title: Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.
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.
authors.affiliation: The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Tsung-Cheng
authors.initials: TC
authors.lastname: Chang
authors.forename: Erik A
authors.initials: EA
authors.lastname: Wentzel
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Kent
authors.forename: Kalyani
authors.initials: K
authors.lastname: Ramachandran
authors.forename: Michael
authors.initials: M
authors.lastname: Mullendore
authors.forename: Kwang Hyuck
authors.initials: KH
authors.lastname: Lee
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Munekazu
authors.initials: M
authors.lastname: Yamakuchi
authors.forename: Marcella
authors.initials: M
authors.lastname: Ferlito
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lowenstein
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beer
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
mesh_terms: 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*
chemical_list: D035683:MicroRNAs; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53