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Molecular and Cellular Biology, July 2000, p. 4745-4753, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Bcl-2 Retards Cell Cycle Entry through p27Kip1, pRB Relative p130, and Altered E2F Regulation

Gino Vairo,1,dagger Timothy J. Soos,2 Todd M. Upton,3 Juan Zalvide,3 James A. DeCaprio,3 Mark E. Ewen,3 Andrew Koff,2 and Jerry M. Adams1,*

The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia1; Memorial Sloan-Kettering Cancer Center, New York, New York 100212; and Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 021153

Received 28 December 1999/Returned for modification 24 February 2000/Accepted 13 April 2000

Independent of its antiapoptotic function, Bcl-2 can, through an undetermined mechanism, retard entry into the cell cycle. Cell cycle progression requires the phosphorylation by cyclin-dependent kinases (Cdks) of retinoblastoma protein (pRB) family members to free E2F transcription factors. We have explored whether retarded cycle entry is mediated by the Cdk inhibitor p27 or the pRB family. In quiescent fibroblasts, enforced Bcl-2 expression elevated levels of both p27 and the pRB relative p130. Bcl-2 still slowed G1 progression in cells deficient in pRB but not in those lacking p27 or p130. Hence, pRB is not required, but both p27 and p130 are essential mediators. The ability of p130 to form repressive complexes with E2F4 is implicated, because the retardation by Bcl-2 was accentuated by coexpressed E2F4. A plausible relevant target of p130/E2F4 is the E2F1 gene, because Bcl-2 expression delayed E2F1 accumulation during G1 progression and overexpression of E2F1 overrode the Bcl-2 inhibition. Hence, Bcl-2 appears to retard cell cycle entry by increasing p27 and p130 levels and maintaining repressive complexes of p130 with E2F4, perhaps to delay E2F1 expression.

* Corresponding author. Mailing address: C/- The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia. Phone: 61 3 9345 2555. Fax: 61 3 9347 0852. E-mail: adams{at}wehi.edu.au.

dagger Present address: ExGenix Operations Ltd, Richmond, Victoria 3121, Australia.

Molecular and Cellular Biology, July 2000, p. 4745-4753, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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