Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215.
Cell cycle arrest in response to DNA damage is an important antitumorigenic mechanism. MicroRNAs (miRNAs) were recently shown to play key regulatory roles in cell cycle progression. For example, miR-34a is induced in response to p53 activation and mediates G(1) arrest by down-regulating multiple cell cycle-related transcripts. Here we show that genotoxic stress promotes the p53-dependent up-regulation of the homologous miRNAs miR-192 and miR-215. Like miR-34a, activation of miR-192/215 induces cell cycle arrest, suggesting that multiple miRNA families operate in the p53 network. Furthermore, we define a downstream gene expression signature for miR-192/215 expression, which includes a number of transcripts that regulate G(1) and G(2) checkpoints. Of these transcripts, 18 transcripts are direct targets of miR-192/215, and the observed cell cycle arrest likely results from a cooperative effect among the modulations of these genes by the miRNAs. Our results showing a role for miR-192/215 in cell proliferation combined with recent observations that these miRNAs are underexpressed in primary cancers support the idea that miR-192 and miR-215 function as tumor suppressors.
Georges
Sara A
SA
Rosetta Inpharmatics LLC, Seattle, Washington WA 98109, USA. sara_georges@merck.com
Biery
Matthew C
MC
Kim
Soo-Yeon
SY
Schelter
Janell M
JM
Guo
Jane
J
Chang
Aaron N
AN
Jackson
Aimee L
AL
Carleton
Michael O
MO
Linsley
Peter S
PS
Cleary
Michele A
MA
Chau
B Nelson
BN
D002453:Cell Cycle / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D016195:G2 Phase / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016158:Genes, p53; D045325:HCT116 Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation
D004273:DNA, Neoplasm; D035683:MicroRNAs; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53