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.

Full 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.

Author information

Author/s: Yang, Xiaojing (X); Feng, Min (M); Jiang, Xia (X); Wu, Zhenlong (Z); Li, Zhimei (Z); Aau, Meiyee (M); Yu, Qiang (Q);

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

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Genes & development (Genes Dev), published in United States. (Language: eng)

Reference: 2009-Oct; vol 23 (issue 20) : pp 2388-93

Dates: Created 2009/10/16; Completed 2009/11/03;

PMID: 19833767, status: MEDLINE (last retrieval date: 11/3/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Cell Line
Cell Line, Tumor
Cyclin-Dependent Kinase 6 - antagonists & inhibitors; metabolism
E2F1 Transcription Factor - metabolism
Epigenesis, Genetic
Feedback, Biochemical - genetics
G1 Phase - physiology

G1 Phase - physiology
Gene Expression Regulation
Histones - metabolism
Humans
MicroRNAs - metabolism
Neoplasms - physiopathology
cdc25 Phosphatases - antagonists & inhibitors; metabolism

Associated Chemicals: E2F1 Transcription Factor (0) ; Histones (0) ; MIRN449 microRNA, human (0) ; MicroRNAs (0) ; Cyclin-Dependent Kinase 6 (EC 2.7.1.37) ; cdc25 Phosphatases (EC 3.1.3.48)

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