BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest

Oncogene. 2001 Jul 27;20(33):4507-18. doi: 10.1038/sj.onc.1204584.

Abstract

The pro-apoptotic molecule BAD binds BCL-[X(L)] or BCL2 and inactivates their survival function. In addition to their anti-apoptotic function, BCL2 and BCL-[X(L)] also delay cell cycle entry from quiescence. We found that the BH3-only molecule BAD also exerted a cell cycle effect. BAD expression resulted in failure to cell cycle block in growth arrest conditions. In low serum and in confluence, fibroblasts constitutively or inducibly expressing BAD persisted in S phase, continued to incorporate BrdU, and exhibited sustained cyclin E/cdk2 activity. Mutation analysis indicated that the cell cycle effect of BAD was not dependent on its phosphorylation status or subcellular localization, but strictly co-segregated with BCL-[X(L)] binding. bclx(-/-) MEFs expressing BAD and bad(-/-) MEFs both arrested in G0/G1 in low serum similar to wild-type controls, suggesting that the ability to overcome the G0/G1 checkpoint resulted from the presence of BAD/BCL-x(L) heterodimers, rather than the absence of BCL-[X(L)] or BAD. These data provide evidence that in addition to regulating apoptosis, the BAD/BCL-[X(L)] heterodimer has a novel cell cycle function.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • CDC2-CDC28 Kinases*
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cell Division
  • Cells, Cultured
  • Contact Inhibition
  • Culture Media, Serum-Free
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases / metabolism
  • DNA Replication
  • Dimerization
  • Enzyme Activation
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • G1 Phase / physiology*
  • Phosphorylation
  • Protein Conformation
  • Protein Multimerization
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Rats
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / physiology
  • Resting Phase, Cell Cycle / physiology*
  • Structure-Activity Relationship
  • bcl-Associated Death Protein
  • bcl-X Protein

Substances

  • Bad protein, rat
  • Bcl2l1 protein, rat
  • Carrier Proteins
  • Culture Media, Serum-Free
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • Cdk2 protein, rat
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases