Nuclear colocalization and interaction between bcl-xL and cdk1(cdc2) during G2/M cell-cycle checkpoint.
In response to cancer chemotherapeutic drugs, cells rapidly trigger the apoptotic program or undergo growth arrest and senescence at specific phases of the cell cycle. Mitochondrial bcl-xL plays a central role in preventing alteration of mitochondrial dysfunction, cytochrome c release, caspase activation, DNA fragmentation and apoptosis. However, its pleitropic function depends on its subcellular localization. Here, we show that in addition to its mitochondrial effect that delays apoptosis, bcl-xL colocalizes and binds to cdk1(cdc2) during G(2)/M cell-cycle checkpoint and its overexpression stabilizes a G(2)/M-arrest senescence program in surviving cells after DNA damage. Bcl-xL potently inhibits cdk1(cdc2) kinase activity, which is reversible by a synthetic peptide between the 41st amino acid and 60th amino acid surrounding of the Thr47 and Ser62 phosphorylation sites, and Asn52 deamidation site, within the flexible loop domain of bcl-xL. A mutant deleted of this region does not alter the antiapoptotic function of bcl-xL, but impedes its effect on cdk1(cdc2) activity and on the G(2)/M-arrest senescence program after DNA damage. The nuclear interaction of bcl-xL and cdk1(cdc2) suggests that bcl-xL is coupled to the stabilization of a cell-cycle checkpoint induced by DNA damage, and this effect is genetically distinct from its function on apoptosis.
Schmitt
E
E
Centre de recherche, Centre hospitalier de l'Université of Montréal-Hôpital Notre-Dame and Institut du Cancer de Montréal, 1560 Sherbrooke Street East, Montréal, Quebec, Canada.
Beauchemin
M
M
Bertrand
R
R
D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D016922:Cellular Senescence; D053938:DNA Fragmentation; D016195:G2 Phase; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D020298:U937 Cells; D051020:bcl-X Protein / Q000378:metabolism / Q000502:physiology*
D051020:bcl-X Protein; D016203:CDC2 Protein Kinase