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Janardan Reddy, MD
Professor of Pathology
Ward 7-076
303 E. Chicago Avenue
Chicago, IL 60611
jkreddy@northwestern.edu
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Phone: (312) 503-7948
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Anatomic Pathology Division
Autopsy
Medical School
Osmania University (India)
Site of Residency
University of Kansas Hospital
Research Interests
The central effort of our laboratory, for several years, has been on a detailed analysis at the cellular and molecular levels of the pleiotropic responses induced by certain structurally diverse class of chemicals. These include fibrate class of hypolipidemic drugs, phthalate ester plasticizers, certain solvents, herbicides and others, which we designated as peroxisome proliferators. Our work has established that peroxisome proliferation is associated with increases in fatty acid oxidation and a reduction in serum lipids, and that peroxisome proliferators, as a class, are novel nongenotoxic hepatocarcinogens. Our studies on peroxisome proliferator-induced liver cancer introduced the concept that sustained generation of reactive oxygen species leads to oxidative stress and serves as the basis for liver cancer development. Furthermore, based on the tissue/cell specificity of pleiotropic responses and the coordinated transcriptional regulation of peroxisomal fatty acid ß-oxidation system genes, we postulated that peroxisome proliferators exert their action by a receptor-mediated mechanism. Our studies on the receptor concept laid the foundation for the discovery of a three member subfamily of nuclear receptors, appropriately designated peroxisome proliferator- activated receptor (PPAR) ?, ß (also called ? ) and ?. Of these PPAR? is responsible for the peroxisome proliferator-induced pleiotropic responses including hepatocarcinogenesis and energy combustion as it serves as a fatty acid sensor. PPARß plays a role in energy metabolism, whereas PPAR? functions in energy storage and conservation.
Our current work focuses on the molecular mechanisms responsible for PPAR action. Transcription of specific genes initiated by transcription factors/nuclear receptors is a complex process and involves the participation of multiprotein complexes composed of transcription coactivators. During the past 15 years, we and others have identified several coactivators. Coactivators contain one or more highly conserved LXXLL (L, leucine; X, any amino acid) motif for direct interaction with AF-2 (activation function 2) region in nuclear receptor. Our laboratory cloned PBP, PRIP, PIMT, PRIC285 and PRIC320 using either yeast two-hybrid screening or by isolating receptor binding proteins and their identification by MALDI-TOF analysis. We are generating gene knockout mouse models to elucidate the role of these coactivators in the regulation of specific gene transcription. Our work demonstrated that the deletion of PBP, PRIP PIMT and PRIC320 genes in the mouse results in embryonic lethality, indicating that these are vital for development and they alter the function of many nuclear receptors and other transcription factors during critical developmental stages. Recent developments in the area of conditional targeted somatic mutagenesis have opened new avenues for analyzing the physiological functions of coactivator signaling in a variety of tissues and cell types during early development and in the adult.
We have generated mice with floxed alleles for PBP, PRIP, PIMT and PRIC320 and are pursuing studies on liver specific conditional deletion. Work with PBP liver conditional null mice (PBP?Liv) has shown that PBP is essential for liver cell proliferation as these PBP null hepatocytes fail to respond to partial hepatectomy and to primary mitogens, such as Wy-14,643 and TCPOBOP. PBP null hepatocytes do not give rise to liver cancer but PBP positive cells in the PBP?Liv mouse livers show profound proliferative advantage and give rise to hepatocellular carcinomas. We described for the first time the amplification and over expression of coactivator PBP gene in breast cancer and that PBP functions as an estrogen receptor coactivator. Recent work with PBP mammary conditional null mice has shown that this coactivator is essential for mammary gland development and mammosphere formation. The amplification of PBP gene in breast cancer strongly favors the concept that it interacts with a wide variety of transcription factors and plays a key role in hormonal/ligand promotion of tumorigenesis. Additional investigations are necessary to dissect out the roles of MED1/PBP and other essential coactivators in selected critical biological processes, including thyroid development, function and neoplasia.
Selected Publications
Reddy JK, Krishnakantha TP. Hepatic peroxisome proliferation: Induction by two novel compounds structurally unrelated to clofibrate. Science 190:787-789, 1975.
Reddy JK, Azarnoff DL, Hignite CE. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature (London) 283:397-398, 1980.
Reddy JK, Goel SK, Nemali MR, Carrino JJ, Laffler TG, Reddy MK, Sperbeck SJ, Osumi T, Hashimoto T, Lalwani ND, Rao MS. Transcriptional regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome
proliferators. Proc Natl Acad Sci USA 83:1747-1751, 1986.
Yu S, Reddy JK. Transcription coactivators for peroxisome proliferator-activated receptors. Biochim Biophys Acta. 1771: 936-951, 2007
Guo D, Sarkar J, Suino-Powell K, Xu Y, Matsumoto K, Jia Y, Yu S, Khare S, Haldar K, Rao MS, Foreman JE, Monga SPS, Peters JM, Xu HE, Reddy JK. Induction of nuclear translocation of constitutive
androstane receptor by peroxisome proliferator-activated receptor alpha synthetic ligands in mouse liver. JBC 282:36766-36776, 2007.
Li H, Gade P, Nallar SC, Raha A, Roy SK, Karra S, Reddy JK, Reddy SP, Kalvakolanu DV. The Med1 subunit of transcriptional mediator plays a central role in regulating CCAAT/enhancer-binding protein-beta-driven transcription in response to interferon-gamma. J Biol Chem. 283:13077-86, 2008.
Surapureddi S, Rana R, Reddy JK, Goldstein JA. The coactivator NCOA6 mediates the synergistic activation of human cytochrome P-450 2C9 by the constitutive androstane receptor and hepatic nuclear factor-4{alpha}Mol Pharmacol. 2008 Jun 13.
Jia Y, Viswakarma N, Fu T, Yu S, Rao MS, Borensztajn J, Reddy JK. Conditional ablation of mediator subunit MED1 (MED1/PPARBP) gene in mouse liver attenuates glucocorticoid receptor-agonist dexamethasone-induced hepatic steatosis. Gene Expression 14:291-306, 2009.
View more Publications by Janardan Reddy, MD
listed in the National Library of Medicine (PubMed)
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