Abstract
Bcl-2 is the prototype of a family of genes that prevent apoptosis. However, several reports indicate that Bcl-2 may also act as a cell cycle modulator. In several human tumors, Bcl-2 expression correlates with a more favorable prognosis and lower tumor proliferative activity. We have shown that Bcl-2 expression delays liver tumor development in transgenic mice even when the gene is turned on shortly before the time of tumor development. We hypothesized that Bcl-2 may delay liver tumorigenesis by interfering with hepatocyte proliferation. To test whether Bcl-2 expression may act on hepatocyte replication we studied liver regeneration in Bcl-2 transgenic mice and wild-type littermates. DNA replication was delayed by approximately 8 h in Bcl-2 transgenic mice compared to the timing of the response in wild-type littermates. Cyclin D expression showed no alterations in the regenerating liver of Bcl-2 transgenic mice. In contrast, there was a delay in the expression of p107, cyclin E and in the activity of cyclin E/cdk 2 activity. These results show that Bcl-2 expression delays cell cycle progression in hepatocytes and suggests that it acts at a step involving cyclin E and p107.
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References
Borner C . 1996 J. Biol. Chem. 271: 12695–12698
Classon M, Dyson N . 2001 Exp. Cell Res. 264: 135–147
de La Coste A, Mignon A, Fabre M, Gilbert E, Porteu A, Van Dyke T, Kahn A, Perret C . 1999 Cancer Res. 59: 5017–5022
Dyson N . 1998 Genes Dev. 12: 2245–2262
Fausto N . 2000 J. Hepatol. 32: 19–31
Furth PA, Bar-Peled U, Li M, Lewis A, Laucirica R, Jager R, Weiher H, Russell RG . 1999 Oncogene 18: 6589–6596
Garriga J, Limon A, Mayol X, Rane SG, Albrecht JH, Reddy EP, Andres V, Grana X . 1998 Biochem. J. 333: 645–654
Huang DC, O'Reilly LA, Strasser A, Cory S . 1997 EMBO J. 16: 4628–4638
Korsmeyer SJ . 1992 Cancer Surv. 15: 105–118
Kuwashima Y, Kobayashi Y, Kurosumi M, Tanuma J, Shiromizu K, Kishi K . 1997 Anticancer Res. 17: 3773–3776
Lin HM, Lee YJ, Li G, Pestell RG, Kim HR . 2001 Cell Death Differ 8: 44–50
Linette GP, Li Y, Roth K, Korsmeyer SJ . 1996 Proc. Natl. Acad. Sci. USA 93: 9545–9552
Mazel S, Burtrum D, Petrie HT . 1996 J. Exp. Med. 183: 2219–2226
Murphy KL, Kittrell FS, Gay JP, Jager R, Medina D, Rosen JM . 1999 Oncogene 18: 6597–6604
Nelsen CJ, Hansen LK, Rickheim DG, Chen C, Stanley MW, Krek W, Albrecht JH . 2001 Oncogene 20: 1825–1831
Nevins JR . 1998 Cell Growth Differ 9: 585–593
O'Reilly LA, Harris AW, Strasser A . 1997 Int. Immunol. 9: 1291–1301
O'Reilly LA, Huang DC, Strasser A . 1996 EMBO J. 15: 6979–6990
Sherr CJ, Roberts JM . 1999 Genes Dev. 13: 1501–1512
Silvestrini R, Benini E, Veneroni S, Daidone MG, Tomasic G, Squicciarini P, Salvadori B . 1996 J. Clin. Oncol. 14: 1604–1610
Sinicrope FA, Hart J, Michelassi F, Lee JJ . 1995 Clin. Cancer Res. 1: 1103–1110
Truchet I, Jozan S, Guerrin M, Mazzolini L, Vidal S, Valette A . 2000 Exp. Cell Res. 254: 241–248
Tzung SP, Fausto N, Hockenbery DM . 1997 Am. J. Pathol. 150: 1985–1995
Vail ME, Pierce RH, Fausto N . 2001 Cancer Res. 61: 594–601
Vairo G, Innes KM, Adams JM . 1996 Oncogene 13: 1511–1519
Vairo G, Soos TJ, Upton TM, Zalvide J, DeCaprio JA, Ewen ME, Koff A, Adams JM . 2000 Mol. Cell Biol. 20: 4745–4753
Webber EM, Wu JC, Wang L, Merlino G, Fausto N . 1994 Am. J. Pathol. 145: 398–408
Winter JN, Andersen J, Reed JC, Krajewski S, Variakojis D, Bauer KD, Fisher RI, Gordon LI, Oken MM, Jiang S, Jeffries D, Domer P . 1998 Blood 91: 1391–1398
Wu JC, Merlino G, Fausto N . 1994 Proc. Natl. Acad. Sci. USA 91: 674–678
Acknowledgements
We thank Gretchen Argast for additional help with partial hepatectomies; John Brooling for technical assistance with the animals and members of the Fausto lab for helpful discussions. This work was supported by grant CA74131 from the National Cancer Institute (NCI). Further support was provided to M Vail and M Chaisson by PHS National Research Grant T32 GMO7270 and to M Chaisson by National Research Service Award CA 09437.
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Vail, M., Chaisson, M., Thompson, J. et al. Bcl-2 expression delays hepatocyte cell cycle progression during liver regeneration. Oncogene 21, 1548–1555 (2002). https://doi.org/10.1038/sj.onc.1205212
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DOI: https://doi.org/10.1038/sj.onc.1205212
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