Necessary and sufficient role for a mitosis skip in senescence induction

Mol Cell. 2014 Jul 3;55(1):73-84. doi: 10.1016/j.molcel.2014.05.003. Epub 2014 Jun 5.

Abstract

Senescence is a state of permanent growth arrest and is a pivotal part of the antitumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear. Using time-lapse live-cell imaging, we demonstrate here that normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell-cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/C(Cdh1) and pRb family protein-dependent transcriptional suppression of mitotic regulators. Importantly, mitotic skipping is necessary and sufficient for senescence induction. p16 is only required for maintenance of senescence. Analysis of human nevi also suggested the role of mitosis skip in in vivo senescence. Our findings provide decisive evidence for the molecular basis underlying the induction and maintenance of cellular senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p16
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Mitosis / physiology*
  • Models, Biological
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology
  • Time-Lapse Imaging
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Neoplasm Proteins
  • P16 protein, human
  • Tumor Suppressor Protein p53