Cdk2-dependent phosphorylation and functional inactivation of the pRB-related p130 protein in pRB(-), p16(INK4A)(+) tumor cells

Lengya Cheng, Ferdinando Rossi, Weizhao Fang, Takahiro Mori, David Cobrinik

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

The retinoblastoma family proteins pRB, p107, and p130 are phosphorylated and released from E2Fs in the late G1 phase of the cell cycle. This phosphorylation is thought to contribute to the derepression of E2F-responsive genes and to be mediated, in part, by Cdk4 and Cdk6. Evidence that Cdk4/6 activity is inhibited by p16(INK4A) in most pRB(-) cells suggests that p107 and p130 may be underphosphorylated and remain associated with E2Fs during G1-S progression in cells that lack pRB. To examine this, we evaluated the cell cycle-dependent phosphorylation and E2F binding abilities of p107 and p130 in pRB(-), p16(+) Saos-2 osteosarcoma cells. p130, but not p107, was phosphorylated and released from E2F-4 in late G1 and S phase cells, although p130 phosphorylation differed qualitatively in these and other pRB(-), p16(+) cells as compared with pRB(+), p16(-) cell types. p130 phosphorylation occurred in the absence of cyclin D-Cdk4/6 complexes, coincided with cyclin E- and Cdk2-associated kinase activity, and was prevented by expression of dominant negative Cdk2. Moreover, dominant negative Cdk2 prevented the dissociation of endogenous p130-E2F-4 complexes and inhibited E2F-4-dependent transcription. These findings show that p130 can be phosphorylated and functionally inactivated in a Cdk2-dependent process, and they highlight the involvement of distinct Cdks in the regulation of different pRB family proteins.

Original languageEnglish
Pages (from-to)30317-30325
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number39
DOIs
Publication statusPublished - 2000 Sep 29

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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