Requirements for cell cycle arrest by p16INK4a

Mol Cell. 2000 Sep;6(3):737-42. doi: 10.1016/s1097-2765(00)00072-1.

Abstract

Analysis of tumor-derived mutations has led to the suggestion that p16INK4a, cyclin D1, cdk4, and the retinoblastoma protein (pRB) are components of a regulatory pathway that is inactivated in most tumor cells. Cell cycle arrest induced by p16INK4a, an inhibitor of cyclin D-dependent kinases, requires pRB, and it has been proposed that this G1 arrest is mediated by pRB-E2F repressor complexes. By comparing the properties of primary mouse embryonic fibroblasts specifically lacking pRB-family members, we find that pRB is insufficient for a p16INK4a-induced arrest. In addition to pRB, a second function provided by either p107 or p130, two pRB-related proteins, is required for p16INK4a to block DNA synthesis. We infer that p16INK4a-induced arrest is not mediated exclusively by pRB, but depends on the nonredundant functions of at least two pRB-family members.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Carrier Proteins / analysis
  • Carrier Proteins / genetics*
  • Cells, Cultured
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinases / analysis
  • Fetus / cytology
  • Fibroblasts / chemistry
  • Fibroblasts / cytology
  • G1 Phase / physiology*
  • Gene Expression Regulation, Neoplastic / physiology*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Phosphoproteins / genetics
  • Proteins*
  • Proto-Oncogene Proteins*
  • Retinoblastoma Protein / genetics*
  • Retinoblastoma-Like Protein p107
  • Retinoblastoma-Like Protein p130
  • S Phase / physiology

Substances

  • Carrier Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Nuclear Proteins
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Rbl1 protein, mouse
  • Rbl2 protein, mouse
  • Retinoblastoma Protein
  • Retinoblastoma-Like Protein p107
  • Retinoblastoma-Like Protein p130
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinases