The investigator is a senior resident in Clinical Pathology Training at Northwestern University Medical School, who will be board-eligible in the spring of year 2000. He will join the Department of Pathology as Assistant Professor, tenure-eligible Investigator-Clinician track, beginning April 1, 2000, to develop an independent hypothesis driven basic research program focusing on the role of nuclear receptor coactivators in development, differentiation and neoplastic conversion in breast induced by natural and synthetic ligands of nuclear receptors. Northwestern University provides an excellent environment for research dealing with nuclear receptors, transcription factors, and nuclear receptor coactivators on the responses of genes, cells, tissues, and species to the influence of natural and synthetic agonists and antagonists. Strong programs in molecular mechanisms of xenobiotic mediated transcriptional activation of genes exist with nationally recognized leaders dealing with: peroxisome proliferators (Drs. J. K. Reddy, T. Hashimoto, and M. S. Rao), responses of cells to environmental stress and altered gene products (Dr. R. Morimoto), molecular mechanisms of copper, mercury and other trace metal toxicity and the role of metallochaperones (Dr. T. O'Halloran), transcriptional corepressors and coactivators (thyroid and estrogen receptor action, Dr. L. Jameson; mitochondrial gene regulation, Dr. R. Scarpulla; and coactivators in cell cycle regulation Dr. B. Thimmapaya), and prevention of breast cancer using antiestrogens tamoxifen and raloxifene (Dr. C. Jordan). Some of these individuals also serve as preceptors on the pre- and postdoctoral Molecular Toxicology Training Program (NIEHS) at Northwestern University. The goal of the mentored Clinical Scientist Development Program is to fully train Dr. Yijun Zhu in an integrated and highly interactive atmosphere in the area of molecular mechanisms responsible for gene expression and in exploring the relevance of single and multiple gene defects in the overall phenotypic outcome by developing transgenic and gene knockout mice. The proposed training program will enable the candidate to enhance his scientific foundation of critical thinking and experimentation. He will also acquire the skills necessary to effectively and intensely interface in the clinical pathology laboratories, in a subspecialty diagnostics area in a major academic medical center. The proposed research focuses on the role of PBP, a peroxisome proliferator activated receptor--binding protein, in breast development and neoplastic conversion. Dr. Zhu cloned PBP, identified it as a nuclear receptor coactivator and found that it is amplified and overexpressed in some human breast cancers. Since a variety of phytoestrogens and environmental endocrine disrupting chemicals possess estrogen receptor activity, exploration of interactions of PBP with estrogen receptor and p53 and the development of transgenic models of overexpression of PBP and the gene disruption model of PBP deficiency will provide fundamental clues as to the role of coactivators in development, differentiation and neoplastic conversion.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Clinical Investigator Award (CIA) (K08)
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Environmental Health Sciences Review Committee (EHS)
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Shreffler, Carol K
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Northwestern University at Chicago
Schools of Medicine
United States
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Mo, Rigen; Tony Zhu, Yiwei; Zhang, Zhongyi et al. (2007) GAS6 is an estrogen-inducible gene in mammary epithelial cells. Biochem Biophys Res Commun 353:189-94
Mo, Rigen; Rao, Sambasiva M; Zhu, Yi-Jun (2006) Identification of the MLL2 complex as a coactivator for estrogen receptor alpha. J Biol Chem 281:15714-20
Jia, Yuzhi; Qi, Chao; Zhang, Zhongyi et al. (2005) Peroxisome proliferator-activated receptor-binding protein null mutation results in defective mammary gland development. J Biol Chem 280:10766-73
Qi, Chao; Zhu, Yiwei Tony; Chang, Jeffrey et al. (2005) Potentiation of estrogen receptor transcriptional activity by breast cancer amplified sequence 2. Biochem Biophys Res Commun 328:393-8
Qi, Chao; Kashireddy, Papreddy; Zhu, Yiwei Tony et al. (2004) Null mutation of peroxisome proliferator-activated receptor-interacting protein in mammary glands causes defective mammopoiesis. J Biol Chem 279:33696-701
Bu, Hengfu; Kashireddy, Papreddy; Chang, Jeffrey et al. (2004) ERBP, a novel estrogen receptor binding protein enhancing the activity of estrogen receptor. Biochem Biophys Res Commun 317:54-9
Qi, Chao; Surapureddi, Sailesh; Zhu, Yi-Jun et al. (2003) Transcriptional coactivator PRIP, the peroxisome proliferator-activated receptor gamma (PPARgamma)-interacting protein, is required for PPARgamma-mediated adipogenesis. J Biol Chem 278:25281-4
Zhu, Yi-Jun; Crawford, Susan E; Stellmach, Veronica et al. (2003) Coactivator PRIP, the peroxisome proliferator-activated receptor-interacting protein, is a modulator of placental, cardiac, hepatic, and embryonic development. J Biol Chem 278:1986-90
Crawford, Susan E; Qi, Chao; Misra, Parimal et al. (2002) Defects of the heart, eye, and megakaryocytes in peroxisome proliferator activator receptor-binding protein (PBP) null embryos implicate GATA family of transcription factors. J Biol Chem 277:3585-92
Misra, Parimal; Owuor, Edward D; Li, Wenge et al. (2002) Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP). Stimulation of transcriptional regulation by mitogen-activated protein kinase. J Biol Chem 277:48745-54

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