Division of Gene Structure and Function Division of Gene Regulation and Signal Transduction
Division of Developmental Biology Division of Pathophysiogy
Division of Gene Therapy and Genome Editing  
Division  of Gene Regulation and Signal Transduction
Research Summary

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.


Figure 1



Visiting Professor Satoshi Inoue
Professor Kuniko Horie-Inoue
Assistant Professor Kazuhiro Ikeda
Assistant Wataru Satou
Project Researcher Sachiko Shiba
Post doctor Yuichi Mitobe
Graduate Student Ikuko Sugitani, Hidetaka Kawabata, Kaori Iino,
Masaya Hosokawa, Toshiyuki Okumura,
Natsuki Kurogi, Takeshi Namekawa,
Saya Nagasawa, Shuhei Kamada, Yang Chiu Jung
Project Technical Assistant Tomoko Suzuki
テーマ Research Projects

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.

文献 Selected Publications
Takayama K, Misawa A, Suzuki T, Takagi K, Hayashizaki Y, Fujimura T, Homma Y, Takahashi S, Urano T, Inoue S. TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression. Nat Commun 6:8219,(2015).
[PMID: 26404510]
Ikeda K, Horie-Inoue K, Ueno T, Suzuki T, Sato W, Shigekawa T, Osaki A, Saeki T, Berezikov E, Mano H, Inoue S. miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A.
Sci Rep 5:13170, (2015).
[PMID: 26255816]
Azuma K, Shiba S, Hasegawa T, Ikeda K, Urano T, Horie-Inoue K, Ouchi Y,Amizuka N, Inoue S. Osteoblast-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Enhanced Bone Formation With Aberrant Mineralization. J Bone Miner Res 30:1245-1254, (2015).
[PMID: 25600070]
Miyazaki T, Ikeda K, Horie-Inoue K, Kondo T, Takahashi S, Inoue S. EBAG9 modulateshost immune defense against tumor formation and metastasis by regulating cytotoxic activity of T lymphocytes. Oncogenesis 3:e126, (2014).
[PMID: 25365482]
Ikeda K, Shiba S, Horie-Inoue K, Shimokata K, Inoue S. A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle. Nat Commun 16:4:2147, (2013).
[PMID: 23857330]
Takayama K, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K, Urano T, Fujimura T, Takagi K, Takahashi S, Homma Y, Ouchi Y, Aburatani H, Hayashizaki Y, Inoue S. Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J 12:1665-1680,(2013).
[PMID: 23644382]
Takayama K, Tsutsumi S, Katayama S, Okayama T, Horie-Inoue K, Ikeda K, Urano T, Kawazu C, Hasegawa A, Ikeo K, Gojyobori T, Ouchi Y, Hayashizaki Y, Aburatani H, Inoue S. Integration of cap analysis of gene expression and chromatin immunoprecipitation analysis on array reveals genome-wide androgen receptor signaling in prostate cancer cells. Oncogene 5:619-630,(2011).
[PMID: 20890304]
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]
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]
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]
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