Novel Role of CHK2 in the intrinsic and Extrinsic Apoptosis Pathway.

摘要

In response to genotoxic stress, cells activate DNA damage checkpoint pathways that maintain genetic fidelity, promote cell survival, and prevent malignant transformation. Checkpoint kinase 2 (CHK2) is an evolutionarily conserved serine/threonine protein kinase that is activated in response to DNA double strand breaks. Upon activation by the DNA damage transducer kinase, ATM, CHK2 phosphorylates a wide variety of down stream effectors to promote cell cycle arrest, DNA repair and apoptosis. One of they key downstream substrate of CHK2 is the tumor suppressor protein, p53. CHK2 is considered as a key kinase in DNA damage-induced p53 regulation and thought to mediate most of its downstream effects through p53.;This dissertation has further strengthened the growing pool of evidence that CHK2 is dispensable for p53 regulation but rather signals to the apoptotic machinery through effector proteins other than p53. I have identified cellular Inhibitor of Apoptosis proteins (cIAPs) as novel CHK2 targets and established their role in CHK2-mediated cell death. In response to DNA damage, CHK2 inhibits both cIAP1 and cIAP2 to relieve their anti-apoptotic effects and drive cells into apoptosis. CHK2 inhibits the E3 ubiquitin ligase activity of cIAP2 in a phosphorylation dependent manner and potentially regulates cIAP1 through its interaction with cIAP2. Furthermore, this work provides preliminary evidence that CHK2 serves as a negative regulator of the NFkappaB pathway through the inhibition of cIAPs. Upon activation, CHK2 potentiates TNF&agr; Related Apoptosis Inducing Ligand (TRAIL)-induced apoptosis through the regulation of the NFkappaB pathway.;Overall, my work has discovered a novel role of CHK2 in the DNA damage induced intrinsic apoptotic pathway and uncovered its potential role in death receptor mediated extrinsic apoptotic pathway.