Bcl-2 retards cell cycle entry through p27(Kip1), pRB relative p130, and altered E2F regulation

Independent of its antiapoptotic function, Bcl-2 can, through an undetermin ed mechanism, retard entry into the cell cycle. Cell cycle progression requ ires the phosphorylation by cyclin-dependent kinases (Cdks) of retinoblasto ma 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 elev ated levels of both p27 and the pRB relative p130. Bcl-2 still slowed G(1) 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 pla usible relevant target of p130/E2F4 is the E2F1 gene, because Bcl-2 express ion delayed E2F1 accumulation during G(1) progression and overexpression of E2F1 overrode the Bcl-2 inhibition. Hence, Bcl-2 appears to retard cell cy cle entry by increasing p27 and p130 levels and maintaining repressive comp lexes of p130 with E2F4, perhaps to delay E2F1 expression.