The cell cycle inhibitor p57(Kip2) promotes cell death via the mitochondrial apoptotic pathway.
The p57(Kip2) gene belongs to the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors and has been suggested to be a tumor suppressor gene, being inactivated in various types of human cancers. However, little is known concerning p57(Kip2) possible interplay with the apoptotic cell death machinery and its possible implication for cancer. Here, we report that selective p57(Kip2) expression sensitizes cancer cells to apoptotic agents such as cisplatin, etoposide and staurosporine (STS) via a mechanism, which does not require p57(Kip2)-mediated inhibition of CDK. Translocation of p57(Kip2) to mitochondria occurs within 20 min after STS application. In fact, p57(Kip2) primarily promotes the intrinsic apoptotic pathways, favoring Bax activation and loss of mitochondrial transmembrane potential, consequent release of cytochrome-c into cytosol, caspase-9 and caspase-3 activation. In accordance, Bcl2 overexpression or voltage-dependent anion channel (VDAC) inhibition is able to inhibit p57(Kip2) cell death promoting effect. Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby p57(Kip2) influences the mitochondrial apoptotic cell death pathway in cancer cells.
Vlachos
P
P
Karolinska Institutet, Institute of Environmental Medicine, 171 77 Stockholm, Sweden.
Nyman
U
U
Hajji
N
N
Joseph
B
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001693:Biological Transport, Active; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D019311:Staurosporine / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D051028:bcl-2-Associated X Protein; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D019311:Staurosporine