title: Oncogenic miR-17/20a Forms a Positive Feed-forward Loop with the p53 Kinase DAPK3 to Promote Tumorigenesis.
abstract: MicroRNAs (miRs) are a class of small regulatory RNAs that have been implicated in diverse biological pathways, including cancer. miR-17/20a encoded by the c13orf25 locus is among the first miRs discovered to have oncogenic functions. The E2F family members have been established as the targets for these oncomiRs, which form a negative feedback loop to control cell cycle progression. However, this pathway does not seem to be sufficient to account for elevated expression of these oncomiRs in cancer cells to promote tumorigenesis. Here we report that miR-17/20a targets a p53 activating kinase DAPK3, leading to p53-dependent transcriptional de-repression of the oncomiRs. We demonstrate that DAPK3 plays a central role in preventing miR-17/20a depletion-induced genome instability and in miR-17/20a overexpression-triggered tumor formation. This newly identified tumorigenic pathway may thus contribute to miR-17/20a amplification and tumor growth in diverse human cancers.
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China and.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Cai
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China and.
authors.forename: Ran
authors.initials: R
authors.lastname: Cao
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China and.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0651.
authors.forename: Yuanchao
authors.initials: Y
authors.lastname: Xue
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China and.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0651.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China and.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China and.
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093-0651 xdfu@ucsd.edu.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
mesh_terms: D000818:Animals; D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C524941:MIRN17 microRNA, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; C579101:DAPK3 protein, human; D064550:Death-Associated Protein Kinases
keywords: DNA damage; microRNA (miRNA); oncogene; p53; tumor