The Apoptotic v-cyclin-CDK6 Complex Phosphorylates and Inactivates Bcl-2

Nat Cell Biol. 2000 Nov;2(11):819-25. doi: 10.1038/35041064.

Abstract

v-cyclin encoded by Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV or HHV8) associates with cellular cyclin-dependent kinase 6 (CDK6) to form a kinase complex that promotes cell-cycle progression, but can also induce apoptosis in cells with high levels of CDK6. Here we show that whereas HHV8-encoded v-Bcl-2 protects against this apoptosis, cellular Bcl-2 has lost its anti-apoptotic potential as a result of an inactivating phosphorylation in its unstructured loop region. Moreover, we identify Bcl-2 as a new substrate for v-cyclin-CDK6 in vitro, and show that it is present in a complex with CDK6 in cell lysates. A Bcl-2 mutant with a S70A S87A double substitution in the loop region is not phosphorylated and provides resistance to apoptosis, indicating that inactivation of Bcl-2 by v-cyclin-CDK6 may be required for the observed apoptosis. Furthermore, the identification of phosphorylated Bcl-2 in HHV8-positive Kaposi's sarcoma indicates that HHV8-mediated interference with host apoptotic signalling pathways may encourage the development of Kaposi's sarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • COS Cells
  • Cell Extracts
  • Chlorocebus aethiops
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases*
  • Cyclins / genetics
  • Cyclins / metabolism*
  • G2 Phase
  • Glutathione Transferase / genetics
  • Herpesvirus 8, Human / physiology
  • Humans
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitosis
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Serine / metabolism
  • Substrate Specificity
  • Tumor Cells, Cultured
  • Viral Proteins

Substances

  • Cell Extracts
  • Cyclins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • Viral Proteins
  • Serine
  • Glutathione Transferase
  • Protein-Serine-Threonine Kinases
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases