miR-34a is essential for p19Arf-driven cell cycle arrest

Nida Iqbal, Jie Mei, Jing Liu, Stephen X. Skapek

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

The Arf tumor suppressor gene product, p19Arf, regulates cell proliferation in incipient cancer cells and during embryo development. Beyond its commonly accepted p53-dependent actions, p19Arf also acts independently of p53 in both contexts. One such p53-independent effect with in vivo relevance includes its repression of Pdgfrβ, a process that is essential for vision in the mouse. We have utilized cell culture-based and mouse models to define a new role for miR-34a in this process. Ectopic expression of Arf in cultured cells enhanced the expression of several microRNAs predicted to target Pdgfrβ synthesis, including the miR-34 family. Because miR-34a has been implicated as a p53-dependent effector, we investigated whether it also contributed to p53-independent effects of p19Arf. Indeed, in mouse embryo fibroblasts (MEFs) lacking p53, Arf-driven repression of Pdgfraβ and its blockade of Pdgf-B stimulated DNA synthesis were both completely interrupted by anti-microRNA against miR-34a. Ectopic miR-34a directly targeted Pdgfrβ and a plasmid reporter containing wild-type Pdgfrβ 3′UTR sequence, but not one in which the miR-34a target sequence was mutated. Although miR-34a expression has been linked to p53 - a well-known effector of p19 Arf - Arf expression and its knockdown correlated with miR-34a level in MEFs lacking p53. Finally, analysis of the mouse embryonic eye demonstrated that Arf controlled expression of miR-34a, and the related miR-34b and c, in vivo during normal mouse development. Our findings indicate that miR-34a provides an essential link between p19Arf and its p53-independent capacity to block cell proliferation driven by Pdgfrβ. This has ramifications for developmental and tumor suppressor roles of Arf.

Original languageEnglish (US)
Pages (from-to)792-800
Number of pages9
JournalCell Cycle
Volume13
Issue number5
DOIs
StatePublished - Mar 1 2014

Keywords

  • Cell cycle
  • Pdgfrβ
  • Tumor suppression
  • Vascular remodeling
  • miR-34a
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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