Apoptosis and autophagy are both tightly regulated cellular processes that play crucial roles in life and death decisions of the cell, tissue homeostasis, development, and cancer biology. The first discovered anti-apoptotic protein was Bcl-2, and our laboratory identified the first mammalian autophagy protein, Beclin 1. In the previous project period, we demonstrated that Bcl-2 functions as an anti-autophagy protein, and identified a key biochemical mechanism (i.e. stress-induced Bcl-2 multisite phosphorylation) underlying the regulation of interactions between Bcl-2 and Beclin 1. During the next project period, we propose to gain a deeper understanding of both the molecular mechanisms regulating the Bcl-2/Beclin 1 interaction, and the in vivo physiological significance of Bcl-2 regulation of Beclin 1-dependent autophagy. In the first specific aim, we will use structural biology, biochemical, and cell biology approaches to define novel molecular determinants that regulate the interaction between Bcl-2 and Beclin 1. We will use nuclear magnetic resonance (NMR) to identify residues in cellular Bcl-2 that are predicted to be selectively involved in binding to Beclin 1 (but not other BH3 domain containing proteins), test these predictions in functional assays, and perform biochemical and cell biology studies to investigate whether starvation-regulated post-translational modifications of Beclin 1 that we have identified in preliminary studies (e.g. serine phosphorylation, arginine methylation) are: (1) regulated by Bcl-2;(2) modify Bcl-2/Beclin 1 interactions;and (3) modify Beclin 1 autophagic activity. In the second specific aim, we will evaluate the in vivo physiological significance of Bcl-2 modulation of the autophagy function of Beclin 1, using targeted mutant mice that express mutant forms of either Bcl-2 or Beclin 1 that alter the normal regulation of the Bcl-2/Beclin 1 interaction. We will characterize previously generated Bcl-2 nonphosphorylatable mutant mice that are predicted to constitutively inhibit Beclin 1 function (as well as newly generated mice based on our results with studies in the first specific aim) with respect to in vivo regulation of autophagy and autophagy-dependent biological processes. Together, these studies are expected to help elucidate the molecular mechanisms underlying the control of autophagy by the Bcl-2/Beclin 1 complex and the significance of this complex in regulating life and death decisions of the cell, tissue homeostasis, development, and cancer biology.

Public Health Relevance

We are studying two proteins, Bcl-2 and Beclin 1, that interact with each other and are each known to play a role in regulating whether cells live or die, how multicellular organisms develop and adapt to different forms of stress, and how human cancers occur and respond to treatment. The goal of our studies is to understand how the interaction between these proteins is regulated and how this interaction contributes to the ability of mammals to successfully adapt to stress, to develop normally, and to avoid cancer.

National Institute of Health (NIH)
Research Project (R01)
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Cellular Signaling and Regulatory Systems Study Section (CSRS)
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Salnikow, Konstantin
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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Lee, Eunmyong; Koo, Yeon; Ng, Aylwin et al. (2014) Autophagy is essential for cardiac morphogenesis during vertebrate development. Autophagy 10:572-87
An, Zhenyi; Tassa, Amina; Thomas, Collin et al. (2014) Autophagy is required for G?/G? quiescence in response to nitrogen starvation in Saccharomyces cerevisiae. Autophagy 10:1702-11
Green, Douglas R; Levine, Beth (2014) To be or not to be? How selective autophagy and cell death govern cell fate. Cell 157:65-75
Nassif, Melissa; Valenzuela, Vicente; Rojas-Rivera, Diego et al. (2014) Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis. Autophagy 10:1256-71
Su, Minfei; Mei, Yang; Sanishvili, Ruslan et al. (2014) Targeting ?-herpesvirus 68 Bcl-2-mediated down-regulation of autophagy. J Biol Chem 289:8029-40
Huang, Shuyi; Jia, Kailiang; Wang, Ying et al. (2013) Autophagy genes function in apoptotic cell corpse clearance during C. elegans embryonic development. Autophagy 9:138-49
He, Congcong; Wei, Yongjie; Sun, Kai et al. (2013) Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 154:1085-99
Wei, Yongjie; Zou, Zhongju; Becker, Nils et al. (2013) EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154:1269-84
He, Congcong; Bassik, Michael C; Moresi, Viviana et al. (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481:511-5
Strappazzon, Flavie; Vietri-Rudan, Matteo; Campello, Silvia et al. (2011) Mitochondrial BCL-2 inhibits AMBRA1-induced autophagy. EMBO J 30:1195-208

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