title: p57(KIP2) control of actin cytoskeleton dynamics is responsible for its mitochondrial pro-apoptotic effect.
abstract: p57 (Kip2, cyclin-dependent kinase inhibitor 1C), often found downregulated in cancer, is reported to hold tumor suppressor properties. Originally described as a cyclin-dependent kinase (cdk) inhibitor, p57(KIP2) has since been shown to influence other cellular processes, beyond cell cycle regulation, including cell death and cell migration. Inhibition of cell migration by p57(KIP2) is attributed to the stabilization of the actin cytoskeleton through the activation of LIM domain kinase-1 (LIMK-1). Furthermore, p57(KIP2) is able to enhance mitochondrial-mediated apoptosis. Here, we report that the cell death promoting effect of p57(KIP2) is linked to its effect on the actin cytoskeleton. Indeed, whereas Jasplakinolide, an actin cytoskeleton-stabilizing agent, mimicked p57(KIP2)'s pro-apoptotic effect, destabilizing the actin cytoskeleton with cytochalsin D reversed p57(KIP2)'s pro-apoptotic function. Conversely, LIMK-1, the enzyme mediating p57(KIP2)'s effect on the actin cytoskeleton, was required for p57(KIP2)'s death promoting effect. Finally, p57(KIP2-)mediated stabilization of the actin cytoskeleton was associated with the displacement of hexokinase-1, an inhibitor of the mitochondrial voltage-dependent anion channel, from the mitochondria, providing a possible mechanism for the promotion of the mitochondrial apoptotic cell death pathway. Altogether, our findings link together two tumor suppressor properties of p57(KIP2), by showing that the promotion of cell death by p57(KIP2) requires its actin cytoskeleton stabilization function.
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kavanagh
authors.forename: P
authors.initials: P
authors.lastname: Vlachos
authors.forename: V
authors.initials: V
authors.lastname: Emourgeon
authors.forename: J
authors.initials: J
authors.lastname: Rodhe
authors.forename: B
authors.initials: B
authors.lastname: Joseph
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects*; D017209:Apoptosis / Q000187:drug effects*; D002465:Cell Movement; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism*; D015638:Cytochalasin D / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology*; D006367:HeLa Cells; D006593:Hexokinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D054461:Lim Kinases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D047630:Depsipeptides; C057531:jasplakinolide; D015638:Cytochalasin D; D050995:Voltage-Dependent Anion Channel 1; C472074:HK1 protein, human; D006593:Hexokinase; C515892:LIMK1 protein, human; D054461:Lim Kinases; D019311:Staurosporine