Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.
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.
Chang
Tsung-Cheng
TC
The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Wentzel
Erik A
EA
Kent
Oliver A
OA
Ramachandran
Kalyani
K
Mullendore
Michael
M
Lee
Kwang Hyuck
KH
Feldmann
Georg
G
Yamakuchi
Munekazu
M
Ferlito
Marcella
M
Lowenstein
Charles J
CJ
Arking
Dan E
DE
Beer
Michael A
MA
Maitra
Anirban
A
Mendell
Joshua T
JT
D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D004249:DNA Damage; D015870:Gene Expression; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D035683:MicroRNAs; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53