incubation. Anal Biochem, 337, 70-75.
Wang, D., Kreutzer, D.A. and Essigmann, J.M. (1998) Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat Res, 400, 99-115.
Wang, Q.E., Zhu, Q., Wani, M.A., Wani, G., Chen, J. and Wani, A.A. (2003) Tumor suppressor p53 dependent recruitment of nucleotide excision repair factors XPC and TFIIH to DNA damage. DNA Repair (Amst), 2, 483-499.
Wang, X.W., Yeh, H., Schaeffer, L., Roy, R., Moncollin, V., Egly, J.M., Wang, Z., Freidberg, E.C., Evans, M.K., Taffe, B.G. and et al. (1995) p53 modulation of TFIIH-associated nucleotide excision repair activity. Nat Genet, 10, 188-195.
Waris, G. and Ahsan, H. (2006) Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog, 5, 14.
Wei, H. and Frenkel, K. (1993) Relationship of oxidative events and DNA oxidation in SENCAR mice to in vivo promoting activity of phorbol ester-type tumor promoters. Carcinogenesis, 14, 1195-1201.
Xiong, Y., Hannon, G.J., Zhang, H., Casso, D., Kobayashi, R. and Beach, D. (1993) p21 is a universal inhibitor of cyclin kinases. Nature, 366, 701-704.
Yang, Y., Cheng, J.Z., Singhal, S.S., Saini, M., Pandya, U., Awasthi, S. and Awasthi, Y.C. (2001) Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation. J Biol Chem, 276, 19220-19230.
Zeng, Y., Forbes, K.C., Wu, Z., Moreno, S., Piwnica-Worms, H. and Enoch, T. (1998) Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1. Nature, 395, 507-510.
Zhou, B.B. and Elledge, S.J. (2000) The DNA damage response: putting checkpoints in perspective. Nature, 408, 433-439.
Zou, H., Li, Y., Liu, X. and Wang, X. (1999) An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem, 274, 11549-11556.