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Faculty Detail     Name KESHAV K SINGH   Campus Address KAUL 620A Zip 0024 Phone 205-934-2735 E-mail kksingh@uab.edu Other websites www.mitochondria.org

Faculty Appointment(s) Appointment Type Department Division Rank Primary  Genetics   Genetics Research Div Professor Center  Center for Aging  Center for Aging Professor Center  Comprehensive Cancer Center  Comprehensive Cancer Center Professor Center  General Clinical Research Center  Ctr for Free Radical Bio Professor

Biographical Sketch  Dr. Singh obtained his undergraduate degree in India, Ph.D. degeree in Australia and the postdoctoral fellowships in USA at University of Florida and at Harvard. After completing his postdoctoral fellowship, he joined Johns Hopkins School of Medicine as Assistant Professor of Oncology and as Assistant Professor of Environmental Health at Johns Hopkins School of Public Health. In 2003, he moved to Roswell Park Cancer Institute, Buffalo, NY as Associate Professor of Oncology. At Roswell he rose through the ranks to Professor and then to Distinguish Professor of Oncology. Since 2011, he is Joy and Bill Harbert Endowed Chair and Director of Cancer Genetics Program at UAB Comprehensive Cancer Center. He is a Professor of Genetics, Pathology and Environmental Health. He is also a member of Center for Free Radical Biology and Center for Aging at UAB. Dr. Singh is the author of more than 80 research publications and three books. He serves on various expert panels in the United States, Italy, UK, France and other countries. He has won numerous awards. He founded the Mitochondria Research and Medicine Society in USA (www.mitoamerica.org) and in India (www.mitoindia.org).

Society Memberships Organization Name Position Held Org Link American Association for Cancer Research  Active Member  www.aacr.org  Mitochondria Research and Medicine Society  Founder  www.mitoamerica.org  Society for Free Radical Biology and Medicine  Active Member  www.sfrbm.org

Research/Clinical Interest Title Mitochondria-to-nucleus retrograde cross talk, oxidative stress, genomic instability and its role in cancer Description With the exception of peripheral red blood cells, mitochondria are present in all eukaroytic cells in varying numbers, from hundreds to thousands. Mitochondria perform multiple cellular function and are the major source of cellular energy and of reactive oxygen species (ROS). It is estimated that human cells produce up to 10 million ROS/mitochondrion/day. In mitochondria, the ROS are formed by the univalent reduction of molecular oxygen that is mediated by reactive compounds such as semi-ubiquinone, which are involved in electron transport chain. ROS cause oxidative stress, mutations, and promote tumor formation and progression. The growth promoting effects of oxidative stress in cancer is due to oxidative stress responsive signal transduction. Oxidative stress is also implicated in aging, and many diseases including heart, lung and neurodegenerative diseases. The long-term goal of our laboratory is to understand the mechanisms of mitochondria mediated oxidative stress, genomic instability and its role in cancer. Currently, research in the laboratory is focused on identifying pathway(s) that protect cells from mitochondrial oxidative stress and genomic instability of both the mitochondrial and nuclear genomes. We are also conducting experiments to identify genes that are involved in monitoring the functional state of mitochondria and transducing signals from dysfunctional mitochondria to the nucleus (Mitochondria-to-Nucleus communication). These studies employ the unicellular eukaryote Saccharomyces cerevisiae yeast, mouse, and mammalian cell culture model systems to study these processes. Environmental carcinogens, pharmacological and chemotherapeutic agents are used to induce oxidative stress and genomic instability. Our approach uses both molecular and genetic methods in concert: molecular assays are used to detect and characterize genes of interest and in vivo function of the proteins is assessed by genetic analysis. In addition to understanding basic mechanisms, we have also taken a multidisciplinary translational approach to identify molecular markers of oxidative stress that help in detection, diagnosis and treatment of cancer and other oxidative stress related diseases. Described below are the ongoing projects in my laboratory: 1)Genetics of mitochondria-to-nucleus communication in human breast epithelial cells and its role in breast cancer: We have determined the global gene expression profile in response to loss of mitochondrial function in breast epithelial cells. This project investigates the role of identified genes in primary breast cancer. Currently we are investigating the function of one such protein called BACH1 (BRCA1 interacting protein) involved in mitochondria-mediated nuclear genomic instability and its role in breast cancer. 2)Genetics of mitochondria-to-nucleus communication in yeast cells: This project investigates the genes and mechanisms involved in monitoring the functional state of mitochondria, the major site of ROS production. We have used cDNA microarray to determine the global gene expression profile in response to loss of mitochondrial function and are currently investigating the pathways that protect cells from mitochondria-mediated nuclear mutator phenotype. 3)Genetics of arsenic induced cancers: Millions of people around the world are exposed to arsenic. Arsenic is one of the few human carcinogens that do not induce tumors in laboratory animals except at extremely high doses that are irrelevant to human exposure conditions. Therefore, development of models for arsenic-induced cancer is critical for understanding the mechanisms underlying the tumorigenic process. We have developed a breast and prostate epithelial cell model for arsenic-induced cancer. This project investigates the genetic mechanisms involved in induction of these cancers due to exposure to arsenic in the environment.

Selected Publications  Publication PUBMEDID Azrak S, Ayyasamy V, Zirpoli G, Ambrosone C, Bandera EV, Bovbjerg DH, Jandorf L, Ciupak G, Davis W, Pawlish KS, Liang P, Singh KK. CAG Repeat variants in the POLG1 gene encoding mtDNA polymerase-gamma and risk of breast cancer in African-American women. PLoS One. 2012;7(1):e29548. Hall BM, Owens K, Singh KK, Distinct Functions of Evolutionary Conserved MSF1 and LEA-like Domains in Mitochondria, Journal of Biological Chemistry, 286:39141–39152, 2011 Ayyasamy V, Owens KM, Desouki MM, Liang P, Bakin A, Thangaraj K, Buchsbaum DJ, LoBuglio AF, Singh KK, Cellular model of Warburg effect identifies tumor promoting function of UCP2 in breast cancer and its suppression by genipin. PloS ONE, 6(9): e24792. doi:10.1371/journal.pone.0024792, 2011 Owens KM, Kulawiec M, Desouki MM, Ayyasamy V, and Singh KK, Impaired OXPHOS Complex III in breast cancer. PloS ONE, 6(8): e23846.doi:10.1371/ journal.pone.0023846, 2011 Desler C, Lise MM, Singh KK, Rasmussen LJ, The importance of mitochondrial DNA in aging and cancer, Journal of Aging research. 2011:407536, 2011. Graham K, Kulawiec M, Owens K, Li X, Desouki MM, Chandra D and Singh KK, NADPH oxidase 4 is an oncoprotein localized to the mitochondria, Cancer Biology and Therapy 10:223-231, 2010. Rangel R, McKeller MR, Sims-Mourtada JC, Cain K, Kashi C, Melnikova V, Ananthaswamy HN, Blackburn MR, Cande C, Larochette N, Kroemer G, Singh K.K., and Martinez-Valdez, H. PRELI protects mitochondria, prevents AIF nuclear translocation and opposes apoptosis. Cell Death and Disease: e21; doi:10.1038/cddis.2009.19, 2009 Kim H, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JP, Riet van der Meer R, Nguyen P, Savage J, Owens K M. Vassilopoulos A, Ozden O, Park S, Singh KK, Abdulkadir SA, Spitz DR. Deng , C and Gius D, SIRT3 is a Mitochondrial Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism, Cancer Cell, 17:41-52, 2010. Yang D, WangM-Z, Tang Y, Chen Y, Jones T, Brewer G, Rao K, Singh K.K. and Nie D, Impairment of Mitochondrial Respiration in Mouse Fibroblasts by Oncogenic H-Ras, Cancer Biology and Therapy, 9:122-133, 2010. Kulawiec M, Owens K, Singh K.K. mtDNA G10398 variant in African-American women with breast cancer provide resistance to apoptosis and promote metastasis in mice. Journal of Human Genetics, 54:647-54, 2009. Singh KK, Ayyasamy V, Owens K, Kaul MS and Vujcic M., Mutations in mitochondrial DNA polymerase γ promote tumorigenesis, Journal of Human Genetics 54:516-524, 2009. Kulawiec M, Owens K, Singh KK., Cancer cell mitochondria confer apoptsois resistance and promote metastatis, Cancer Biology and Therapy, 8: 69 – 76, 2009. Hall BM, Ma C-X Liang P and Singh KK, Fluctuation AnaLysis CalculatOR (FALCOR): a web tool for the determination of mutation rate using Luria-Delbrück fluctuation analysis. Bioinformatics, 25:1564-1565, 2009.

Keywords mitochondria, genomic instability, cancer, breast cancer, prostate, arsenic, oxidative stress

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