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Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and

David T Terrano1, Meenakshi Upreti, Timothy C Chambers

  • 1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.

Molecular and Cellular Biology
|November 18, 2009
PubMed

Insights

Cyclin-dependent kinase 1 (CDK1)/cyclin B phosphorylates antiapoptotic proteins Bcl-x(L) and Bcl-2, linking prolonged mitotic arrest to cell death. This phosphorylation disables their protective function, triggering apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The spindle assembly checkpoint (SAC) prevents aneuploidy but its role in cell death is unclear.
  • Antiapoptotic proteins Bcl-x(L) and Bcl-2 are phosphorylated during mitotic arrest, suggesting inactivation of their function.
  • The kinase responsible for this critical phosphorylation has remained unidentified.

Purpose of the Study:

  • To identify the kinase that phosphorylates Bcl-x(L) and Bcl-2 during prolonged mitotic arrest.
  • To elucidate the mechanism linking mitotic arrest to apoptosis.
  • To confirm Bcl-x(L) as a key target in CDK1-mediated apoptosis.

Main Methods:

  • Investigated the role of cyclin-dependent kinase 1 (CDK1)/cyclin B in phosphorylating Bcl-x(L) and Bcl-2.
  • Analyzed Bcl-x(L)/Bcl-2 phosphorylation during normal mitosis and prolonged mitotic arrest.
  • Utilized transient overexpression of nondegradable cyclin B1 and phosphodefective/mimetic Bcl-x(L) mutants.

Main Results:

  • CDK1/cyclin B was identified as the kinase catalyzing mitotic arrest-induced Bcl-x(L)/Bcl-2 phosphorylation.
  • Mitotic arrest led to increased Bcl-x(L)/Bcl-2 phosphorylation compared to normal mitosis.
  • Overexpression of cyclin B1 induced apoptosis, which was blocked by a phosphodefective Bcl-x(L) mutant.

Conclusions:

  • Sustained CDK1 activation during mitotic arrest, unlike transient activation during normal mitosis, leads to extensive Bcl-x(L)/Bcl-2 phosphorylation.
  • Phosphorylation inactivates the antiapoptotic function of Bcl-x(L) and Bcl-2, linking mitotic arrest to apoptosis.
  • Bcl-x(L) acts as a crucial target of proapoptotic CDK1 signaling, with its phosphorylation serving as a sensor for CDK1 signal duration.

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