Abstract
Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30–40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated β-galactosidase (SA-β-gal). Levels of p16INK4a and p57KIP2 rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19INK4d and p27KIP1 decrease in both cell types. We find that p53, p21CIP1 and p15INK4b are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21CIP1, p15INK4b, p16INK4a, and p57KIP2 reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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References
Belair CD, Yeager TR, Lopez PM, Reznikoff CA . 1997 Proc. Natl. Acad. Sci. USA 94: 13677–13682
Bright RK, Vocke CD, Emmert-Buck MR, Duray PH, Solomon D, Fetsch P, Rhim JS, Linehan WM, Topalian SL . 1997 Cancer Res. 57: 995–1002
Burkhart BA, Alcorta DA, Chiao C, Isaacs JS, Barrett JC . 1999 Exp. Cell. Res. 247: 168–175
Campisi J . 2000 In Vivo. 14: 183–188
Chang BD, Broude EV, Dokmanovic M, Zhu H, Ruth A, Xuan Y, Kandel ES, Lausch E, Christov K, Roninson IB . 1999 Cancer Res. 59: 3761–3767
Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ . 1999 EMBO. J. 18: 1571–1583
Choi J, Shendrik I, Peacocke M, Peehl D, Buttyan R, Ikeguchi EF, Katz AE, Benson MC . 2000 Urology 56: 160–166
Dimri GP, Itahana K, Acosta M, Campisi J . 2000 Mol. Cell. Biol. 20: 273–285
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J . 1995 Proc. Natl. Acad. Sci. USA 92: 9363–9367
Dyer MA, Cepko CL . 2000 Development 127: 3593–3605
England NL, Cuthbert AP, Trott DA, Jezzard S, Nobori T, Carson DA, Newbold RF . 1996 Carcinogenesis 17: 1567–1575
Fanton CP, McMahon M, Pieper RO . 2001 J. Biol. Chem. 276: 18871–18877
Fink JR, LeBien TW . 2001 Exp. Hematol. 29: 490–498
Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA . 1997 Genes Dev. 11: 2090–2100
Greenlee RT, Hill-Harmon MB, Murray T, Thun M . 2001 Ca Cancer J. Clin. 51: 15–36
Halbert CL, Demers GW, Galloway DA . 1991 J. Virol. 65: 473–478
Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G . 1996 Mol. Cell. Biol. 16: 859–867
Hayflick L . 1965 Exp. Cell. Res. 25: 585–621
Herman JG, Jen J, Merlo A, Baylin SB . 1996 Cancer Res. 56: 722–727
Itahana K, Dimri G, Campisi J . 2001 Eur. J. Biochem. 268: 2784–2791
Jarrard DF, Sarkar S, Shi Y, Yeager TR, Magrane G, Kinoshita H, Nassif N, Meisner L, Newton MA, Waldman FM, Reznikoff CA . 1999 Cancer Res. 59: 2957–2964
Kaelin Jr WG . 1999 Bioessays 21: 950–958
Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ . 1997 Cell 91: 649–659
Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, Brothman AR, Lamb DJ, Marcelli M, Belldegrun A, Witte ON, Sawyers CL . 1997 Nat. Med. 3: 402–408
Lissy NA, Van Dyk LF, Becker-Hapak M, Vocero-Akbani A, Mendler JH, Dowdy SF . 1998 Immunity 8: 57–65
McConnell BB, Starborg M, Brookes S, Peters G . 1998 Curr. Biol. 8: 351–354
Morrison TB, Weis JJ, Wittwer CT . 1998 Biotechniques 24: 954–958, 960, 962
Nagahama H, Hatakeyama S, Nakayama K, Nagata M, Tomita K . 2001 Anat. Embryol. (Berl.) 203: 77–87
Nijjar T, Wigington D, Garbe JC, Waha A, Stampfer MR, Yaswen P . 1999 Cancer Res. 59: 5112–5118
Oya M, Schulz WA . 2000 Br. J. Cancer 83: 626–631
Pardee AB . 1989 Science 246: 603–608
Ran Q, Pereira-Smith OM . 2000 Exp. Gerontol. 35: 7–13
Reynaud EG, Leibovitch MP, Tintignac LA, Pelpel K, Guillier M, Leibovitch SA . 2000 J. Biol. Chem. 275: 18767–18776
Reznikoff CA, Belair C, Savelieva E, Zhai Y, Pfeifer K, Yeager T, Thompson KJ, DeVries S, Bindley C, Newton MA et al. 1994 Genes Dev. 8: 2227–2240
Reznikoff CA, Johnson MD, Norback DH, Bryan GT . 1983 In Vitro 19: 326–343
Reznikoff CA, Loretz LJ, Pesciotta DM, Oberley TD, Ignjatovic MM . 1987 J. Cell. Physiol. 131: 285–301
Reznikoff CA, Yeager TR, Belair CD, Savelieva E, Puthenveettil JA, Stadler WM . 1996 Cancer Res. 56: 2886–2890
Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD . 2001 Nature 409: 633–637
Sandhu C, Peehl DM, Slingerland J . 2000 Cancer Res. 60: 2616–2622
Sarkar S, Julicher KP, Burger MS, Della Valle V, Larsen CJ, Yeager TR, Grossman TB, Nickells RW, Protzel C, Jarrard DF, Reznikoff CA . 2000 Cancer Res. 60: 3862–3871
Sasaki M, Honda T, Yamada H, Wake N, Barrett JC, Oshimura M . 1994 Cancer Res. 54: 6090–6093
Savelieva E, Belair CD, Newton MA, DeVries S, Gray JW, Waldman F, Reznikoff CA . 1997 Oncogene 14: 551–560
Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . 1997 Cell 88: 593–602
Sherr CJ, DePinho RA . 2000 Cell 102: 407–410
Sherr CJ, Roberts JM . 1999 Genes Dev. 13: 1501–1512
Solomon MJ, Kaldis P . 1998 Results Probl. Cell. Differ. 22: 79–109
Staller P, Peukert K, Kiermaier A, Seoane J, Lukas J, Karsunky H, Moroy T, Bartek J, Massague J, Hanel F, Eilers M . 2001 Nat. Cell. Biol. 3: 392–399
Tanaka H, Shimizu M, Horikawa I, Kugoh H, Yokota J, Barrett JC, Oshimura M . 1998 Genes Chromosomes Cancer 23: 123–133
Taniguchi T, Okamoto K, Reeve AE . 1997 Oncogene 14: 1201–1206
Tsugu A, Sakai K, Dirks PB, Jung S, Weksberg R, Fei YL, Mondal S, Ivanchuk S, Ackerley C, Hamel PA, Rutka JT . 2000 Am. J. Pathol. 157: 919–932
Vogt M, Haggblom C, Yeargin J, Christiansen-Weber T, Haas M . 1998 Cell. Growth Differ. 9: 139–146
Weinberg RA . 1995 Cell 81: 323–330
Wittwer CT, Herrmann MG, Moss AA, Rasmussen RP . 1997 Biotechniques 22: 130–131, 134–138
Xiong Y, Kuppuswamy D, Li Y, Livanos EM, Hixon M, White A, Beach D, Tlsty TD . 1996 J. Virol. 70: 999–1008
Yeager TR, DeVries S, Jarrard DF, Kao C, Nakada SY, Moon TD, Bruskewitz R, Stadler WM, Meisner LF, Gilchrist KW, Newton MA, Waldman FM, Reznikoff CA . 1998 Genes Dev. 12: 163–174
Young JI, Smith JR . 2001 J. Biol. Chem. 276: 19610–19616
Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA, Elledge SJ . 1997 Nature 387: 151–158
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This work was supported by National Institutes of Health number CA76184-01 and the University of Wisconsin Comprehensive Cancer Center.
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Schwarze, S., Shi, Y., Fu, V. et al. Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. Oncogene 20, 8184–8192 (2001). https://doi.org/10.1038/sj.onc.1205049
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DOI: https://doi.org/10.1038/sj.onc.1205049
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