Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway

Oliver A. Kent, Raghu R. Chivukula, Michael Mullendore, Erik A. Wentzel, Georg Feldmann, Kwang H. Lee, Shu Liu, Steven D. Leach, Anirban Maitra, Joshua T. Mendell

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220 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2754-2759
Number of pages6
JournalGenes and Development
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2010

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Keywords

  • Pancreatic cancer
  • Primary transcript
  • Ras
  • miR-143/145
  • microRNA

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Kent, O. A., Chivukula, R. R., Mullendore, M., Wentzel, E. A., Feldmann, G., Lee, K. H., Liu, S., Leach, S. D., Maitra, A., & Mendell, J. T. (2010). Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway. Genes and Development, 24(24), 2754-2759. https://doi.org/10.1101/gad.1950610