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.

[1]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A. Levine,et al.  The p53 pathway: positive and negative feedback loops , 2005, Oncogene.

[3]  O. Halevy,et al.  Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53 , 1990, Cell.

[4]  M. Oren,et al.  Decision making by p53: life, death and cancer , 2003, Cell Death and Differentiation.

[5]  C. Perou,et al.  A custom microarray platform for analysis of microRNA gene expression , 2004, Nature Methods.

[6]  K. Kinzler,et al.  Identification of p53 as a sequence-specific DNA-binding protein , 1991, Science.

[7]  D. Ginsberg E2F3-a novel repressor of the ARF/p53 pathway. , 2004, Developmental cell.

[8]  T. Golde,et al.  Notch signaling in cancer. , 2006, Current molecular medicine.

[9]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[10]  J. M. Thomson,et al.  Direct Regulation of an Oncogenic Micro-RNA Cluster by E2F Transcription Factors* , 2007, Journal of Biological Chemistry.

[11]  W. Filipowicz,et al.  Repression of protein synthesis by miRNAs: how many mechanisms? , 2007, Trends in cell biology.

[12]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[13]  Sathish Kumar Mungamuri,et al.  Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. , 2006, Cancer research.

[14]  Mariette Schrier,et al.  A Genetic Screen Implicates miRNA-372 and miRNA-373 As Oncogenes in Testicular Germ Cell Tumors , 2006, Cell.

[15]  Carlos Caldas,et al.  Sizing up miRNAs as cancer genes , 2005, Nature Medicine.

[16]  G. Wahl,et al.  Regulating the p53 pathway: in vitro hypotheses, in vivo veritas , 2006, Nature Reviews Cancer.

[17]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[18]  D. Felsher,et al.  Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression. , 2005, Cancer research.

[19]  R. Aharonov,et al.  Identification of hundreds of conserved and nonconserved human microRNAs , 2005, Nature Genetics.

[20]  A. Karsan,et al.  Recent insights into the role of Notch signaling in tumorigenesis. , 2006, Blood.

[21]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[22]  Vincent De Guire,et al.  An E2F/miR-20a Autoregulatory Feedback Loop* , 2007, Journal of Biological Chemistry.

[23]  M. Oren,et al.  The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression. , 2004, Molecular cell.

[24]  Baohong Zhang,et al.  MicroRNAs and their regulatory roles in animals and plants , 2007, Journal of cellular physiology.

[25]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Ott,et al.  The p53MH algorithm and its application in detecting p53-responsive genes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  C. Prives,et al.  P53 and Prognosis New Insights and Further Complexity , 2005, Cell.

[28]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[29]  Yitzhak Pilpel,et al.  Differentially Regulated Micro-RNAs and Actively Translated Messenger RNA Transcripts by Tumor Suppressor p53 in Colon Cancer , 2006, Clinical Cancer Research.

[30]  Jason H. Moore,et al.  Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. , 2007, Cancer research.

[31]  R. Agami,et al.  Classifying microRNAs in cancer: the good, the bad and the ugly. , 2007, Biochimica et biophysica acta.

[32]  Karl T Kelsey,et al.  MicroRNA responses to cellular stress. , 2006, Cancer research.

[33]  O. Kent,et al.  A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes , 2006, Oncogene.

[34]  K. Brown,et al.  The monofunctional alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine triggers apoptosis through p53-dependent and -independent pathways. , 2005, Toxicology and applied pharmacology.

[35]  M. Oren,et al.  A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. , 2006, Genes & development.

[36]  Z. Weng,et al.  A Global Map of p53 Transcription-Factor Binding Sites in the Human Genome , 2006, Cell.

[37]  V. Ambros,et al.  Identification of microRNAs and other tiny noncoding RNAs by cDNA cloning. , 2004, Methods in molecular biology.

[38]  Eugene Berezikov,et al.  Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis. , 2006, Genome research.

[39]  B. Osborne,et al.  p53 regulates thymic Notch1 activation , 2004, European journal of immunology.

[40]  T. Dalmay,et al.  MicroRNAs and the hallmarks of cancer , 2006, Oncogene.

[41]  E. Furth,et al.  Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster , 2006, Nature Genetics.

[42]  R. Stallings,et al.  MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells , 2007, Oncogene.

[43]  R. Plasterk,et al.  Micro RNAs in Animal Development , 2006, Cell.

[44]  O. Myklebost,et al.  Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. , 2006, Proceedings of the National Academy of Sciences of the United States of America.