58-kDa微小球蛋白(MSP58)在維持細胞功能上扮演很重要的角色，包括轉錄調控、細
胞增生以及細胞轉型等。而到目前為止，對於MSP58扮演致癌基因的角色仍然需要進
一步的釐清研究。在我們的研究結果發現，MSP58由小干擾RNA將其基因剔除會導
致染色體非整倍體和細胞凋亡。而MSP58過度表現時會誘導細胞老化或是轉型主要依
賴於控制老化過程中p53是否有完整的功能存在。然而，過度表現MSP58在HT1080、
NIH3T3、人類乳腺表皮細胞株(H184B5F5/M10)以及正常人類雙套纖維母細胞株(Hs68
和IMR90)會誘導細胞提早老化，主要透過Rb的磷酸化減少、DNA損害活化以及活化
p53/p21訊息傳遞路徑。更重要的是，MSP58誘導細胞老化，p53是必須存在的。此外，
利用酵母菌雙雜交篩選找到兩個新穎MSP58交互作用蛋白質，Brg1和TEIF。我們證明
MSP58、Brg1和p53會形成複合體座落在p21啟動子上並啟動基因轉錄。利用小干擾
RNA將Brg1或p53基因剔除後會抑制MSP58所調控的老化。除此之外，MSP58也擔任
一個hTERT轉錄負向調控因子並且抑制TEIF所調控的hTERT轉錄活性、端粒酶活性、
細胞增生以及腫瘤生成。而MSP58抑制hTERT轉錄主要是透過抑制TEIF和DNA結合
的能力。利用組織晶片分析MSP58在腫瘤和正常樣品中的表現，結果顯示MSP58在不
同形態腫瘤中有過度表現和減少表現的情況存在。總結以上的結果，這些研究使我們
對於MSP58經由不同的交互作用蛋白質去調控細胞老化和端粒酶活性有更深入的了
解並且也暗示著MSP58可能同時具有致癌和抑癌基因的雙重特性。

58-kDa microspherule protein (MSP58) plays an important role in a variety of cellular function including transcriptional regulation, cell proliferation and oncogenic transformation. To date, the mechanisms underlying the oncogenic effect of MSP58 remain elusive. In our study, MSP58 silencing by siRNA results in aneuploidy and apoptosis. Forced expression of MSP58 induces either cellular senescence or transformation dependent on the integrity of a senescence program controlled by functional p53. MSP58 overexpression induces premature senescence in HT1080, NIH3T3 cell lines, human mammary epithelial cell line (H184B5F5/M10) and normal human diploid fibroblasts (Hs68 and IMR90) through hypophosporylated Rb, activation of the DNA damage response and upregulation of p53/p21 pathway. Importantly, p53 is required for MSP58-induced premature senescence. Furthermore, novel MSP58-interacting proteins
were identified by yeast two-hybrid screen, including the Brg1 (Brahma-related gene 1) and TEIF (telomerase transcriptional elements-interacting factor). Notably, MSP58 complex colocalizes with both p53 and Brg1 on the p21 promoter and collaborate to activate p21 gene transcription. Brg1 or p53 knockdown by RNA interferences results in MSP58-mediated senescence bypassed. Additionally, MSP58 serves as a negative regulator of hTERT transcription and suppresses TEIF-induced hTERT transcriptional activity, telomerase activity, cell proliferation and tumor formation. The inhibitory effect
of MSP58 on hTERT transcription occurred through inhibition of TEIF binding to DNA. Analysis the expression level of MSP58 in tumor and normal samples in tissue microarrays showed that MSP58 was both up-regulated and down-regulated in different types of tumors compared to the normal tissue counterparts. Taken together, these studies provide new
insights into the role of MSP58 in regulation of cellular proliferation and telomerase
activity via different interacting proteins and suggest that MSP58 has both oncogenic and
tumor-suppressive properties.

(XII) References
1. Burrows, A.E., Smogorzewska, A. and Elledge, S.J. Polybromo-associated
BRG1-associated factor components BRD7 and BAF180 are critical regulators of
p53 required for induction of replicative senescence. Proceedings of the National
Academy of Sciences of the United States of America, 107, 14280-14285.
2. Goldstein, S. (1990) Replicative senescence: the human fibroblast comes of age.
Science (New York, N.Y, 249, 1129-1133.
3. Ben-Porath, I. and Weinberg, R.A. (2005) The signals and pathways activating
cellular senescence. The international journal of biochemistry & cell biology, 37,
961-976.
4. Gire, V., Roux, P., Wynford-Thomas, D., Brondello, J.M. and Dulic, V. (2004)
DNA damage checkpoint kinase Chk2 triggers replicative senescence. The EMBO
journal, 23, 2554-2563.
5. d'Adda di Fagagna, F., Reaper, P.M., Clay-Farrace, L., Fiegler, H., Carr, P., Von
Zglinicki, T., Saretzki, G., Carter, N.P. and Jackson, S.P. (2003) A DNA damage
checkpoint response in telomere-initiated senescence. Nature, 426, 194-198.
6. Webley, K., Bond, J.A., Jones, C.J., Blaydes, J.P., Craig, A., Hupp, T. and
Wynford-Thomas, D. (2000) Posttranslational modifications of p53 in replicative
senescence overlapping but distinct from those induced by DNA damage.
Molecular and cellular biology, 20, 2803-2808.
7. Dyson, N. (1998) The regulation of E2F by pRB-family proteins. Genes &
development, 12, 2245-2262.
8. Chen, Z., Trotman, L.C., Shaffer, D., Lin, H.K., Dotan, Z.A., Niki, M., Koutcher,
J.A., Scher, H.I., Ludwig, T., Gerald, W. et al. (2005) Crucial role of
p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis.
Nature, 436, 725-730.
9. Hanahan, D. and Weinberg, R.A. (2000) The hallmarks of cancer. Cell, 100, 57-70.
10. Feldser, D.M. and Greider, C.W. (2007) Short telomeres limit tumor progression in
vivo by inducing senescence. Cancer cell, 11, 461-469.
11. Cosme-Blanco, W., Shen, M.F., Lazar, A.J., Pathak, S., Lozano, G., Multani, A.S.
and Chang, S. (2007) Telomere dysfunction suppresses spontaneous tumorigenesis
in vivo by initiating p53-dependent cellular senescence. EMBO reports, 8, 497-503.
12. Christophorou, M.A., Ringshausen, I., Finch, A.J., Swigart, L.B. and Evan, G.I.
(2006) The pathological response to DNA damage does not contribute to
p53-mediated tumour suppression. Nature, 443, 214-217.
13. Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N.,
57
Vassiliou, L.V., Kolettas, E., Niforou, K., Zoumpourlis, V.C. et al. (2006)
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA
damage checkpoints. Nature, 444, 633-637.
14. Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C.,
Schurra, C., Garre, M., Nuciforo, P.G., Bensimon, A. et al. (2006)
Oncogene-induced senescence is a DNA damage response triggered by DNA
hyper-replication. Nature, 444, 638-642.
15. Funayama, R. and Ishikawa, F. (2007) Cellular senescence and chromatin structure.
Chromosoma, 116, 431-440.
16. Artandi, S.E., Chang, S., Lee, S.L., Alson, S., Gottlieb, G.J., Chin, L. and DePinho,
R.A. (2000) Telomere dysfunction promotes non-reciprocal translocations and
epithelial cancers in mice. Nature, 406, 641-645.
17. Ahmed, A. and Tollefsbol, T.O. (2003) Telomerase, telomerase inhibition, and
cancer. Journal of anti-aging medicine, 6, 315-325.
18. Kyo, S., Takakura, M., Taira, T., Kanaya, T., Itoh, H., Yutsudo, M., Ariga, H. and
Inoue, M. (2000) Sp1 cooperates with c-Myc to activate transcription of the human
telomerase reverse transcriptase gene (hTERT). Nucleic acids research, 28,
669-677.
19. Wang, J., Xie, L.Y., Allan, S., Beach, D. and Hannon, G.J. (1998) Myc activates
telomerase. Genes & development, 12, 1769-1774.
20. Sagawa, Y., Nishi, H., Isaka, K., Fujito, A. and Takayama, M. (2001) The
correlation of TERT expression with c-myc expression in cervical cancer. Cancer
letters, 168, 45-50.
21. Wu, K.J., Grandori, C., Amacker, M., Simon-Vermot, N., Polack, A., Lingner, J.
and Dalla-Favera, R. (1999) Direct activation of TERT transcription by c-MYC.
Nature genetics, 21, 220-224.
22. Greenberg, R.A., O'Hagan, R.C., Deng, H., Xiao, Q., Hann, S.R., Adams, R.R.,
Lichtsteiner, S., Chin, L., Morin, G.B. and DePinho, R.A. (1999) Telomerase
reverse transcriptase gene is a direct target of c-Myc but is not functionally
equivalent in cellular transformation. Oncogene, 18, 1219-1226.
23. Kanaya, T., Kyo, S., Hamada, K., Takakura, M., Kitagawa, Y., Harada, H. and
Inoue, M. (2000) Adenoviral expression of p53 represses telomerase activity
through down-regulation of human telomerase reverse transcriptase transcription.
Clinical cancer research : an official journal of the American Association for
Cancer Research, 6, 1239-1247.
24. Xu, D., Wang, Q., Gruber, A., Bjorkholm, M., Chen, Z., Zaid, A., Selivanova, G.,
Peterson, C., Wiman, K.G. and Pisa, P. (2000) Downregulation of telomerase
58
reverse transcriptase mRNA expression by wild type p53 in human tumor cells.
Oncogene, 19, 5123-5133.
25. Won, J., Yim, J. and Kim, T.K. (2002) Sp1 and Sp3 recruit histone deacetylase to
repress transcription of human telomerase reverse transcriptase (hTERT) promoter
in normal human somatic cells. The Journal of biological chemistry, 277,
38230-38238.
26. Xu, H.J., Zhou, Y., Ji, W., Perng, G.S., Kruzelock, R., Kong, C.T., Bast, R.C.,
Mills, G.B., Li, J. and Hu, S.X. (1997) Reexpression of the retinoblastoma protein
in tumor cells induces senescence and telomerase inhibition. Oncogene, 15,
2589-2596.
27. Nguyen, D.C. and Crowe, D.L. (1999) Intact functional domains of the
retinoblastoma gene product (pRb) are required for downregulation of telomerase
activity. Biochimica et biophysica acta, 1445, 207-215.
28. Li, H., Zhao, L.L., Funder, J.W. and Liu, J.P. (1997) Protein phosphatase 2A
inhibits nuclear telomerase activity in human breast cancer cells. The Journal of
biological chemistry, 272, 16729-16732.
29. Kim, J.H., Park, S.M., Kang, M.R., Oh, S.Y., Lee, T.H., Muller, M.T. and Chung,
I.K. (2005) Ubiquitin ligase MKRN1 modulates telomere length homeostasis
through a proteolysis of hTERT. Genes & development, 19, 776-781.
30. Nakayama, J., Tahara, H., Tahara, E., Saito, M., Ito, K., Nakamura, H., Nakanishi,
T., Tahara, E., Ide, T. and Ishikawa, F. (1998) Telomerase activation by hTRT in
human normal fibroblasts and hepatocellular carcinomas. Nature genetics, 18,
65-68.
31. Liu, Y., Snow, B.E., Hande, M.P., Yeung, D., Erdmann, N.J., Wakeham, A., Itie,
A., Siderovski, D.P., Lansdorp, P.M., Robinson, M.O. et al. (2000) The telomerase
reverse transcriptase is limiting and necessary for telomerase function in vivo.
Current biology : CB, 10, 1459-1462.
32. Niida, H., Matsumoto, T., Satoh, H., Shiwa, M., Tokutake, Y., Furuichi, Y. and
Shinkai, Y. (1998) Severe growth defect in mouse cells lacking the telomerase
RNA component. Nature genetics, 19, 203-206.
33. Koyanagi, Y., Kobayashi, D., Yajima, T., Asanuma, K., Kimura, T., Sato, T., Kida,
T., Yagihashi, A., Kameshima, H. and Watanabe, N. (2000) Telomerase activity is
down regulated via decreases in hTERT mRNA but not TEP1 mRNA or hTERC
during the differentiation of leukemic cells. Anticancer research, 20, 773-778.
34. Blackburn, E.H., Greider, C.W. and Szostak, J.W. (2006) Telomeres and
telomerase: the path from maize, Tetrahymena and yeast to human cancer and
aging. Nature medicine, 12, 1133-1138.
59
35. Ren, Y., Busch, R.K., Perlaky, L. and Busch, H. (1998) The 58-kDa microspherule
protein (MSP58), a nucleolar protein, interacts with nucleolar protein p120.
European journal of biochemistry / FEBS, 253, 734-742.
36. Durocher, D. and Jackson, S.P. (2002) The FHA domain. FEBS letters, 513, 58-66.
37. Davidovic, L., Bechara, E., Gravel, M., Jaglin, X.H., Tremblay, S., Sik, A., Bardoni,
B. and Khandjian, E.W. (2006) The nuclear microspherule protein 58 is a novel
RNA-binding protein that interacts with fragile X mental retardation protein in
polyribosomal mRNPs from neurons. Human molecular genetics, 15, 1525-1538.
38. Shimono, K., Shimono, Y., Shimokata, K., Ishiguro, N. and Takahashi, M. (2005)
Microspherule protein 1, Mi-2beta, and RET finger protein associate in the
nucleolus and up-regulate ribosomal gene transcription. The Journal of biological
chemistry, 280, 39436-39447.
39. Lin, D.Y. and Shih, H.M. (2002) Essential role of the 58-kDa microspherule
protein in the modulation of Daxx-dependent transcriptional repression as revealed
by nucleolar sequestration. The Journal of biological chemistry, 277, 25446-25456.
40. Ivanova, A.V., Ivanov, S.V. and Lerman, M.L. (2005) Association, mutual
stabilization, and transcriptional activity of the STRA13 and MSP58 proteins.
Cellular and molecular life sciences : CMLS, 62, 471-484.
41. Wu, J.L., Lin, Y.S., Yang, C.C., Lin, Y.J., Wu, S.F., Lin, Y.T. and Huang, C.F.
(2009) MCRS2 represses the transactivation activities of Nrf1. BMC cell biology,
10, 9.
42. Hirohashi, Y., Wang, Q., Liu, Q., Du, X., Zhang, H., Sato, N. and Greene, M.I.
(2006) p78/MCRS1 forms a complex with centrosomal protein Nde1 and is
essential for cell viability. Oncogene, 25, 4937-4946.
43. Du, X., Wang, Q., Hirohashi, Y. and Greene, M.I. (2006) DIPA, which can localize
to the centrosome, associates with p78/MCRS1/MSP58 and acts as a repressor of
gene transcription. Experimental and molecular pathology, 81, 184-190.
44. Meunier, S. and Vernos, I. (2011) K-fibre minus ends are stabilized by a
RanGTP-dependent mechanism essential for functional spindle assembly. Nature
cell biology, 13, 1406-1414.
45. Song, H., Li, Y., Chen, G., Xing, Z., Zhao, J., Yokoyama, K.K., Li, T. and Zhao, M.
(2004) Human MCRS2, a cell-cycle-dependent protein, associates with
LPTS/PinX1 and reduces the telomere length. Biochemical and biophysical
research communications, 316, 1116-1123.
46. Benavides, M., Chow-Tsang, L.F., Zhang, J. and Zhong, H. (2013) The novel
interaction between microspherule protein Msp58 and ubiquitin E3 ligase EDD
regulates cell cycle progression. Biochimica et biophysica acta, 1833, 21-32.
60
47. Karagiannidis, A.I., Bader, A.G., Hartl, M. and Bister, K. (2008) TOJ3, a v-jun
target with intrinsic oncogenic potential, is directly regulated by Jun via a novel
AP-1 binding motif. Virology, 378, 371-376.
48. Okumura, K., Zhao, M., Depinho, R.A., Furnari, F.B. and Cavenee, W.K. (2005)
Cellular transformation by the MSP58 oncogene is inhibited by its physical
interaction with the PTEN tumor suppressor. Proceedings of the National Academy
of Sciences of the United States of America, 102, 2703-2706.
49. Zhou, X.Z., Huang, P., Shi, R., Lee, T.H., Lu, G., Zhang, Z., Bronson, R. and Lu,
K.P. (2011) The telomerase inhibitor PinX1 is a major haploinsufficient tumor
suppressor essential for chromosome stability in mice. The Journal of clinical
investigation, 121, 1266-1282.
50. Reisman, D., Glaros, S. and Thompson, E.A. (2009) The SWI/SNF complex and
cancer. Oncogene, 28, 1653-1668.
51. Harbour, J.W. and Dean, D.C. (2000) Chromatin remodeling and Rb activity.
Current opinion in cell biology, 12, 685-689.
52. Dunaief, J.L., Strober, B.E., Guha, S., Khavari, P.A., Alin, K., Luban, J.,
Begemann, M., Crabtree, G.R. and Goff, S.P. (1994) The retinoblastoma protein
and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell, 79,
119-130.
53. Hendricks, K.B., Shanahan, F. and Lees, E. (2004) Role for BRG1 in cell cycle
control and tumor suppression. Molecular and cellular biology, 24, 362-376.
54. Kang, H., Cui, K. and Zhao, K. (2004) BRG1 controls the activity of the
retinoblastoma protein via regulation of p21CIP1/WAF1/SDI. Molecular and
cellular biology, 24, 1188-1199.
55. Napolitano, M.A., Cipollaro, M., Cascino, A., Melone, M.A., Giordano, A. and
Galderisi, U. (2007) Brg1 chromatin remodeling factor is involved in cell growth
arrest, apoptosis and senescence of rat mesenchymal stem cells. Journal of cell
science, 120, 2904-2911.
56. Ito, T., Watanabe, H., Yamamichi, N., Kondo, S., Tando, T., Haraguchi, T.,
Mizutani, T., Sakurai, K., Fujita, S., Izumi, T. et al. (2008) Brm transactivates the
telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns
of its transcripts in concert with p54(nrb). The Biochemical journal, 411, 201-209.
57. Bultman, S., Gebuhr, T., Yee, D., La Mantia, C., Nicholson, J., Gilliam, A.,
Randazzo, F., Metzger, D., Chambon, P., Crabtree, G. et al. (2000) A Brg1 null
mutation in the mouse reveals functional differences among mammalian SWI/SNF
complexes. Molecular cell, 6, 1287-1295.
58. Wong, A.K., Shanahan, F., Chen, Y., Lian, L., Ha, P., Hendricks, K., Ghaffari, S.,
61
Iliev, D., Penn, B., Woodland, A.M. et al. (2000) BRG1, a component of the
SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer research,
60, 6171-6177.
59. Tang, Z., Zhao, Y., Mei, F., Yang, S., Li, X., Lv, J., Hou, L. and Zhang, B. (2004)
Molecular cloning and characterization of a human gene involved in transcriptional
regulation of hTERT. Biochemical and biophysical research communications, 324,
1324-1332.
60. Zhao, Y., Zheng, J., Ling, Y., Hou, L. and Zhang, B. (2005) Transcriptional
upregulation of DNA polymerase beta by TEIF. Biochemical and biophysical
research communications, 333, 908-916.
61. Gong, Y., Sun, Y., McNutt, M.A., Sun, Q., Hou, L., Liu, H., Shen, Q., Ling, Y.,
Chi, Y. and Zhang, B. (2009) Localization of TEIF in the centrosome and its
functional association with centrosome amplification in DNA damage, telomere
dysfunction and human cancers. Oncogene, 28, 1549-1560.
62. Hsu, C.C., Lee, Y.C., Yeh, S.H., Chen, C.H., Wu, C.C., Wang, T.Y., Chen, Y.N.,
Hung, L.Y., Liu, Y.W., Chen, H.K. et al. (2012) 58-kDa microspherule protein
(MSP58) is novel Brahma-related gene 1 (BRG1)-associated protein that modulates
p53/p21 senescence pathway. The Journal of biological chemistry, 287,
22533-22548.
63. Lam, E.W. and Watson, R.J. (1993) An E2F-binding site mediates cell-cycle
regulated repression of mouse B-myb transcription. The EMBO journal, 12,
2705-2713.
64. Wu, R.C. and Schonthal, A.H. (1997) Activation of p53-p21waf1 pathway in
response to disruption of cell-matrix interactions. The Journal of biological
chemistry, 272, 29091-29098.
65. Hsin, I.L., Sheu, G.T., Chen, H.H., Chiu, L.Y., Wang, H.D., Chan, H.W., Hsu, C.P.
and Ko, J.L. (2010) N-acetyl cysteine mitigates curcumin-mediated telomerase
inhibition through rescuing of Sp1 reduction in A549 cells. Mutat Res, 688, 72-77.
66. McCabe, N., Turner, N.C., Lord, C.J., Kluzek, K., Bialkowska, A., Swift, S.,
Giavara, S., O'Connor, M.J., Tutt, A.N., Zdzienicka, M.Z. et al. (2006) Deficiency
in the repair of DNA damage by homologous recombination and sensitivity to
poly(ADP-ribose) polymerase inhibition. Cancer research, 66, 8109-8115.
67. Shats, I., Milyavsky, M., Tang, X., Stambolsky, P., Erez, N., Brosh, R., Kogan, I.,
Braunstein, I., Tzukerman, M., Ginsberg, D. et al. (2004) p53-dependent
down-regulation of telomerase is mediated by p21waf1. The Journal of biological
chemistry, 279, 50976-50985.
68. Zhang, J., Ohta, T., Maruyama, A., Hosoya, T., Nishikawa, K., Maher, J.M.,
62
Shibahara, S., Itoh, K. and Yamamoto, M. (2006) BRG1 interacts with Nrf2 to
selectively mediate HO-1 induction in response to oxidative stress. Molecular and
cellular biology, 26, 7942-7952.
69. Vojtek, A.B. and Hollenberg, S.M. (1995) Ras-Raf interaction: two-hybrid analysis.
Methods in enzymology, 255, 331-342.
70. Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C.B., West, M.D., Ho, P.L.,
Coviello, G.M., Wright, W.E., Weinrich, S.L. and Shay, J.W. (1994) Specific
association of human telomerase activity with immortal cells and cancer. Science,
266, 2011-2015.
71. Wright, W.E., Shay, J.W. and Piatyszek, M.A. (1995) Modifications of a telomeric
repeat amplification protocol (TRAP) result in increased reliability, linearity and
sensitivity. Nucleic acids research, 23, 3794-3795.
72. Falchetti, M.L., Levi, A., Molinari, P., Verna, R. and D'Ambrosio, E. (1998)
Increased sensitivity and reproducibility of TRAP assay by avoiding direct primers
interaction. Nucleic acids research, 26, 862-863.
73. Chen, C.H., Lu, P.J., Chen, Y.C., Fu, S.L., Wu, K.J., Tsou, A.P., Lee, Y.C., Lin,
T.C., Hsu, S.L., Lin, W.J. et al. (2007) FLJ10540-elicited cell transformation is
through the activation of PI3-kinase/AKT pathway. Oncogene, 26, 4272-4283.
74. Fujita, M., Inoue, M., Tanizawa, O., Iwamoto, S. and Enomoto, T. (1992)
Alterations of the p53 gene in human primary cervical carcinoma with and without
human papillomavirus infection. Cancer research, 52, 5323-5328.
75. Reiss, M., Brash, D.E., Munoz-Antonia, T., Simon, J.A., Ziegler, A., Vellucci, V.F.
and Zhou, Z.L. (1992) Status of the p53 tumor suppressor gene in human squamous
carcinoma cell lines. Oncology research, 4, 349-357.
76. Song, H., Li, Y., Chen, G., Xing, Z., Zhao, J., Yokoyama, K.K., Li, T. and Zhao, M.
(2004) Human MCRS2, a cell-cycle-dependent protein, associates with
LPTS/PinX1 and reduces the telomere length. Biochemical and biophysical
research communications, 316, 1116-1123.
77. Ferbeyre, G., de Stanchina, E., Lin, A.W., Querido, E., McCurrach, M.E., Hannon,
G.J. and Lowe, S.W. (2002) Oncogenic ras and p53 cooperate to induce cellular
senescence. Molecular and cellular biology, 22, 3497-3508.
78. Pearson, M., Carbone, R., Sebastiani, C., Cioce, M., Fagioli, M., Saito, S.,
Higashimoto, Y., Appella, E., Minucci, S., Pandolfi, P.P. et al. (2000) PML
regulates p53 acetylation and premature senescence induced by oncogenic Ras.
Nature, 406, 207-210.
79. Shieh, S.Y., Ikeda, M., Taya, Y. and Prives, C. (1997) DNA damage-induced
phosphorylation of p53 alleviates inhibition by MDM2. Cell, 91, 325-334.
63
80. Zou, L. and Elledge, S.J. (2003) Sensing DNA damage through ATRIP recognition
of RPA-ssDNA complexes. Science (New York, N.Y, 300, 1542-1548.
81. Allen, M.D., Religa, T.L., Freund, S.M. and Bycroft, M. (2007) Solution structure
of the BRK domains from CHD7. Journal of molecular biology, 371, 1135-1140.
82. el-Deiry, W.S., Tokino, T., Velculescu, V.E., Levy, D.B., Parsons, R., Trent, J.M.,
Lin, D., Mercer, W.E., Kinzler, K.W. and Vogelstein, B. (1993) WAF1, a potential
mediator of p53 tumor suppression. Cell, 75, 817-825.
83. Shi, H., Chen, S., Jin, H., Xu, C., Dong, G., Zhao, Q., Wang, W., Zhang, H., Lin,
W., Zhang, J. et al. (2009) Downregulation of MSP58 inhibits growth of human
colorectal cancer cells via regulation of the cyclin D1-cyclin-dependent kinase
4-p21 pathway. Cancer science, 100, 1585-1590.
84. Meyerson, M., Counter, C.M., Eaton, E.N., Ellisen, L.W., Steiner, P., Caddle, S.D.,
Ziaugra, L., Beijersbergen, R.L., Davidoff, M.J., Liu, Q. et al. (1997) hEST2, the
putative human telomerase catalytic subunit gene, is up-regulated in tumor cells
and during immortalization. Cell, 90, 785-795.
85. Poole, J.C., Andrews, L.G. and Tollefsbol, T.O. (2001) Activity, function, and gene
regulation of the catalytic subunit of telomerase (hTERT). Gene, 269, 1-12.
86. Andersen, D.S., Raja, S.J., Colombani, J., Shaw, R.L., Langton, P.F., Akhtar, A.
and Tapon, N. (2010) Drosophila MCRS2 associates with RNA polymerase II
complexes to regulate transcription. Molecular and cellular biology, 30,
4744-4755.
87. Bartkova, J., Horejsi, Z., Koed, K., Kramer, A., Tort, F., Zieger, K., Guldberg, P.,
Sehested, M., Nesland, J.M., Lukas, C. et al. (2005) DNA damage response as a
candidate anti-cancer barrier in early human tumorigenesis. Nature, 434, 864-870.
88. Mallette, F.A., Gaumont-Leclerc, M.F. and Ferbeyre, G. (2007) The DNA damage
signaling pathway is a critical mediator of oncogene-induced senescence. Genes &
development, 21, 43-48.
89. Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D. and Lowe, S.W. (1997)
Oncogenic ras provokes premature cell senescence associated with accumulation of
p53 and p16INK4a. Cell, 88, 593-602.
90. Drost, J., Mantovani, F., Tocco, F., Elkon, R., Comel, A., Holstege, H., Kerkhoven,
R., Jonkers, J., Voorhoeve, P.M., Agami, R. et al. BRD7 is a candidate tumour
suppressor gene required for p53 function. Nature cell biology, 12, 380-389.
91. Lee, D., Kim, J.W., Seo, T., Hwang, S.G., Choi, E.J. and Choe, J. (2002) SWI/SNF
complex interacts with tumor suppressor p53 and is necessary for the activation of
p53-mediated transcription. The Journal of biological chemistry, 277,
22330-22337.
64
92. Xu, Y., Zhang, J. and Chen, X. (2007) The activity of p53 is differentially regulated
by Brm- and Brg1-containing SWI/SNF chromatin remodeling complexes. The
Journal of biological chemistry, 282, 37429-37435.
93. Zhang, H.S., Gavin, M., Dahiya, A., Postigo, A.A., Ma, D., Luo, R.X., Harbour,
J.W. and Dean, D.C. (2000) Exit from G1 and S phase of the cell cycle is regulated
by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell,
101, 79-89.
94. Cai, Y., Jin, J., Swanson, S.K., Cole, M.D., Choi, S.H., Florens, L., Washburn,
M.P., Conaway, J.W. and Conaway, R.C. (2010) Subunit composition and substrate
specificity of a MOF-containing histone acetyltransferase distinct from the
male-specific lethal (MSL) complex. The Journal of biological chemistry, 285,
4268-4272.
95. Crowe, D.L. and Nguyen, D.C. (2001) Rb and E2F-1 regulate telomerase activity in
human cancer cells. Biochimica et biophysica acta, 1518, 1-6.
96. Won, J., Yim, J. and Kim, T.K. (2002) Opposing regulatory roles of E2F in human
telomerase reverse transcriptase (hTERT) gene expression in human tumor and
normal somatic cells. FASEB journal : official publication of the Federation of
American Societies for Experimental Biology, 16, 1943-1945.
97. Hallstrom, T.C. and Nevins, J.R. (2006) Jab1 is a specificity factor for
E2F1-induced apoptosis. Genes & development, 20, 613-623.
98. Yao, Y., Bellon, M., Shelton, S.N. and Nicot, C. (2012) Tumor suppressors p53,
p63TAalpha, p63TAy, p73alpha, and p73beta use distinct pathways to repress
telomerase expression. The Journal of biological chemistry, 287, 20737-20747.
99. Okawa, T., Michaylira, C.Z., Kalabis, J., Stairs, D.B., Nakagawa, H., Andl, C.D.,
Johnstone, C.N., Klein-Szanto, A.J., El-Deiry, W.S., Cukierman, E. et al. (2007)
The functional interplay between EGFR overexpression, hTERT activation, and
p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts
induces tumor development, invasion, and differentiation. Genes & development,
21, 2788-2803.
100. Smith, L.L., Coller, H.A. and Roberts, J.M. (2003) Telomerase modulates
expression of growth-controlling genes and enhances cell proliferation. Nature cell
biology, 5, 474-479.
101. Chang, J.T., Yang, H.T., Wang, T.C. and Cheng, A.J. (2005) Upstream stimulatory
factor (USF) as a transcriptional suppressor of human telomerase reverse
transcriptase (hTERT) in oral cancer cells. Molecular carcinogenesis, 44, 183-192.
102. Horikawa, I., Cable, P.L., Mazur, S.J., Appella, E., Afshari, C.A. and Barrett, J.C.
(2002) Downstream E-box-mediated regulation of the human telomerase reverse
65
transcriptase (hTERT) gene transcription: evidence for an endogenous mechanism
of transcriptional repression. Molecular biology of the cell, 13, 2585-2597.
103. Goueli, B.S. and Janknecht, R. (2003) Regulation of telomerase reverse
transcriptase gene activity by upstream stimulatory factor. Oncogene, 22,
8042-8047.
104. Racek, T., Mise, N., Li, Z., Stoll, A. and Putzer, B.M. (2005) C-terminal p73
isoforms repress transcriptional activity of the human telomerase reverse
transcriptase (hTERT) promoter. The Journal of biological chemistry, 280,
40402-40405.
105. Beitzinger, M., Oswald, C., Beinoraviciute-Kellner, R. and Stiewe, T. (2006)
Regulation of telomerase activity by the p53 family member p73. Oncogene, 25,
813-826.
106. Toh, W.H., Kyo, S. and Sabapathy, K. (2005) Relief of p53-mediated telomerase
suppression by p73. The Journal of biological chemistry, 280, 17329-17338.
107. Liang, Y., Liu, M., Wang, P., Ding, X. and Cao, Y. (2013) Analysis of 20 genes at
chromosome band 12q13: RACGAP1 and MCRS1 overexpression in nonsmall-cell
lung cancer. Genes, chromosomes & cancer, 52, 305-315.
108. Hahn, W.C., Stewart, S.A., Brooks, M.W., York, S.G., Eaton, E., Kurachi, A.,
Beijersbergen, R.L., Knoll, J.H., Meyerson, M. and Weinberg, R.A. (1999)
Inhibition of telomerase limits the growth of human cancer cells. Nature medicine,
5, 1164-1170.
109. Zhang, X., Mar, V., Zhou, W., Harrington, L. and Robinson, M.O. (1999) Telomere
shortening and apoptosis in telomerase-inhibited human tumor cells. Genes &
development, 13, 2388-2399.
110. Wu, L., Zhang, Z.G., Qin, H.Z., Zhang, J., Gao, G.D., Lin, W., Wang, J. and Zhang,
J. (2012) Downregulation of MSP58 suppresses cell proliferation in neuroblastoma
cell lines. Neuroreport, 23, 932-936.
111. Xu, C.S., Zheng, J.Y., Zhang, H.L., Zhao, H.D., Zhang, J., Wu, G.Q., Wu, L.,
Wang, Q., Wang, W.Z. and Zhang, J. (2012) MSP58 knockdown inhibits the
proliferation of esophageal squamous cell carcinoma in vitro and in vivo. Asian
Pacific journal of cancer prevention : APJCP, 13, 3233-3238.
112. Lin, W., Zhang, J., Zhang, J., Liu, X., Fei, Z., Li, X., Davidovic, L., Tang, Z., Shen,
L., Deng, Y. et al. (2009) RNAi-mediated inhibition of MSP58 decreases tumour
growth, migration and invasion in a human glioma cell line. Journal of cellular and
molecular medicine, 13, 4608-4622.
113. Che-Chia Hsu. (2009) Molecular mechanism of cell cycle control and senescence
by the 58-kDa Microspherule protein (MSP58), Master’s thesis, Department of
66
Pharmacology, College of Medicine, National Cheng Kung University, Tainan,
Taiwan
114. Tsui-Ying Wang. (2010) Functional analysis of a novel candidate oncogene, 58-kDa
microspherule protein (MSP58), Master’s thesis, Department of Pharmacology,
College of Medicine, National Cheng Kung University, Tainan, Taiwan
115. Yu-Nong Chen. (2008) Overexpression of the Microspherule Protein 58 (MSP58)
gene induces senescence-like state in HT1080 cells, Master’s thesis, Department of
Pharmacology, College of Medicine, National Cheng Kung University, Tainan,
Taiwan