title: Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway.
abstract: Although activating mutations in RAS oncogenes are known to result in aberrant signaling through multiple pathways, the role of microRNAs (miRNAs) in the Ras oncogenic program remains poorly characterized. Here we demonstrate that Ras activation leads to repression of the miR-143/145 cluster in cells of human, murine, and zebrafish origin. Loss of miR-143/145 expression is observed frequently in KRAS mutant pancreatic cancers, and restoration of these miRNAs abrogates tumorigenesis. miR-143/145 down-regulation requires the Ras-responsive element-binding protein (RREB1), which represses the miR-143/145 promoter. Additionally, KRAS and RREB1 are targets of miR-143/miR-145, revealing a feed-forward mechanism that potentiates Ras signaling.
authors.affiliation: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Kent
authors.forename: Raghu R
authors.initials: RR
authors.lastname: Chivukula
authors.forename: Michael
authors.initials: M
authors.lastname: Mullendore
authors.forename: Erik A
authors.initials: EA
authors.lastname: Wentzel
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Lee
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000209:etiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C117307:KRAS protein, human; C542359:MIRN143 microRNA, human; C549612:MIRN143 microRNA, zebrafish; C541010:MIRN145 microRNA, human; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; C544858:Mirn145 microRNA, zebrafish; D011518:Proto-Oncogene Proteins; C101743:RREB1 protein, human; D014157:Transcription Factors; D029961:Zebrafish Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins