Oncoprotein MCT-1(Multiple Copies in T-cell malignancy)是在T-cell leukemia/lymphoma cell lines被發現的，在T-cell lymphoma的染色體 Xq22-24位置有被大量複製的情形。MCT-1的蛋白質大小為20 kDa ，由181個氨基酸所組成，穿梭於細胞質與細胞核中，參與細胞週期調控以及蛋白質分子轉譯功能。在本篇論文中發現，在人類乳腺細胞中大量表現MCT-1，可以藉由增加磷酸化AKT蛋白而活化細胞內PI3K/AKT訊息傳遞路徑。過度活化MCT -1於正常乳腺細胞，會增加磷酸化AKT蛋白的表現量、降低p53抗癌蛋白質的活性與穩定性與抑制PI3K p110次單位，進而增加細胞生長速度以及細胞存活率，並且破壞細胞週期之監控調節而減少因為DNA受損所產生之細胞週期抑制及細胞凋亡。MCT-1過度表現也可以增加細胞內低準確度之DNA修復能力，使細胞在DNA受損時，增加細胞內遺傳物質的變異性。MCT-1可藉由上述之過程而促使正常細胞癌化異常，而且增加癌細胞對抗生化抗癌藥物。在細胞中加入持續活化之PI3K，反而會提高腫瘤抑制蛋白p53的活性，進一步增加藥物造成之細胞週期被限制在G2/M期的程度及細胞凋亡的情形，但是同時擁有PI3K p110與MCT-1過度表現的細胞中，MCT-1依然有增強其對於Doxorubicin的抗藥性。

1. Shi B, Hsu HL, Evens AM, Gordon LI, Gartenhaus RB. Expression of the candidate MCT-1 oncogene in B- and T-cell lymphoid malignancies. Blood 2003;102(1):297-302.
2. Prosniak M, Dierov J, Okami K, et al. A novel candidate oncogene, MCT-1, is involved in cell cycle progression. Cancer Res 1998;58(19):4233-7.
3. Dierov J, Prosniak M, Gallia G, Gartenhaus RB. Increased G1 cyclin/cdk activity in cells overexpressing the candidate oncogene, MCT-1. J Cell Biochem 1999;74(4):544-50.
4. Nandi S, Reinert LS, Hachem A, et al. Phosphorylation of MCT-1 by p44/42 MAPK is required for its stabilization in response to DNA damage. Oncogene 2007;26(16):2283-9.
5. Mazan-Mamczarz K, Gartenhaus RB. Post-transcriptional control of the MCT-1-associated protein DENR/DRP by RNA-binding protein AUF1. Cancer Genomics Proteomics 2007;4(3):233-9.
6. Hsu HL, Choy CO, Kasiappan R, et al. MCT-1 oncogene downregulates p53 and destabilizes genome structure in the response to DNA double-strand damage. DNA Repair (Amst) 2007;6(9):1319-32.
7. Hsu HL, Shi B, Gartenhaus RB. The MCT-1 oncogene product impairs cell cycle checkpoint control and transforms human mammary epithelial cells. Oncogene 2005;24(31):4956-64.
8. Levenson AS, Thurn KE, Simons LA, et al. MCT-1 oncogene contributes to increased in vivo tumorigenicity of MCF7 cells by promotion of angiogenesis and inhibition of apoptosis. Cancer Res 2005;65(23):10651-6.
9. Herbert GB, Shi B, Gartenhaus RB. Expression and stabilization of the MCT-1 protein by DNA damaging agents. Oncogene 2001;20(46):6777-83.
10. Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem 1991;201(2):475-81.
11. Altomare DA, Guo K, Cheng JQ, Sonoda G, Walsh K, Testa JR. Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene 1995;11(6):1055-60.
12. Brodbeck D, Cron P, Hemmings BA. A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem 1999;274(14):9133-6.
13. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 1999;96(8):4240-5.
14. Lemmon MA, Ferguson KM, Schlessinger J. PH domains: diverse sequences with a common fold recruit signaling molecules to the cell surface. Cell 1996;85(5):621-4.
15. Shaw G. The pleckstrin homology domain: an intriguing multifunctional protein module. Bioessays 1996;18(1):35-46.
16. Andjelkovic M, Suidan HS, Meier R, Frech M, Alessi DR, Hemmings BA. Nerve growth factor promotes activation of the alpha, beta and gamma isoforms of protein kinase B in PC12 pheochromocytoma cells. Eur J Biochem 1998;251(1-2):195-200.
17. Franke TF, Yang SI, Chan TO, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 1995;81(5):727-36.
18. Ahmed NN, Grimes HL, Bellacosa A, Chan TO, Tsichlis PN. Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc Natl Acad Sci U S A 1997;94(8):3627-32.
19. Coffer PJ, Schweizer RC, Dubois GR, Maikoe T, Lammers JW, Koenderman L. Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5. Blood 1998;91(7):2547-57.
20. Songyang Z, Baltimore D, Cantley LC, Kaplan DR, Franke TF. Interleukin 3-dependent survival by the Akt protein kinase. Proc Natl Acad Sci U S A 1997;94(21):11345-50.
21. Konishi H, Matsuzaki H, Tanaka M, et al. Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A 1996;93(15):7639-43.
22. Franke TF, Tartof KD, Tsichlis PN. The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies in the genome of vertebrate and invertebrate eucaryotes. Cloning and characterization of the Drosophila melanogaster c-akt homolog Dakt1. Oncogene 1994;9(1):141-8.
23. Waterston R, Martin C, Craxton M, et al. A survey of expressed genes in Caenorhabditis elegans. Nat Genet 1992;1(2):114-23.
24. Chan TO, Rittenhouse SE, Tsichlis PN. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu Rev Biochem 1999;68:965-1014.
25. Alessi DR, Andjelkovic M, Caudwell B, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 1996;15(23):6541-51.
26. Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 1999;253(1):210-29.
27. Tonks NK, Myers MP. Structural assets of a tumor suppressor. Science 1999;286(5447):2096-7.
28. Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 1999;24(5):186-91.
29. Gajewski TF, Thompson CB. Apoptosis meets signal transduction: elimination of a BAD influence. Cell 1996;87(4):589-92.
30. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998;12(22):3499-511.
31. Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A 2001;98(20):11598-603.
32. Zhou BP, Hung MC. Novel targets of Akt, p21(Cipl/WAF1), and MDM2. Semin Oncol 2002;29(3 Suppl 11):62-70.
33. Michell BJ, Griffiths JE, Mitchelhill KI, et al. The Akt kinase signals directly to endothelial nitric oxide synthase. Curr Biol 1999;9(15):845-8.
34. Dimmeler S, Zeiher AM. Akt takes center stage in angiogenesis signaling. Circ Res 2000;86(1):4-5.
35. Johnson DG, Walker CL. Cyclins and cell cycle checkpoints. Annu Rev Pharmacol Toxicol 1999;39:295-312.
36. Morgan DO. Principles of CDK regulation. Nature 1995;374(6518):131-4.
37. Sherr CJ. Growth factor-regulated G1 cyclins. Stem Cells 1994;12 Suppl 1:47-55; discussion -7.
38. Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol 1995;15(5):2612-24.
39. Walker DH, Maller JL. Role for cyclin A in the dependence of mitosis on completion of DNA replication. Nature 1991;354(6351):314-7.
40. Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science 1989;246(4930):629-34.
41. Paulovich AG, Toczyski DP, Hartwell LH. When checkpoints fail. Cell 1997;88(3):315-21.
42. Richardson C, Jasin M. Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 2000;405(6787):697-700.
43. Rich T, Allen RL, Wyllie AH. Defying death after DNA damage. Nature 2000;407(6805):777-83.
44. Lindahl T, Wood RD. Quality control by DNA repair. Science 1999;286(5446):1897-905.
45. Haber JE. Partners and pathwaysrepairing a double-strand break. Trends Genet 2000;16(6):259-64.
46. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature 2001;411(6835):366-74.
47. Goedecke W, Eijpe M, Offenberg HH, van Aalderen M, Heyting C. Mre11 and Ku70 interact in somatic cells, but are differentially expressed in early meiosis. Nat Genet 1999;23(2):194-8.
48. Karran P. DNA double strand break repair in mammalian cells. Curr Opin Genet Dev 2000;10(2):144-50.
49. Pierce AJ, Jasin M. NHEJ deficiency and disease. Mol Cell 2001;8(6):1160-1.
50. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998;273(10):5858-68.
51. Celeste A, Fernandez-Capetillo O, Kruhlak MJ, et al. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol 2003;5(7):675-9.
52. Jacobson MD. Programmed cell death: a missing link is found. Trends Cell Biol 1997;7(12):467-9.
53. Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell 1997;88(3):347-54.
54. Hart BA, Lee CH, Shukla GS, et al. Characterization of cadmium-induced apoptosis in rat lung epithelial cells: evidence for the participation of oxidant stress. Toxicology 1999;133(1):43-58.
55. Lennon SV, Martin SJ, Cotter TG. Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli. Cell Prolif 1991;24(2):203-14.
56. Meyn RE, Stephens LC, Mason KA, Medina D. Radiation-induced apoptosis in normal and pre-neoplastic mammary glands in vivo: significance of gland differentiation and p53 status. Int J Cancer 1996;65(4):466-72.
57. Cohen JJ. Apoptosis: the physiologic pathway of cell death. Hosp Pract (Off Ed) 1993;28(12):35-43.
58. Cohen JJ. Apoptosis. Immunol Today 1993;14(3):126-30.
59. Cohen GM. Caspases: the executioners of apoptosis. Biochem J 1997;326 ( Pt 1):1-16.
60. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993;75(4):641-52.
61. Hengartner M. Apoptosis. Death by crowd control. Science 1998;281(5381):1298-9.
62. Nakagawa T, Zhu H, Morishima N, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000;403(6765):98-103.
63. Janicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 1998;273(16):9357-60.
64. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7(8):606-19.
65. Garcia Z, Kumar A, Marques M, Cortes I, Carrera AC. Phosphoinositide 3-kinase controls early and late events in mammalian cell division. EMBO J 2006;25(4):655-61.
66. Hellyer NJ, Cheng K, Koland JG. ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem J 1998;333 ( Pt 3):757-63.
67. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2(7):489-501.
68. Shtivelman E, Sussman J, Stokoe D. A role for PI 3-kinase and PKB activity in the G2/M phase of the cell cycle. Curr Biol 2002;12(11):919-24.
69. Levine AJ, Chang A, Dittmer D, et al. The p53 tumor suppressor gene. J Lab Clin Med 1994;123(6):817-23.
70. Almazov VP, Kochetkov DV, Chumakov PM. [The use of p53 as a tool for human cancer therapy]. Mol Biol (Mosk) 2007;41(6):947-63.
71. Chipuk JE, Green DR. Dissecting p53-dependent apoptosis. Cell Death Differ 2006;13(6):994-1002.
72. Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A 2003;100(22):12871-6.
73. Kim JS, Lee C, Bonifant CL, Ressom H, Waldman T. Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Mol Cell Biol 2007;27(2):662-77.
74. Jeong SJ, Dasgupta A, Jung KJ, et al. PI3K/AKT inhibition induces caspase-dependent apoptosis in HTLV-1-transformed cells. Virology 2008;370(2):264-72.