title: Cdk2 phosphorylation of Bcl-xL after stress converts it to a pro-apoptotic protein mimicking Bax/Bak.
abstract: Apoptosis is a regulated form of cell death that proceeds by defined biochemical pathways. Most apoptosis is controlled by interactions between pro-survival and pro-apoptotic Bcl-2 family proteins in which death is often the consequence of permeabilization of the mitochondrial outer membrane. Many drugs affect this equilibrium to favor apoptosis but this process is not completely understood. We show that the chemotherapeutic drug cisplatin initiates an apoptotic pathway by phosphorylation of a pro-survival Bcl-2 family member, Bcl-xL, by cyclin-dependent kinase 2. The phosphorylation occurred at a previously unreported site and its biologic significance was demonstrated by a phosphomimetic modification of Bcl-xL that was able to induce apoptosis without addition of cisplatin. The mechanism of cell death induction was similar to that initiated by pro-apoptotic Bcl-2 family proteins, that is, phosphorylated Bcl-xL translocated to the mitochondrial membrane, and formed pores in the membrane. This initiated cytochromecrelease and caspase activation that resulted in cell death.
authors.affiliation: Department 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.
authors.forename: J
authors.initials: J
authors.lastname: Megyesi
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tarcsafalvi
authors.affiliation: Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Nshl
authors.initials: N
authors.lastname: Seng
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar.
authors.forename: R
authors.initials: R
authors.lastname: Hodeify
authors.affiliation: Department 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.
authors.forename: P M
authors.initials: PM
authors.lastname: Price