Organ size control is dominant over Rb family inactivation to restrict proliferation in vivo

Cell Rep. 2014 Jul 24;8(2):371-81. doi: 10.1016/j.celrep.2014.06.025. Epub 2014 Jul 10.

Abstract

In mammals, a cell's decision to divide is thought to be under the control of the Rb/E2F pathway. We previously found that inactivation of the Rb family of cell cycle inhibitors (Rb, p107, and p130) in quiescent liver progenitors leads to uncontrolled division and cancer initiation. Here, we show that, in contrast, deletion of the entire Rb gene family in mature hepatocytes is not sufficient for their long-term proliferation. The cell cycle block in Rb family mutant hepatocytes is independent of the Arf/p53/p21 checkpoint but can be abrogated upon decreasing liver size. At the molecular level, we identify YAP, a transcriptional regulator involved in organ size control, as a factor required for the sustained expression of cell cycle genes in hepatocytes. These experiments identify a higher level of regulation of the cell cycle in vivo in which signals regulating organ size are dominant regulators of the core cell cycle machinery.

Publication types

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

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins
  • Cell Proliferation*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Genes, cdc
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Hepatocytes / physiology
  • Liver / growth & development*
  • Liver / metabolism
  • Mice
  • Organ Size
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Retinoblastoma-Like Protein p107 / genetics
  • Retinoblastoma-Like Protein p107 / metabolism*
  • Retinoblastoma-Like Protein p130 / genetics
  • Retinoblastoma-Like Protein p130 / metabolism*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Phosphoproteins
  • Rbl1 protein, mouse
  • Rbl2 protein, mouse
  • Retinoblastoma-Like Protein p107
  • Retinoblastoma-Like Protein p130
  • Tumor Suppressor Protein p53
  • Yap1 protein, mouse
  • ADP-Ribosylation Factors