c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms

EMBO J. 1999 Jan 4;18(1):188-97. doi: 10.1093/emboj/18.1.188.

Abstract

c-Jun is a component of the transcription factor AP-1, which is activated by a wide variety of extracellular stimuli. The regulation of c-Jun is complex and involves both increases in the levels of c-Jun protein as well as phosphorylation of specific serines (63 and 73) by Jun N-terminal kinase (JNK). We have used fibroblasts derived from c-Jun null embryos to define the role of c-Jun in two separate processes: cell growth and apoptosis. We show that in fibroblasts, c-Jun is required for progression through the G1 phase of the cell cycle; c-Jun-mediated G1 progression occurs by a mechanism that involves direct transcriptional control of the cyclin D1 gene, establishing a molecular link between growth factor signaling and cell cycle regulators. In addition, c-Jun protects cells from UV-induced cell death and cooperates with NF-kappaB to prevent apoptosis induced by tumor necrosis factor alpha (TNFalpha). c-Jun mediated G1 progression is independent of phosphorylation of serines 63/73; however, protection from apoptosis in response to UV, a potent inducer of JNK/SAP kinase activity, requires serines 63/73. The results reveal critical roles for c-Jun in two different cellular processes and show that different extracellular stimuli can target c-Jun by distinct biochemical mechanisms.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Base Sequence
  • Binding Sites / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Cycle / genetics
  • Cell Cycle / physiology*
  • Cell Division / genetics
  • Cell Division / physiology
  • Cells, Cultured
  • DNA / genetics
  • DNA / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Fibroblasts / radiation effects
  • Genes, jun
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases*
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / physiology*
  • Ultraviolet Rays

Substances

  • Proto-Oncogene Proteins c-jun
  • DNA
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases