The focus of the Cheng laboratory is to elucidate the molecular mechanisms underlying cell death with the hope that the knowledge derived from our research can be translated into targeted therapeutics that trigger cell death in cancer.
Our prior studies have helped delineate the mammalian core apoptotic pathway governed by the BCL-2 family proteins at the mitochondrion. The BH3-only molecules activate multidomain pro-apoptotic BAX and BAK to trigger a mitochondrion-dependent cell death program, which releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction. On the contrary, anti-apoptotic BCL-2 family proteins including BCL-2, BCL-XL, and MCL-1 inhibit apoptosis by sequestering BH3-only molecules, thus preventing the activation of BAX and BAK.
Our recent work (1) subdivides the BH3-only molecules into BAX/BAK “activator” or BCL-2/BCL-XL/MCL-1 “inactivator” subgroups and establishes a hierarchical regulatory schema to integrate the interplay among various BCL-2 subfamilies; (2) defines a p53-cathepsin axis in DNA damage-induced programmed necrotic death; (3) discovers a VDAC2-BAK rheostat in controlling thymocyte survival and negative selection; and (4) proposes a stepwise activation model of BAX and BAK driven by BID, BIM, and PUMA in the initiation of mitochondrial apoptosis.
Our ongoing research seeks to delineate three major cell death pathways: (1) BAX/BAK-controlled mitochondrial apoptotic program, (2) BAX/BAK-dependent caspase-independent mitochondrial dysfunction, and (3) BAX/BAK-independent cell death. Moreover, we will explore whether and how deregulation of these cell death pathways contributes to the pathogenesis and treatment response of human cancer.