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Genes Dev. 2009 Oct 15;23(20):2388-93. doi: 10.1101/gad.1819009.

miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A.

Author information

1
Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology, and Research), Singapore 138672.

Abstract

The Rb-E2F pathway drives cell cycle progression and cell proliferation, and the molecular strategies safeguarding its activity are not fully understood. Here we report that E2F1 directly transactivates miR-449a/b. miR-449a/b targets and inhibits oncogenic CDK6 and CDC25A, resulting in pRb dephosphorylation and cell cycle arrest at G1 phase, revealing a negative feedback regulation of the pRb-E2F1 pathway. Moreover, miR-449a/b expression in cancer cells is epigenetically repressed through histone H3 Lys27 trimethylation, and epigenetic drug treatment targeting histone methylation results in strong induction of miR-449a/b. Our study reveals a tumor suppressor function of miR-449a/b through regulating Rb/E2F1 activity, and suggests that escape from this regulation through an aberrant epigenetic event contributes to E2F1 deregulation and unrestricted proliferation in human cancer.

PMID:
19833767
PMCID:
PMC2764491
DOI:
10.1101/gad.1819009
[Indexed for MEDLINE]
Free PMC Article

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