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Our research focuses on dissecting the molecular mechanisms of programmed cell death. Apoptosis is essential for the successful development and maintenance of tissue homeostasis in all metazoans. Deregulation of apoptosis contributes to a variety of pathologic processes including cancer, neurodegenerative disorders, and autoimmune disease.

The BCL-2 family constitutes a crucial checkpoint in apoptosis and consists of both anti-apoptotic and pro-apoptotic members. Pro-apoptotic BCL-2 members can be further subdivided into more fully conserved, "multidomain" members or "BH3-only" members. Using genetic and biochemical approaches, we have helped delineate the core apoptotic pathway in mammals. The "BH3-only" molecules activate "multidomain" pro-apoptotic BAX and BAK to trigger a mitochondrion-dependent cell death pathway. Conversely, anti-apoptotic BCL-2/BCL-XL sequesters translocated "BH3-only" molecules in stable mitochondrial complexes, thus preventing the activation of BAX/BAK. Loss of function studies revealed that the absence of pro-apoptotic BAX and BAK creates a profound block in apoptosis triggered by diverse death signals. Thus, activation of a "multidomain" member, BAX or BAK, appears to be an essential gateway to the mitochondrion-mediated cell death program. However, how cells keep the potentially lethal BAX and BAK in check and how "BH3-only" molecules activate BAX and BAK remain unclear. Using protein cross-linking in conjunction with serial protein chromatographic purification steps, we have identified VDAC2 as a negative regulator of BAK activation.

We are currently investigating how "BH3-only" molecules integrate specific death signals to activate "multidomain" BAX/BAK and utilizing a proteomic approach to identify higher order multi-protein complexes at the mitochondrion that regulate apoptosis and mitochondrial homeostasis. Mouse genetic approaches are undertaken to probe the physiologic roles of death regulators in development. The apoptotic machinery is a promising target of cancer therapy since cancer cells often have a defect in the apoptotic pathway. Our ultimate goal is to apply the information obtained from studies of death regulators to develop novel anti-cancer therapeutics.

Comparison of apoptotic hallmarks in VDAC2-/- and wt cells Two-color fluorescence microscopy of wt and VDAC2-/- MEF lines at 4 hours after 1 µM STS. Red indicates cytochrome c and blue is Hoechst staining of DNA. From: Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsmeyer SJ VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 2003 Jul 25;301(5632):513-7

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Updated: April 29, 2008