MicroRNAs 221 and 222 bypass quiescence and compromise cell survival

Ricardo Medina, Sayyed K. Zaidi, Chang Gong Liu, Janet L. Stein, Andre J. VanWijnen, Carlo M. Croce, Gary S. Stein

Research output: Contribution to journalArticlepeer-review

247 Scopus citations

Abstract

MicroRNAs (miRNA) have tumor suppressive and oncogenic potential in human cancer, but whether and how miRNAs control cell cycle progression is not understood. To address this question, we carried out a comprehensive analysis of miRNA expression during serum stimulation of quiescent human cells. Time course analyses revealed that four miRNAs are up-regulated and >100 miRNAs are down-regulated, as cells progress beyond the G1-S phase transition. We analyzed the function of two up-regulated miRNAs (miR-221 and miR-222) that are both predicted to target the cell growth suppressive cyclin-dependent kinase inhibitors p27 and p57. Our results show that miR-221 and miR-222 both directly target the 3′ untranslated regions of p27 and p57 mRNAs to reduce reporter gene expression, as well as diminish p27 and p57 protein levels. Functional studies show that miR-221 and miR-222 prevent quiescence when elevated during growth factor deprivation and induce precocious S-phase entry, thereby triggering cell death. Thus, the physiologic upregulation of miR-221 and miR-222 is tightly linked to a cell cycle checkpoint that ensures cell survival by coordinating competency for initiation of S phase with growth factor signaling pathways that stimulate cell proliferation.

Original languageEnglish (US)
Pages (from-to)2773-2780
Number of pages8
JournalCancer research
Volume68
Issue number8
DOIs
StatePublished - Apr 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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