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リエゾンラボ研究会
発表内容

Title:
Novel Targets for Sex Hormones

Satoshi Inoue 1,2
1 Departments of Geriatric Medicine and Anti-Aging Medicine,Graduate School of Medicine , The University of Tokyo ;
2 Division of Gene Regulation and Signal Transduction,Research Center for Genomic Medicine, Saitama Medical University

Abstract:
Androgen and estrogen have distinct roles in diseases. It is well-known that these sex hormones could promote growth of prostate and breast tumors, respectively. Although most of these tumors initially respond to endocrine therapy, the patients would often acquire resistance to this therapy later. We assumed that identification of hormone-dependent targets that regulate the growth and progression of the tumors is indispensable to understand the mechanism of sex hormone actions and to develop new strategies for therapy and diagnosis of these diseases. We have utilized ChIP-chip analysis, as well as a method ‘Genomic binding site cloning (GBSC)’ in which genomic DNA fragments are screened for hormone-responsive elements by binding with the nuclear receptor protein. The GBSC method revealed that estrogen-responsive finger protein (Efp) is novel estrogen target genes in vivo . Inhibition of Efp expression reduced the breast tumor growth, suggesting an application of this molecule as a therapeutic target ( Nature 417:871, 2002) . Efp, a member of TRIM RING-finger protein family, is a tumor-promoting factor as an E3 ubiquitin ligase for 14-3-3sigma which is a cell cycle brake and causes G2 arrest. It was also demonstrated that Efp is essential for RIG-I-mediated antiviral activity ( Nature 446, 2007). Meanwhile, we also identified novel targets for androgen, such as UGT1A1, CDH2 and APP, utilizing ChIP-chip analysis, a method to isolate in vivo binding sites of transcription factors ( Oncogene 26:4453, 2007); Cancer Res 69:137, 2009); ( Oncogene in press); . We will discuss roles of these androgen/estrogen targets identified by isolation of nuclear receptor-binding sites in the human genome.