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Research
Summary |
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Our research aim is to understand the molecular mechanisms of gene regulation and signal transduction initiated by steroid hormones. A specific focus of our studies is the mechanism of estrogen action, which closely relates to the pathogenesis, diagnosis, and therapeutics of age-related diseases and hormone-dependent cancers.
Estrogen is a sex steroid hormone, which plays crucial roles in the development and function of female reproductive organs as well as serves as a pathogenetic factor of hormone-related diseases and cancers. A prominent example of endocrine-dependent cancers is breast cancer, for which the estrogen receptor status has been used in the diagnosis, and antiestrogens such as tamoxifen have been successfully used in the treatment and prevention. Postmenopausal estrogen depletion can result in various menopause symptoms and osteoporosis, so that hormone replacement therapy has been performed for the treatment. The alteration of estrogen levels also contributes to the development of dementia, arteriosclerosis, and disorders of skin and immunity system in both men and women. These physiological and pathophysiologycal roles of estrogen are mediated through estrogen receptors, ligand-dependent transcription factors that belong to nuclear receptor superfamily. To understand fundamental mechanisms underlying estrogen functions, it is essential to study the regulation of transcription through estrogen receptor cascades and the functions of estrogen-responsive genes.
Various approaches are utilized for analysis of the cascades, including molecular biology, biochemistry, physiology, genetics and developmental biology. Through the recent advance of human whole genome sequences and genome-wide analyses using DNA microarray and proteomics, we aim to reveal the whole entity of gene network associated with signaling cascades of estrogen and other sex steroid hormones. Whole animal approaches are utilized for the understanding the in vivo regulatory mechanism of estrogen action, by generating genetically altered knockout and transgenic mice. We previously developed a technique of “genomic-binding site cloning” and isolated several novel estrogen-responsive genes. Efp is a good example, which has been identified as a RING finger-type ubiquitin ligase that regulates cell cycle mechanism through protein degradation. Efp has been also revealed that this E3 ligase is deeply involved in the defense mechanism against infection by ubiquitinating an intracellular sensor for RNA viruses, RIG-I. Elucidation of the new signaling network mediated through RING finger family is another series of our projects.
Based on the information through molecular researches, we aim to devise diagnostic and therapeutic approaches for hormone-related diseases and cancers.
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Figure
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Staff |
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| Visiting Professor |
Satoshi Inoue |
| Associate Professor |
Kuniko Horie-Inoue |
| Assistant Professor |
Kazuhiro Ikeda |
| Assistant |
Wataru Satou |
| Project Researcher |
Toshiaki Miyazaki |
| Post doctor |
Sachiko Shiba |
| Project Technician |
Takashi Oishi, Akane Kitamura, Saki Kawashima |
| Graduate Student |
Yojiro Maruayama, Takahumi Ujihira |
| Project Technical Assitant |
Tomoko Suzuki，Akemi Sato |
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Research
Projects |
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| Our laboratory is focused on elucidation of the molecular mechanisms of steroid hormones and nuclear receptors and the regulatory network cascades of hormone responsive genes. Our current studies are 1) analysis of the transcriptional regulatory mechanisms of nuclear steroid receptors, 2) systematic identification and analysis of the regulatory mechanisms in regard to steroid/ nuclear receptor target genes, 3) analysis of the gene regulatory network mediated through ubiquitin ligase-dependent proteolysis and modification, and 4) systematic identification and analysis of the regulatory mechanisms in regard to genes associated with age-related diseases. |
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Selected
Publications |
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1) |
Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, Hannesschlager N, Schlee M, Rothenfusser S, Barchet W, Kato H, Akira S, Inoue S, Endres S, Peschel C, Hartmann G, Hornung V, Ruland J.
Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol 11: 63-69, (2010).
[PMID: 19915568] |
2) |
Takayama K, Tsutsumi S, Suzuki T, Horie-Inoue K, Ikeda K, Kaneshiro K, Fujimura T, Kumagai J, Urano T, Sakaki Y, Shirahige K, Sasano H, Takahashi S, Kitamura T, Ouchi Y, Aburatani H, Inoue S.
Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res 69: 137-142, (2009).
[PMID: 19117996] |
3) |
Azuma K, Urano T, Horie-Inoue K, Hayashi S, Sakai R, Ouchi Y, Inoue S.
Association of estrogen receptor alpha and histone deacetylase 6 causes rapid deacetylation of tubulin in breast cancer cells. Cancer Res 69: 2935-2940, (2009).
[PMID: 19318565] |
4) |
Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, Farzan M, Inoue S, Jung JU, Garcia-Sastre A.
Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 5: 439-449, (2009).
[PMID: 19454348] |
5) |
Gack MU, Shin YC, Joo CH, Urano T, Liang C, Sun L, Takeuchi O, Akira S, Chen Z, Inoue S, Jung JU.
TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature 446:916-920, (2007).
[PMID: 17392790] |
6) |
Takayama K, Kaneshiro K, Tsutsumi S, Horie-Inoue K, Ikeda K, Urano T, Ijichi N, Ouchi Y, Shirahige K, Aburatani H, Inoue S.
Identification of novel androgen response genes in prostate cancer cells by coupling chromatin immunoprecipitation and genomic microarray analysis. Oncogene 26: 4453-4463, (2007).
[PMID: 17297473] |
7) |
Ichikawa T, Horie-Inoue K, Ikeda K, Blumberg B, Inoue S.
Steroid and Xenobiotic Receptor SXR Mediates Vitamin K2-activated Transcription of Extracellular Matrix-related Genes and Collagen Accumulation in Osteoblastic Cells. J Bio Chem 281: 16927-16934, (2006).
[PMID: 16606623] |
8) |
Ogushi T, Takahashi S, Takeuchi T, Urano T, Horie-Inoue K, Kumagai J, Kitamura T, Ouchi Y, Muramatsu M, Inoue S.
Estrogen receptor-binding fragment-associated antigen 9 is a tumor-promoting and prognostic factor for renal cell carcinoma. Cancer Res 65: 3700-3706, (2005).
[PMID: 15867365] |
9) |
Ikeda K, Ogawa S, Tsukui T, Horie-Inoue K, Ouchi Y, Kato S, Muramatsu M, Inoue S.
Protein Phosphatase 5 is a negative regulator of estrogen receptor-mediated transcription. Mol Endocrinol 18: 1131-1143, (2004).
[PMID: 14764652] |
10) |
Urano T, Saito T, Tsukui T, Fujita M, Hosoi T, Muramatsu M, Ouchi Y, Inoue S.
Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth. Nature 417: 871-875, (2002).
[PMID: 12075357] |
11) |
Ogawa S, Fujita M, Ishii Y, Tsurukami H, Hirabayashi M, Ikeda K, Orimo A, Hosoi T, Ueda M, Nakamura T, Ouchi Y, Muramatsu M, Inoue S.
Impaired estrogen sensitivity in bone by inhibiting both estrogen receptor α and β pathways. J Biol Chem 275: 21372-21379, (2000)
[PMID: 10806217] |
12) |
Orimo A, Inoue S, Minowa O, Tominaga N, Tomioka Y, Sato M, Kuno J, Hiroi H, Shimizu Y, Suzuki M, Noda T, Muramatsu M.
Underdeveloped uterus and reduced estrogen responsiveness in mice with disruption of the estrogen-responsive finger protein gene, which is a direct target of estrogen receptor α. Proc Natl Acad Sci USA 96: 12027-12032, (1999).
[PMID: 10518570] |
13) |
Inoue S, Kondo S, Muramatsu M.
Identification of target genes for a transcription factor by genomic binding site (GBS) cloning. In: Latchman DS, eds. Transcription Factors -A Practical Approach. 2nd ed. New York: Oxford University Press. pp. 165-178, (1999). |
14) |
Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM.
Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811-814, (1998).
[PMID: 9486654] |
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