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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 6 / metabolism*
  • E2F1 Transcription Factor / metabolism*
  • Epigenesis, Genetic
  • Feedback, Physiological / genetics*
  • G1 Phase / physiology
  • Gene Expression Regulation*
  • Histones / metabolism
  • Humans
  • MicroRNAs / metabolism*
  • Neoplasms / physiopathology
  • cdc25 Phosphatases / antagonists & inhibitors
  • cdc25 Phosphatases / metabolism*


  • E2F1 Transcription Factor
  • Histones
  • MIRN449 microRNA, human
  • MicroRNAs
  • Cyclin-Dependent Kinase 6
  • cdc25 Phosphatases