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Cdk2 phosphorylation of Bcl-xL after stress converts it to a pro-apoptotic protein mimicking Bax/Bak

J Megyesi1, A Tarcsafalvi2, Nshl Seng3

  • 1Department of Internal Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.

Cell Death Discovery
|May 27, 2016
PubMed

Insights

The chemotherapy drug cisplatin triggers programmed cell death (apoptosis) by altering the Bcl-xL protein. This modification leads to mitochondrial damage and cell death, offering new insights into cancer drug mechanisms.

Area of Science:

  • Molecular Biology
  • Cell Death Research
  • Biochemistry

Background:

  • Apoptosis, or programmed cell death, is crucial for development and disease.
  • The Bcl-2 protein family regulates apoptosis, often through mitochondrial outer membrane permeabilization.
  • The precise mechanisms by which chemotherapy drugs induce apoptosis are not fully understood.

Purpose of the Study:

  • To investigate the molecular mechanism by which cisplatin induces apoptosis.
  • To identify specific protein modifications and pathways affected by cisplatin.
  • To explore the role of Bcl-xL phosphorylation in cisplatin-induced cell death.

Main Methods:

  • Utilized biochemical assays to study protein interactions and modifications.
  • Employed cyclin-dependent kinase 2 (CDK2) to investigate Bcl-xL phosphorylation.
  • Created phosphomimetic Bcl-xL mutants to assess biological significance.
  • Analyzed mitochondrial membrane potential, cytochrome c release, and caspase activation.

Main Results:

  • Cisplatin induces apoptosis via phosphorylation of the pro-survival protein Bcl-xL by CDK2 at a novel site.
  • A phosphomimetic Bcl-xL mutant mimicked cisplatin's effect, inducing apoptosis independently.
  • Phosphorylated Bcl-xL translocated to mitochondria, forming pores and initiating cytochrome c release.
  • This led to caspase activation and subsequent cell death, mirroring pathways activated by pro-apoptotic proteins.

Conclusions:

  • Cisplatin's apoptotic effect is mediated by CDK2-dependent phosphorylation of Bcl-xL at a previously unknown site.
  • This phosphorylation event is critical for Bcl-xL's pro-apoptotic function and mitochondrial permeabilization.
  • The findings elucidate a key mechanism of cisplatin action and suggest potential therapeutic targets for enhancing cancer cell death.

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