| Title | 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(s) | Yang X, Feng M, Jiang X, Wu Z, Li Z, Aau M, Yu Q | | Institution | Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology, and Research), Singapore 138672. | | Source | Genes Dev 2009 Oct 15; 23(20):2388-93. | | MeSH | Cell Line
Cell Line, Tumor
Cyclin-Dependent Kinase 6
E2F1 Transcription Factor
Epigenesis, Genetic
Feedback, Biochemical
G1 Phase
Gene Expression Regulation
Histones
Humans
MicroRNAs
Neoplasms
cdc25 Phosphatases
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19833767 |
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