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PMID: 17540599 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.

Molecular cell ·Vol. 26 ·No. 5 ·2007-06-08 ·Pages 745-52

Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, Arking DE, Beer MA, Maitra A, Mendell JT

Abstract

The p53 tumor suppressor protein is a critical regulator of the cellular response to cancer-initiating insults such as genotoxic stress. In this report, we demonstrate that microRNAs (miRNAs) are important components of the p53 transcriptional network. Global miRNA expression analyses identified a cohort of miRNAs that exhibit p53-dependent upregulation following DNA damage. One such miRNA, miR-34a, is commonly deleted in human cancers and, as shown here, frequently absent in pancreatic cancer cells. Characterization of the miR-34a primary transcript and promoter demonstrates that this miRNA is directly transactivated by p53. Expression of miR-34a causes dramatic reprogramming of gene expression and promotes apoptosis. Much like the known set of p53-regulated genes, miR-34a-responsive genes are highly enriched for those that regulate cell-cycle progression, apoptosis, DNA repair, and angiogenesis. Therefore, it is likely that an important function of miR-34a is the modulation and fine-tuning of the gene expression program initiated by p53.

MeSH Terms
Apoptosis/genetics,physiology Base Sequence Cell Line, Tumor DNA Damage Gene Expression Humans MicroRNAs/genetics,metabolism Pancreatic Neoplasms/genetics,metabolism Promoter Regions, Genetic RNA, Neoplasm/genetics,metabolism Transcriptional Activation Tumor Suppressor Protein p53/metabolism
Chemicals
MicroRNAs RNA, Neoplasm TP53 protein, human Tumor Suppressor Protein p53
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Chang Tsung-Cheng
The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Wentzel Erik A
Kent Oliver A
Ramachandran Kalyani
Mullendore Michael
Lee Kwang Hyuck
Feldmann Georg
Yamakuchi Munekazu
Ferlito Marcella
Lowenstein Charles J
Arking Dan E
Beer Michael A
Maitra Anirban
Mendell Joshua T
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-2765
DOI
10.1016/j.molcel.2007.05.010
Published
2007-06-08
Epub
2007-00-31
Pages
745-52
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC1939978
Subset
IM
Grants
NCI NIH HHS · R01CA113669 · United States
NCI NIH HHS · R01 CA120185 · United States
NCI NIH HHS · R01 CA113669-02 · United States
NCI NIH HHS · R01 CA120185-01A2 · United States
NCI NIH HHS · R01CA120185 · United States
NCI NIH HHS · R01 CA113669 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2007.05.010 PMC Full Text View journal details
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