Rb Protein is Essential to the Senescence-Associated Heterochromatic Foci Formation Induced by HMGA2 in Primary WI38 Cells

a.
The Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun 130024, China
b.
The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China
c.
School of Life Sciences, Changchun Normal University, Changchun 130032, China

More Information

Corresponding author: E-mail address: zhangy288@nenu.edu.cn (Yu Zhang)

摘要

- /
- /
- /
Abstract: Cellular senescence is an irreversible form of cell cycle arrest that provides a barrier to neoplastic transformation. The integrity of the Rb (Retinoblastoma) pathway is necessary for the formation of the senescence-associated heterochromatin foci (SAHF) that offers a molecular basis for the stability of the senescent state. Surprisingly, although high mobility group A2 protein (HMGA2) can promote tumorigenesis and inhibit Rb function in tumor cells, high-level expression of HMGA2 is sufficient to induce SAHF formation in primary cells. It therefore becomes significant to determine whether Rb protein is necessary in HMGA2-induced SAHF formation. In this study, we established the cellular senescence and SAHF assembly WI38 cell model by ectopic expression of HMGA2, in which typical senescent markers were seen, including notable upregulation of p53, p21 and p16, and elevated SA-β-galactosidase staining together with downregulation of E2F target genes. We then showed that the Rb pathway inhibitor E7 protein was able to partly abolish the ability of SAHF formation after HMGA2 expression in WI38 cells, indicating that Rb is a crucial factor for HMGA2-induced SAHF formation. However, Rb depletion did not completely rescue the cell growth arrest induced by HMGA2, suggesting that Rb is not an exclusive pathway for HMGA2-induced senescence in WI38 cells.
- HMGA2 /
- SAHF /
- Cellular senescence /
- Rb

HTML全文

参考文献(41)

[1]	Ait-Si-Ali, S., Guasconi, V., Fritsch, L. et al. A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells EMBO J., 23 (2004),pp. 605-615
[2]	Allegri, R.F., Sarasola, D., Serrano, C.M. et al. Neuropsychiatric symptoms as a predictor of caregiver burden in Alzheimer's disease Neuropsychiatr. Dis. Treat., 2 (2006),pp. 105-110
[3]	Bakkenist, C.J., Drissi, R., Wu, J. et al. Disappearance of the telomere dysfunction-induced stress response in fully senescent cells Cancer Res., 64 (2004),pp. 3748-3752
[4]	Ben-Porath, I., Weinberg, R.A. When cells get stressed: an integrative view of cellular senescence J. Clin. Invest., 113 (2004),pp. 8-13
[5]	Berezutskaya, E., Yu, B., Morozov, A. et al. Differential regulation of the pocket domains of the retinoblastoma family proteins by the HPV16 E7 oncoprotein Cell Growth Differ., 8 (1997),pp. 1277-1286
[6]	Bodnar, A.G., Ouellette, M., Frolkis, M. et al. Extension of life-span by introduction of telomerase into normal human cells Science, 279 (1998),pp. 349-352
[7]	Campisi, J. Cellular senescence as a tumor-suppressor mechanism Trends Cell Biol., 11 (2001),pp. S27-S31
[8]	Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors Cell, 120 (2005),pp. 513-522
[9]	Campisi, J., d'Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells Nat. Rev. Mol. Cell Biol., 8 (2007),pp. 729-740
[10]	Chandra, T., Kirschner, K., Thuret, J.Y. et al. Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation Mol. Cell, 47 (2012),pp. 203-214
[11]	Collado, M., Serrano, M. The power and the promise of oncogene-induced senescence markers Nat. Rev. Cancer, 6 (2006),pp. 472-476
[12]	Dantur, K., Alonso, L., Castano, E. et al. Cytosolic accumulation of HPV16 E7 oligomers supports different transformation routes for the prototypic viral oncoprotein: the amyloid-cancer connection Int. J. Cancer, 125 (2009),pp. 1902-1911
[13]	DeFilippis, R.A., Goodwin, E.C., Wu, L. et al. Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells J. Virol., 77 (2003),pp. 1551-1563
[14]	Dimri, G.P., Hara, E., Campisi, J. Regulation of two E2F-related genes in presenescent and senescent human fibroblasts J. Biol. Chem., 269 (1994),pp. 16180-16186
[15]	Dimri, G.P., Lee, X., Basile, G. et al. Proc. Natl. Acad. Sci. USA, 92 (1995),pp. 9363-9367
[16]	Dimri, G.P., Testori, A., Acosta, M. et al. Replicative senescence, aging and growth-regulatory transcription factors Biol. Signals, 5 (1996),pp. 154-162
[17]	Droge, P., Davey, C.A. Do cells let-7 determine stemness? Cell Stem Cell, 2 (2008),pp. 8-9
[18]	Fedele, M., Battista, S., Kenyon, L. et al. Oncogene, 21 (2002),pp. 3190-3198
[19]	Fedele, M., Fusco, A. HMGA and cancer Biochim. Biophys. Acta, 1799 (2010),pp. 48-54
[20]	Fedele, M., Visone, R., De Martino, I. et al. HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity Cancer Cell, 9 (2006),pp. 459-471
[21]	Funayama, R., Saito, M., Tanobe, H. et al. Loss of linker histone H1 in cellular senescence J. Cell Biol., 175 (2006),pp. 869-880
[22]	Harley, C.B., Futcher, A.B., Greider, C.W. Telomeres shorten during ageing of human fibroblasts Nature, 345 (1990),pp. 458-460
[23]	Hayflick, L. Exp. Cell Res., 37 (1965),pp. 614-636
[24]	Helt, A.M., Galloway, D.A. Destabilization of the retinoblastoma tumor suppressor by human papillomavirus type 16 E7 is not sufficient to overcome cell cycle arrest in human keratinocytes J. Virol., 75 (2001),pp. 6737-6747
[25]	Herbig, U., Ferreira, M., Condel, L. et al. Cellular senescence in aging primates Science, 311 (2006),p. 1257
[26]	Jeyapalan, J.C., Sedivy, J.M. Cellular senescence and organismal aging Mech. Ageing Dev., 129 (2008),pp. 467-474
[27]	Johnson, K.R., Lehn, D.A., Reeves, R. Alternative processing of mRNAs encoding mammalian chromosomal high-mobility-group proteins HMG-I and HMG-Y Mol. Cell Biol., 9 (1989),pp. 2114-2123
[28]	Manfioletti, G., Giancotti, V., Bandiera, A. et al. cDNA cloning of the HMGI-C phosphoprotein, a nuclear protein associated with neoplastic and undifferentiated phenotypes Nucleic Acids Res., 19 (1991),pp. 6793-6797
[29]	Mathon, N.F., Lloyd, A.C. Cell senescence and cancer Nat. Rev. Cancer, 1 (2001),pp. 203-213
[30]	Nagpal, S., Ghosn, C., DiSepio, D. et al. Retinoid-dependent recruitment of a histone H1 displacement activity by retinoic acid receptor J. Biol. Chem., 274 (1999),pp. 22563-22568
[31]	Narita, M. Cellular senescence and chromatin organisation Br. J. Cancer, 96 (2007),pp. 686-691
[32]	Narita, M., Narita, M., Krizhanovsky, V. et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation Cell, 126 (2006),pp. 503-514
[33]	Narita, M., Nunez, S., Heard, E. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence Cell, 113 (2003),pp. 703-716
[34]	Nielsen, S.J., Schneider, R., Bauer, U.M. et al. Rb targets histone H3 methylation and HP1 to promoters Nature, 412 (2001),pp. 561-565
[35]	Schulz, L., Tyler, J. Heterochromatin focuses on senescence Mol. Cell, 17 (2005),pp. 168-170
[36]	Serrano, M., Lin, A.W., McCurrach, M.E. et al. Cell, 88 (1997),pp. 593-602
[37]	Sgarra, R., Zammitti, S., Lo Sardo, A. et al. HMGA molecular network: from transcriptional regulation to chromatin remodeling Biochim. Biophys. Acta, 1799 (2010),pp. 37-47
[38]	Shay, J.W., Wright, W.E. Senescence and immortalization: role of telomeres and telomerase Carcinogenesis, 26 (2005),pp. 867-874
[39]	von Zglinicki, T., Saretzki, G., Ladhoff, J. et al. Human cell senescence as a DNA damage response Mech. Ageing Dev., 126 (2005),pp. 111-117
[40]	Wang, X., Pan, L., Feng, Y. et al. P300 plays a role in p16(INK4a) expression and cell cycle arrest Oncogene, 27 (2008),pp. 1894-1904
[41]	Zhang, Y., Gao, Y., Zhang, G. et al. DNMT3a plays a role in switches between doxorubicin-induced senescence and apoptosis of colorectal cancer cells Int. J. Cancer, 128 (2011),pp. 551-561