Transcriptional activation of miR-34a contributes to p53-mediated apoptosis.
p53 is a potent tumor suppressor, whose biological effects are largely due to its function as a transcriptional regulator. Here we report that, in addition to regulating the expression of hundreds of protein-coding genes, p53 also modulates the levels of microRNAs (miRNAs). Specifically, p53 can induce expression of microRNA-34a (miR-34a) in cultured cells as well as in irradiated mice, by binding to a perfect p53 binding site located within the gene that gives rise to miR-34a. Processing of the primary transcript into mature miR-34a involves the excision of a 30 kb intron. Notably, inactivation of miR-34a strongly attenuates p53-mediated apoptosis in cells exposed to genotoxic stress, whereas overexpression of miR-34a mildly increases apoptosis. Hence, miR-34a is a direct proapoptotic transcriptional target of p53 that can mediate some of p53's biological effects. Perturbation of miR-34a expression, as occurs in some human cancers, may thus contribute to tumorigenesis by attenuating p53-dependent apoptosis.
Raver-Shapira
Nina
N
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Marciano
Efi
E
Meiri
Eti
E
Spector
Yael
Y
Rosenfeld
Nitzan
N
Moskovits
Neta
N
Bentwich
Zvi
Z
Oren
Moshe
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D020224:Expressed Sequence Tags; D016158:Genes, p53; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013696:Temperature; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D035683:MicroRNAs; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53