p300 is required for orderly G1/S transition in human cancer cells.
Oncogene
; 26(1): 21-9, 2007 Jan 04.
Article
in En
| MEDLINE
| ID: mdl-16878158
ABSTRACT
The role of the transcriptional coactivator p300 in cell cycle control has not been analysed in detail due to the lack of appropriate experimental systems. We have now examined cell cycle progression of p300-deficient cancer cell lines, where p300 was disrupted either by gene targeting (p300(-) cells) or knocked down using RNAi. Despite significant proliferation defects under normal growth conditions, p300-deficient cells progressed rapidly through G1 with premature S-phase entry. Accelerated G1/S transition was associated with early retinoblastoma (RB) hyperphosphorylation and activation of E2F targets. The p300-acetylase activity was dispensable since expression of a HAT-deficient p300 mutant reversed these changes. Co-immunoprecipitation showed p300/RB interaction occurs in vivo during G1, and this interaction has two peaks in early G1 with unphosphorylated RB and in late G1 with phosphorylated RB. In vitro kinase assays showed that p300 directly inhibits cdk6-mediated RB phosphorylation, suggesting p300 acts in early G1 to prevent RB hyperphosphorylation and delay premature S-phase entry. Paradoxically, continued cycling of p300(-) cells despite prolonged serum depletion was observed, and this occurred in association with persistent RB hyperphosphorylation. Altogether, these results suggest that p300 has an important role in G1/S control, possibly by modulating RB phosphorylation.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
G1 Phase
/
S Phase
/
P300-CBP Transcription Factors
/
Neoplasms
Limits:
Humans
Language:
En
Journal:
Oncogene
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2007
Document type:
Article
Affiliation country:
Reino Unido