Silencing of CDK2, but not CDK1, separates mitogenic from anti-apoptotic signaling, sensitizing p53 defective cells for synthetic lethality.

ABSTRACT: Small molecule inhibitors targeting CDK1/CDK2 have been clinically proven effective against a variety of tumors, albeit at the cost of profound off target toxicities. To separate potential therapeutic from toxic effects, we selectively knocked down CDK1 or CDK2 in p53 mutated HACAT cells by siRNA silencing. Using dynamic, cell cycle wide proteome arrays, we observed minor changes in overall abundance of proteins critically involved in cell cycle transition despite profound G₂/M or G₁/S arrest, respectively. Employing phospho site specific analyses, we identified uncoupled mitogenic, yet pro-apoptotic signaling from counter balancing anti-apoptotic activity in CDK2 disrupted cells. Moreover, a crucial role of CDK2 activity in early serum response was observed, extendin

SUBMITTER: Nekova TS 

PROVIDER: S-EPMC5176141 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature