James R. Broach Position Professor of Molecular Biology, Emeritus Email [email protected] Bio/Description Biography Current Position Professor and Chair Department of Biochemistry and Molecular Biology Penn State College of Medicine Director Penn State Institute for Personalized Medicine Contact Princeton University Email: [email protected] Penn State C5757 Penn State Hershey Medical Center 500 University Drive Hershey, PA 17033 Tel: (717) 531-8556 Fax: (717) 531-7072 Email: [email protected] Dr. Broach is Chair of the Department of Biochemistry and Molecular Biology at Penn State Hershey, Director of the Penn State Institute for Personalized Medicine and Professor Emeritus of Princeton University. He completed his undergraduate studies in Chemistry at Yale University in 1969 and his Ph.D. in Biochemistry from the University of California, Berkeley in 1973, where he also completed a Postdoctoral Fellowship in Medical Physics. Dr. Broach served on the Scientific Review Board of the Frederick Cancer Center of the National Cancer Institute and has served as a member of both the Genetics and the Genomics Study Sections and Chair of the Genomics, Computational Biology and Technology Study Section of the National Institutes of Health. He was Co-Founder and Director of Research for Cadus Pharmaceuticals and sits on the Board of Directors of Cadus Corporation. Dr. Broach was Professor of Molecular Biology at Princeton University from 1984-2012, where he served as Associate Director of the Lewis Sigler Institute for Integrative Genomics and Co-Director of the Center for Computational Biology. Dr. Broach is a Fellow of the American Academy of Microbiology and the Co-Director of the Life Sciences Research Foundation, a private organization that provides postdoctoral fellowships in the life sciences. Dr. Broach is a member of the Science Board of the Food and Drug Administration and served as Trustee of the University of Medicine and Dentistry of New Jersey and Commissioner on the New Jersey Commission on Cancer Research until 2012. He is a member of the executive committee of the Cancer Biology Training Consortium, a national organization promoting graduate and postdoctoral training in cancer biology. Dr. Broach has published more than 150 articles in the area of molecular biology and holds a number of patents in drug discovery technologies. Research Focus Our studies focus on determining how the cell makes the decision to grow, how it modulates its growth in response to nutrient availability and how it survives when conditions are inhospitable for growth. These studies span short term events, such as metabolic remodeling, through intermediate effects of stress response to long term adaptation of quiescence. These studies are conceptually joined by the role of signaling pathways as the drivers of these processes. Research in the Broach lab addresses the fundamental question of how cells regulate their growth and development in response to environmental conditions, such as their nutritional status and external stress. Two major nutrient sensing networks – the Ras/protein kinase A (PKA) pathway and the rapamycin-sensitive TORC1 - link nutrient status to cellular processes, including ribosome biogenesis and growth, autophagy, stress response and entry into quiescence. Our studies have led us to the unexpected conclusion that yeast cells make their growth decisions on the basis of their perception of nutrient availability, as monitored through these signaling networks, rather than on the basis of their use of those nutrients. Consistent with that interpretation, activating alleles of Ras in yeast drive a proliferative program even in the absence of nutrients. This observation resonates with the fact that oncogenic, activating mutations of ras in mammalian cells drive cells into proliferation in spite of external countervailing signaling enjoining the cells to stop growing. Thus, besides addressing the fundamental question of control of cell growth, our ongoing studies into the means by which input from these two pathways yield a coherent growth response highlight means by which higher cells integrate external cues and address how manipulation of signaling networks can be leveraged to achieve therapeutic ends. Regulation of metabolism through signaling networks. Central to cell growth is the metabolism of nutrients, which generates energy, creates building blocks for macromolecular biosynthesis and promotes synthesis of the panoply of chemical entities that are needed to make two cells from one. We have found that signaling pathways impinge on metabolic enzymes, not only as regulators of the transcript levels and stability of the proteins but also as regulators of enzymatic activity through post-translational modifications. Many such post-translational modifications have been identified and studied, including rate limiting steps in the glycolyic pathway regulated by PKA in yeast. We continue to study, though a marriage of molecular genetics, proteomic and metabolomic methods, how these posttranslational modifications affect metabolic flow in the cell. Cellular stress response. All cells perceive and respond to environmental stresses and that response is critical to a cell’s survival under continued adverse conditions. In yeast cells, a number of sensing pathways provide input regarding potentially stressful environmental conditions and converge on stress sensitive transcription factors, one of which is encoded redundantly by MSN2 and MSN4. These transcription factors serve as foci through which cells integrate information on their environmental state and develop responses that are appropriate to that state. By examining the response of individual cells to stress in microfluidic devices, we have defined the network of signaling pathways transmitting the stress response. We have established that noise in the signaling network permits genetically identical cells to mount different responses to identical stimuli, a process that allows populations of cells to “hedge their bets” with regard to survival strategies in a changing and unpredictable environment. Quiescence – the essence of chronological aging. Under prolonged stress or sustained starvation, cells exit the proliferation state and enter a poorly defined quiescence state. Mammalian cells such as fibroblasts, stem cells and memory T and B lymphocytes can exit the proliferative state in response to specific cues and enter a quiescent state called G0 to indicate that this state is distinct from any that are traversed during the normal cell cycle. Despite the ubiquity and importance of quiescence, we have little understanding of the nature or this state or the means by which cells transit into and out of it. We are using a combination of highly parallel genetic screens in conjunction with proteomic and phosphoproteomic analysis to define the essential characteristics of quiescence and identify the means of inducing entry and exit from that state. Analysis in yeast of chronological lifespan, the functional equivalent of quiescence, has been uncannily predictive of processes that influence lifespan in mammalian organisms. Thus, understanding the forces that regulate entry and exit from quiescence could profoundly affect our ability to manipulate lifespan in mammalian species such as ourselves. Awards American Heart Association Established Investigator; Fellow, American Academy of Microbiology; President (2010-2011) Cancer Biology Training Consortium; Commissioner, NJ Commission on Cancer Research; Trustee, University of Medicine and Dentistry of NJ. Selected Publications Tolkunov D, Zawadzki KA, Singer C, Elfving N, Morozov AV, Broach JR. (2011) Chromatin remodelers clear nucleosomes from intrinsically unfavorable sites to establish nucleosome-depleted regions at promoters. Mol Biol Cell. [Epub ahead of print] Klosinska MM, Crutchfield CA, Bradley PH, Rabinowitz JD, Broach JR. (2011) Yeast cells can access distinct quiescent states. Genes Dev. 25: 336-349. PubMed Lippman SI, Broach JR. (2009) Protein kinase A and TORC1 activate genes for ribosomal biogenesis by inactivating repressors encoded by Dot6 and its homolog Tod6. Proc Natl Acad Sci 106: 19928-19933. PubMed Zawadzki KA, Morozov AV, Broach JR. (2009) Chromatin-dependent transcription factor accessibility rather than nucleosome remodeling predominates during global transcriptional restructuring in Saccharomyces cerevisiae. Mol Biol Cell. 20: 3503-3513. PubMed Freckleton G, Lippman SI, Broach JR, Tavazoie S. (2009) Microarray profiling of phage-display selections for rapid mapping of transcription factor-DNA interactions. PLoS Genet. 5: e1000449. PubMed Zaman S, Lippman SI, Schneper L, Slonim N, Broach JR. (2009) Glucose regulates transcription in yeast through a network of signaling pathways. Mol Syst Biol. 5: 245. PubMed Airoldi EM, Huttenhower C, Gresham D, Lu C, Caudy AA, Dunham MJ, Broach JR, Botstein D, Troyanskaya OG. (2009) Predicting cellular growth from gene expression signatures. PLoS Comput Biol. 5: e1000257. PubMed Zaman S, Lippman SI, Zhao X, Broach JR. (2008) How Saccharomyces responds to nutrients. Annu Rev Genet 42: 27-81. PubMed. Tan MP, Broach JR, Floudas CA. (2007) Evaluation of normalization and pre-clustering issues in a novel clustering approach: global optimum search with enhanced positioning. J Bioinform Comput Biol 5: 895-913. PubMed McClean NM, Broach JR, Ramanathan S. (2007) Cross-talk and decision making in MAPK pathways. Nat Genet 39: 409-414. PubMed Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, Broach JR, De Virgilio C, Hall MN, Loewith R. (2007) Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell 26: 663-674. PubMed Tan MP, Broach JR, Floudas CA (2007) A novel clusting approach and prediction of optimum number of clusters: Global optimization search with enhanced positioning. J Global Optim 39: 323-346. Ramanathan S, Broach JR. (2007) Do cells think? Cell Mol Life Sci 64: 1801-1804. PubMed Yorimitsu T, Zaman S, Broach JR, Klionsky DJ. (2007) Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. Mol Biol Cell 18: 4180-4189. PubMed Tan MP, Broach JR, Floudas CA. (2007) Evaluation of normalization and pre-clustering issues in a novel clustering approach: global optimum search with enhanced positioning. J Bioinform Comput Biol.5: 895-913. PubMed Xu EY, Zawadzki KA, Broach JR. (2006) Single cell observations reveal intermediate transcriptional silencing states. Mol Cell 23: 219-229. PubMed Houston PL, Broach JR. (2006) The dynamics of homologous pairing during mating type interconversion in budding yeast. PLoS Genet 2: e98. PubMed Ault AD, Broach JR. (2006) Creation of GPCR-based chemical sensors by directed evolution in yeast. Protein Eng Des Sel 19: 1-8. PubMed Broach JR. (2006) Cell Growth. In: Landmark Papers in Yeast Biology. Cold Spring Harbor Lab Press, Cold Spring Harbor, NY, pp. 127-140. Ault AD, Broach JR. (2005) Creation of GPCR based chemical sensors by directed evolution in yeast. Protein Eng Des Sel 19: 1-8. PubMed Niida A, Wang Z, Tomita K, Oishi S, Tamamura H, Otaka A, Navenot JM, Broach JR, Peiper SC, Fujii N. (2005) Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity. Bioorg Med Chem Lett 16: 134-137. PubMed Xu E, Bi X, Holland M, Gottschling DE, Broach JR. (2005) Mutations in the nucleosome core enhance transcriptional silencing. Mol Cell Biol 25: 1846-1859. PubMed Broach JR. (2004) Making the right choice--long-range chromosomal interactions in development. Cell 119: 583-589. PubMed Schneper L, Düvel K, Broach JR. (2004) Sense and sensibility: Nutritional response and signal integration in yeast. Curr Opin Microbiol 7: 624-630. PubMed Jorgensen P, Rupes I, Sharom JR, Schneper L, Broach JR, Tyers M. (2004) A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18: 2491-2505. PubMed Santhanam A, Hartley A, Düvel K, Broach JR, Garrett S. (2004) PP2A phosphatase is required for stress and TOR kinase regulation of yeast stress response factor Msn2. Euk Cell 3: 1261-1271. PubMed Düvel K, Broach JR. (2004) The role of phosphatases in TOR signaling in yeast. Curr Top Microbiol Immunol 279: 19-38. PubMed Houston P, Simon P, and Broach JR (2004). The Saccharomyces cerevisiae recombination enhancer biases recombination during inter-chromosomal mating type switching but not in inter-chromosomal homologous recombination. Genetics 166: 1187-1197. PubMed Masui T, Doi R, Mori T, Toyoda E, Koizumi M, Kami K, Ito D, Peiper SC, Broach JR, Oishi S, Niida A, Fujii N, Imamura M (2004). Metastin and its variant forms suppress migration of pancreatic cancer cells. Biochem Biophys Res Commun 315: 85-92. PubMed Zhang WB, Wang ZX, Murray JL, Fujii N, Broach J, Peiper SC (2004). Functional expression of CXCR4 in S. cerevisiae: development of tools for mechanistic and pharmacologic studies. Ernst Schering Res Found Workshop 45: 125-152. PubMed Schneper L, Krauss A, Miyamoto R, Fang S and Broach JR (2004). The Ras/Protein kinase A pathway acts in parallel with the Mob2/Cbk1 pathway to effect cell growth and proper bipolar bud site selection. Euk Cell 3: 108-120. PubMed Wang Y, Pierce M, Schneper L, Guldul C, Zhang X, Tavazoie S, and Broach JR (2004). Ras and Gpa2 mediate the primary branch of a redundant glucose signal pathway in yeast. PLOS 2: 610-622. PubMed Fujii N, Oishi S, Hiramatsu K, Araki T, Ueda S, Tamamura H, Otaka A, Kusano S, Terakubo S, Nakashima H, Broach JR, Trent JO, Wang ZX, Peiper SC (2003). Molecular-size reduction of a potent CXCR4-chemokine antagonist using orthogonal combination of conformation- and sequence-based libraries. Angew Chem Int Ed Engl 42: 3251-3253. PubMed Lin X, Floudas C, Wang Y and Broach JR (2003). Theoretical and computational studies of glucose signaling pathways in yeast using global gene expression data. Biotechnol Bioeng 84: 864-886. PubMed Arias DA, Navenot JD, Zhang W, Broach JR and Peiper SC (2003). Constitutive activation of CCR5 and CCR2 induced by conformational changes in the conserved T-X-P motif in transmembrane helix 2. J Biol Chem 278: 36513-36521. PubMed Düvel K, Santhanam A, Garrett S and Broach JR (2003). Multiple roles of Tap42 in mediating rapamycin-induced transcriptional changes in yeast. Mol Cell 11: 1467-1489. PubMed Yu Q, Qiu R, Foland TB, Griesen D, Galloway CS, Chiu Y, Broach JR and Bi X (2003). Rap1p and other transcriptional regulators can function in defining distinct domains of gene expression. Nucleic Acids Res 31: 1224-1233. PubMed Simon P, Houston P and Broach JR (2002). Directional bias during mating type switching in Saccharomyces is independent of chromosomal architecture. EMBO J 21: 2282-2291. PubMed Zhang WB, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A, Pei G, Manfredi JP, Fujii N, Broach JR, Peiper SC (2002). A point mutation that confers constitutive activity to chemokine receptor CXCR4 reveals T140 is an inverse agonist and AMD3100 and ALX40-4C are weak partial agonists. J Biol Chem 277: 24515-24521. PubMed Johnston SD, Enomoto S, Schneper L, McClellan MC, Twu F, Montgomery N, Haney S, Broach JR and Berman J (2001). Suppression of the RAS/cAMP signal transduction pathway by CAC3/MS11 is independent of Chromatin Assembly Factor-I and is mediated by NPR1. Mol Cell Biol 21: 1784-1794. PubMed Nielsen KH, Gredsted L, Broach JR, and Willumsen BM (2001). Sensitivity of wild type and mutant Ras alleles to ras specific exchange factors: Identification of factor specific requirements. Oncogene 20: 2091-2100. PubMed Haney S, Xu J, Lee S-Y, Broach JR, and Manfredi JP (2001). Genetic selection in Saccharomyces of mutant mammalian adenylyl cyclases with elevated basal activities. Mol Gen Genet 265: 1120-1128. PubMed