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Mol Cell Biol. 1998 Feb;18(2):753-61.

Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes.

Author information

  • 1The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. Lundberg@wi.mit.edu

Abstract

The retinoblastoma protein (pRb) acts to constrain the G1-S transition in mammalian cells. Phosphorylation of pRb in G1 inactivates its growth-inhibitory function, allowing for cell cycle progression. Although several cyclins and associated cyclin-dependent kinases (cdks) have been implicated in pRb phosphorylation, the precise mechanism by which pRb is phosphorylated in vivo remains unclear. By inhibiting selectively either cdk4/6 or cdk2, we show that endogenous D-type cyclins, acting with cdk4/6, are able to phosphorylate pRb only partially, a process that is likely to be completed by cyclin E-cdk2 complexes. Furthermore, cyclin E-cdk2 is unable to phosphorylate pRb in the absence of prior phosphorylation by cyclin D-cdk4/6 complexes. Complete phosphorylation of pRb, inactivation of E2F binding, and activation of E2F transcription occur only after sequential action of at least two distinct G1 cyclin kinase complexes.

PMID:
9447971
[PubMed - indexed for MEDLINE]
PMCID:
PMC108786
Free PMC Article

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