Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

BCL-xL and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases

Abstract

The anti-apoptotic molecules BCL-xL and BCL2 delay cell cycle entry from quiescence. We used serum induction and induction of a Myc-estrogen receptor fusion protein (MycER) in quiescent fibroblasts to investigate the mechanisms underlying the cell cycle activity of BCL-xL and BCL2. We demonstrate for the first time that BCL-xL and BCL2 delayed serum-induced and Myc-induced, but not E2F-induced, cell cycle entry. The cyclin-dependent kinase inhibitor p27 was elevated during serum deprivation and cell cycle entry in BCL-xL or BCL2-expressing NIH3T3 cells and a Rat1MycER cell line. Activation of cyclin-dependent kinase 2 (cdk2) and cyclin-dependent kinase 4 (cdk4) were delayed during progression to S phase, while the induction of cyclin D1 protein, as well as the levels of cyclin E, cdk2, and cdk4 were unaltered by BCL-xL or BCL2. Inhibition of cyclin/cdk activities in BCL-xL or BCL2 expressing cells was associated with excess p27 in the cyclin/cdk complexes. Neither BCL-xL nor BCL2 delayed S phase entry in cells deficient in p27, thus p27 is required for the cell cycle function of BCL-xL and BCL2. The cell cycle effects of BCL-xL and BCL2 were more profound in Myc-induced than in serum-induced cell cycle entry. Our results suggest that one possible mechanism by which BCL-xL and BCL2 delay cell cycle entry may be the inhibition of Myc activity through the elevation of p27.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 6
Figure 4
Figure 5
Figure 7

Similar content being viewed by others

References

  • Adams MR, Sears R, Nuckolls F, Leone G, Nevins JR . 2000 Mol. Cell Biol. 20: 3633–3639

  • Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, Reed S, Sicinski P, Bartek J, Eilers M . 1999 EMBO J. 18: 5321–5333

  • Brady HJ, Gil-Gomez G, Kirberg J, Berns AJ . 1996 EMBO J. 15: 6991–7001

  • Chattopadhyay A, Chiang CW, Yang E . 2001 Oncogene 20: 4507–4518

  • Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Sherr CJ . 1999 EMBO J. 18: 1571–1583

  • Cory S, Vaux DL, Strasser A, Harris AW, Adams JM . 1999 Cancer Res. 59: 1685s–1692s

  • Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW, Burgering BM, Raaijmakers JA, Lammers JW, Koenderman L, Coffer PJ . 2000 Mol. Cell Biol. 20: 9138–9148

  • Eilers M, Schirm S, Bishop JM . 1991 EMBO J. 10: 133–141

  • Eischen CM, Packham G, Nip J, Fee BE, Hiebert SW, Zambetti GP, Cleveland JL . 2001a Oncogene 20: 6983–6993

  • Eischen CM, Woo D, Roussel MF, Cleveland JL . 2001b Mol. Cell Biol. 21: 5063–5070

  • Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ, Hancock DC . 1992 Cell 69: 119–128

  • Fanidi A, Harrington EA, Evan GI . 1992 Nature 359: 554–556

  • Hengstschlager M, Holzl G, Hengstschlager-Ottnad E . 1999 Oncogene 18: 843–848

  • Huang DC, O'Reilly LA, Strasser A, Cory S . 1997 EMBO J. 16: 4628–4638

  • Hueber AO, Evan GI . 1998 Trends Genet. 14: 364–367

  • Johnson DG, Schwarz JK, Cress WD, Nevins JR . 1993 Nature 365: 349–352

  • Kaczmarek L, Hyland JK, Watt R, Rosenberg M, Baserga R . 1985 Science 228: 1313–1315

  • Leone G, Sears R, Huang E, Rempel R, Nuckolls F, Park CH, Giangrande P, Wu L, Saavedra HI, Field SJ, Thompson MA, Yang H, Fujiwara Y, Greenberg ME, Orkin S, Smith C, Nevins JR . 2001 Mol. Cell 8: 105–113

  • Lind EF, Wayne J, Wang QZ, Staeva T, Stolzer A, Petrie HT . 1999 J. Immunol. 162: 5374–5379

  • Linette GP, Li Y, Roth K, Korsmeyer SJ . 1996 Proc. Natl. Acad. Sci. USA 93: 9545–9552

  • Marin MC, Hsu B, Stephens LC, Brisbay S, McDonnell TJ . 1995 Exp. Cell Res. 217: 240–247

  • Mazel S, Burtrum D, Petrie HT . 1996 J. Exp. Med. 183: 2219–2226

  • Medema RH, Kops GJ, Bos JL, Burgering BM . 2000 Nature 404: 782–787

  • Meyerson M, Harlow E . 1994 Mol. Cell Biol. 14: 2077–2086

  • O'Hagan RC, Ohh M, David G, de Alboran IM, Alt FW, Kaelin Jr WG, DePinho RA . 2000 Genes Dev. 14: 2185–2191

  • O'Reilly LA, Huang DC, Strasser A . 1996 EMBO J. 15: 6979–6990

  • Obaya AJ, Mateyak MK, Sedivy JM . 1999 Oncogene 18: 2934–2941

  • Perez-Roger I, Kim SH, Griffiths B, Sewing A, Land H . 1999 EMBO J. 18: 5310–5320

  • Perez-Roger I, Solomon DL, Sewing A, Land H . 1997 Oncogene 14: 2373–2381

  • Persson H, Gray HE, Godeau F . 1985 Mol. Cell Biol. 5: 2903–2912

  • Philipp-Staheli J, Payne SR, Kemp CJ . 2001 Exp. Cell Res. 264: 148–168

  • Rabbitts PH, Watson JV, Lamond A, Forster A, Stinson MA, Evan G, Fischer W, Atherton E, Sheppard R, Rabbitts TH . 1985 EMBO J. 4: 2009–2015

  • Resnitzky D, Gossen M, Bujard H, Reed SI . 1994 Mol. Cell Biol. 14: 1669–1679

  • Resnitzky D, Reed SI . 1995 Mol. Cell Biol. 15: 3463–3469

  • Sears R, Ohtani K, Nevins JR . 1997 Mol. Cell Biol. 17: 5227–5235

  • Shan B, Lee WH . 1994 Mol. Cell Biol. 14: 8166–8173

  • Tomoda K, Kubota Y, Arata Y, Mori S, Maeda M, Tanaka T, Yoshida M, Yoneda-Kato N, Kato Jy J . 2001 J. Biol. Chem. 9: 9

  • Tomoda K, Kubota Y, Kato J . 1999 Nature 398: 160–165

  • 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

  • Wu X, Levine AJ . 1994 Proc. Natl. Acad. Sci. USA 91: 3602–3606

  • Yang W, Shen J, Wu M, Arsura M, FitzGerald M, Suldan Z, Kim DW, Hofmann CS, Pianetti S, Romieu-Mourez R, Freedman LP, Sonenshein GE . 2001 Oncogene 20: 1688–1702

Download references

Acknowledgements

We thank Drs Carlos Arteaga and Richard Pestell for providing p27 heterozygous matings and p27−/− MEFs. We thank Drs Scott Hiebert and Stephen Hann for critical reading of the manuscript. We are grateful to Drs Stephen Hann and Chi-Wu Chiang for continuous scientific input and technical expertise. Courtney Greider was supported by NIH Training grant T32CA09385. This work was supported by NIH grant RO1CA78443 and in part through the use of the VUMC Cell Imaging Core Resource supported by NIH grants CA58485 and DK20593.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Elizabeth Yang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Greider, C., Chattopadhyay, A., Parkhurst, C. et al. BCL-xL and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases. Oncogene 21, 7765–7775 (2002). https://doi.org/10.1038/sj.onc.1205928

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205928

Keywords

This article is cited by

Search

Quick links