miR-335 directly targets Rb1 (pRb/p105) in a proximal connection to p53-dependent stress response

Cancer Res. 2010 Sep 1;70(17):6925-33. doi: 10.1158/0008-5472.CAN-10-0141. Epub 2010 Aug 16.


Loss-of-function mutations of retinoblastoma family (Rb) proteins drive tumorigenesis by overcoming barriers to cellular proliferation. Consequently, factors modulating Rb function are of great clinical import. Here, we show that miR-335 is differentially expressed in human cancer cells and that it tightly regulates the expression of Rb1 (pRb/p105) by specifically targeting a conserved sequence motif in its 3' untranslated region. We found that by altering Rb1 (pRb/p105) levels, miR-335 activates the p53 tumor suppressor pathway to limit cell proliferation and neoplastic cell transformation. DNA damage elicited an increase in miR-335 expression in a p53-dependent manner. miR-335 and p53 cooperated in a positive feedback loop to drive cell cycle arrest. Together, these results indicate that miR-335 helps control proliferation by balancing the activities of the Rb and p53 tumor suppressor pathways. Further, they establish that miR-335 activation plays an important role in the induction of p53-dependent cell cycle arrest after DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Growth Processes / genetics
  • Cell Line, Tumor
  • DNA Damage
  • Feedback
  • Humans
  • Mice
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics*
  • NIH 3T3 Cells
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • RNA, Small Interfering / genetics
  • Retinoblastoma Protein / biosynthesis
  • Retinoblastoma Protein / genetics*
  • Retinoblastoma Protein / metabolism
  • Transfection
  • Tumor Suppressor Protein p53 / metabolism*


  • MicroRNAs
  • Mirn335 microRNA, mouse
  • RNA, Small Interfering
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53