Glucose metabolism and apoptosis are considered major, but independent pathways critical for cell survival and cellular transformation. Much of the mammalian apoptotic pathway operates at organelles, especially mitochondria. The BCL-2 family proteins constitute a critical control point in apoptosis and regulate the release of cytochrome c from mitochondria. The BH3-only pro-apoptotic molecules, including BAD require BAX/BAK to mediate death and operate upstream connecting proximal death and survival signals to the core apoptotic pathway. Loss of function models show that individual BH3-only proteins respond to selected signals in restricted cell types as specialized """"""""sentinels"""""""" that monitor physiologic pathways. The pro-apoptotic activity of BAD is regulated through serine phosphorylation by kinases activated in response to extra cellular growth/survival factors, including PKA. Proteomic analysis of liver mitochondrial complexes revealed that BAD resides in a functional holoenzyme complex together with PKA and PP1 catalytic units, Wiskott-Aldrich family member WAVE-1 as an A Kinase Anchoring Protein (AKAP) and glucokinase. Bad mouse models endorse a role for BAD in regulation of glucose withdrawal induced apoptosis and glucose homeostasis. Thus BAD may function both as a specialized apoptotic """"""""sentinel"""""""" responding to abnormalities in glucose metabolism and as an integral regulator embedded in pathways of glucose sensing and utilization. This proposal investigates how BAD integrates glycolysis and apoptosis through the complex it forms at mitochondria. This knowledge will help uncover the molecular mechanism(s) whereby BAD regulates in vivo physiology making use of aberrations in the Bad-/- and Bad3SA mouse models. This includes the development of diffuse large B cell lymphoma (DLBCL) in Bad-/- mice. In SA1, detailed whole animal physiology studies are proposed to establish how the BAD/GK complex may cue the function of key tissues involved in maintaining glucose homeostasis. The experiments described in SA2, would utilize biochemical and genetic approaches to address the contribution of individual components of the complex to its physiological roles. In SA3, the generality of BAD regulation of glucose metabolism in tissues expressing hexokinases other than GK is explored. Specific emphasis is given to the B cell lineage origin of tumors found in Bad-/-mice. This provides a unique opportunity to examine whether BAD-dependent regulation of glycolysis and metabolism-regulated apoptosis contribute to cellular transformation. A diverse team of internationally-recognized mentors, collaborators, and advisors with expertise in the fields of biochemistry, genetics, cell biology, and physiology will provide an ideal training environment for Dr. Danial's development as an independent investigator. Dr. Korsmeyer, a world leader in the fields of oncogenesis and apoptosis, has an excellent record of training and fostering independent investigators.
|Giménez-Cassina, Alfredo; Garcia-Haro, Luisa; Choi, Cheol Soo et al. (2014) Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab 19:272-84|
|Giménez-Cassina, Alfredo; Martínez-François, Juan Ramón; Fisher, Jill K et al. (2012) BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron 74:719-30|
|Danial, Nika N; Walensky, Loren D; Zhang, Chen-Yu et al. (2008) Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14:144-53|