西亚试剂 :Cancer-Associated Protein Kinase C Mutations Reveal Kin

Summary：Protein kinase C (PKC) isozymes have remained elusive cancer targets despite the unambiguous tumor promoting function of their potent ligands， phorbol esters， and the prevalence of their mutations. We analyzed 8% of PKC mutations identified in human cancers and found that， surprisingly， most were loss of function and none were activating. Loss-of-function mutations occurred in all PKC subgroups and impeded second-messenger binding， phosphorylation， or catalysis. Correction of a loss-of-function PKCβ mutation by CRISPR-mediated genome editing in a patient-derived colon cancer cell line suppressed anchorage-independent growth and reduced tumor growth in a xenograft model. Hemizygous deletion promoted anchorage-independent growth， revealing that PKCβ is haploinsufficient for tumor suppression. Several mutations were dominant negative， suppressing global PKC signaling output， and bioinformatic analysis suggested that PKC mutations cooperate with co-occurring mutations in cancer drivers. These data establish that PKC isozymes generally function as tumor suppressors， indicating that therapies should focus on restoring， not inhibiting， PKC activity.以上资料由西亚试剂：http://www.xiyashiji.com/提供