Implications of cellular senescence in tissue damage response, tumor suppression, and stem cell biology

Cold Spring Harb Symp Quant Biol. 2008:73:513-22. doi: 10.1101/sqb.2008.73.048. Epub 2009 Jan 15.

Abstract

Cellular senescence is characterized by an irreversible cell cycle arrest that, when bypassed by mutation, contributes to cellular immortalization. Activated oncogenes induce a hyperproliferative response, which might be one of the senescence cues. We have found that expression of such an oncogene, Akt, causes senescence in primary mouse hepatoblasts in vitro. Additionally, AKT-driven tumors undergo senescence in vivo following p53 reactivation and show signs of differentiation. In another in vivo system, i.e., liver fibrosis, hyperproliferative signaling through AKT might be a driving force of the senescence in activated hepatic stellate cells. Senescent cells up-regulate and secrete molecules that, on the one hand, can reinforce the arrest and, on the other hand, can signal to an innate immune system to clear the senescent cells. The mechanisms governing senescence and immortalization are overlapping with those regulating self-renewal and differentiation. These respective control mechanisms, or their disregulation, are involved in multiple pathological conditions including fibrosis, wound healing, and cancer. Understanding extracellular cues that regulate these processes may enable new therapies for these conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cellular Senescence* / genetics
  • Cellular Senescence* / physiology
  • Gene Expression
  • Genes, p53
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / immunology
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Immunity, Innate
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / prevention & control
  • Liver Neoplasms, Experimental / genetics
  • Liver Neoplasms, Experimental / pathology
  • Mice
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism
  • Oncogenes
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Wound Healing

Substances

  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt