Fusao Hirata M.D., Ph.D.
EACPHS, Room 3118
Professor, Department of Pharmaceutical Sciences
Degrees and Certifications
School of Medicine, Tokyo Medical & Dental M.D. 1967 Medicine
University, Tokyo, Japan
School of Medicine, Tokyo Medical & Dental 1968 Internship
University, Tokyo, Japan
Department of Medical Chemistry, Faculty of Ph.D. 1972 Biochemistry
Medicine, Kyoto University, Japan
Positions and Employment
1972 Fellow, Japanese Society for Promotion of Science
Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Japan
1972 - 1980 Assistant Professor, Dept. of Medical Chem. (Biochemistry), Kyoto Univ., Japan
1977 - 1982 Visiting Scientist, Laboratory of Clinical Science, NIMH, Bethesda, MD
1982 - 1986 Unit Chief, Laboratory of Cell Biology, NIMH, Bethesda, MD
1986 - 1990 Associate Professor, Dept. Environ. Health Sci., Johns Hopkins Univ., Baltimore, MD
1988 - 1990 Assoc. Prof. (Adj.), Dept. of Biochemistry, The Johns Hopkins Univ., Baltimore, MD
1990 - present Professor, Dept. of Pharmaceutical Sciences, Wayne State Univ., Detroit, MI
1990 - 2003 Professor (Adjunct), Institute of Environ. Health Sci., Wayne State Univ., Detroit, MI
1990 - 1994 Adjunct Faculty, Dept. Environ. Health Sci., Johns Hopkins Univ., Baltimore, MD
1991 - 2008 Professor (Adjunct), Dept. of Pharmacology, Sch. Med., Wayne State Univ., Detroit, MI
1991 - 1993 Associate Chair, Dept. of Pharmaceutical Sciences, Wayne State Univ., Detroit, MI
1993 - 1996 Interim Chair, Dept. of Pharmaceutical Sciences, Wayne State Univ., Detroit, MI
1996- 1999 Associate Chair, Depat. of Pharmaceutical Sciences, Wayne State Univ. , Detroit, MI
2001-present Chair, University Radiation Safety Committee, Wayne State University, Detroit, MI
Awards and Honors
1972 Fellowship, Japanese Society for Promotion of Science
1977 Distinguished Service Award, Japanese Biochemical Society
1977 Fogarty International Research Fellowship
1980 Ad Hoc Life Science Committee, FASEB
1982 State-of-the Art Lecture, Am. Association of Endocrinology
1984 Appreciation of Japanese Endocrine Society for Plenary Lecture
1988 NIH Study Section, Neurological Sciences I
1992 Distinguished Faculty Fellowship, Wayne State University
Primary Research Interest
Annexin A1, a 37 KDa protein previously termed as lipomodulin or lipocortin, is a member of the family of proteins that bind to phospholipids in a Ca2+ dependent manner. Our laboratory was the first to isolate and characterize it as a phospholipase A2 inhibitory protein and proposed that annexin A1 is a putative second messenger protein of anti-inflammatory and immunosuppressive actions of glucocorticoids. In addition, we have demonstrated that annexin A1 is involved in the pathophysiology of various inflammatory and immunological diseases which are treated by glucocorticoids. To extend our strategy, we will study biological functions of annexin A1 and develop the clinical application of annexin A1 towards inflammatory and immunological diseases.
We also discovered that annexin A1 is a major substrate for the oncogenic tyrosine kinases, but mechanisms for its signal transduction remain poorly understood. SUMOylation-ubiquitination in nuclei apparently plays an important role in cell proliferation-differentiation. Indeed, monoubiquitinated annexin A1 exhibits a helicase activity and promotes translesion DNA synthesis leading to mutagenesis. Inhibitors of monoubiquitination are expected to prevent DNA damage induced mutation, thereby exhibiting cancer chemopreventing action. Therefore, we will study biological roles of annexin A1 in cell transformation and differentiation of stem cells, and develop inhibitors of annexin A1 helicase for cancer chemoprevention.
Selected from 174 publications, excluding abstracts
- Hirata, F., Schiffmann, E., Venkatasubramanian, K., Salomon, D. and Axelrod, J. (1980) A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc. Natl. Acad. Sci. USA 77:2533-2536.
- Hirata, F. (1981) The regulation of lipomodulin, a phospholipase inhibitory protein in rabbit neutrophils by phosphorylation. J. Biol. Chem. 256:7730-7733.
- Hirata, F., DelCarmine, R., Nelson, C.A., Axelrod, J., Schiffmann, E., Warabi, A., DeBlas, A.L., Nirenberg, M., Manganiello, V., Vaughan, M., Kumagai, S., Green, I., Decker, J.L. and Steinberg, A.D. (1981) Presence of autoantibody for phospholipase inhibitory protein, lipomodulin, in patients with rheumatic diseases. Proc. Natl. Acad. Sci. USA 78:3190-3194.
- Hirata, F., Notsu, T., Iwata, M., Parente, L., DiRosa, M. and Flower, R.J. (1982) Identification of several species of phospholipase inhibitory protein(s) by radioimmunoassay for lipomodulin. Biochem. Biophys. Res. Commun. 109:223-230.
- Hirata, F. and Iwata, M. (1983) Role of lipomodulin, a phospholipase inhibitory protein, in immuno-regulation by thymocytes. J. Immunol. 130:1903-1909.
- Hirata, F., Matsuda, K., Notsu, Y., Hattori, T. and Del Carmine, R. (1984) Phosphorylation at tyrosine residue of lipomodulin in mitogen-stimulated murine thymocytes. Proc. Natl. Acad. Sci. USA 81:4717-4721.
- Hirata, F., Stracke, M.L. and Schiffmann, E. (1987) Regulation of prostaglandin formation by glucocorticoids & their second messenger, lipocortins. J. Steroid Biochem. 27:1053-1056.
- Hirata, F. (1989) Role of lipocortins in cellular function as a second messenger of glucocorticoids. in Anti-inflammatory Steroid Action: Basic and Clinical Aspects, L.M. Lichtenstein, H. Claman, A. Oronsky and R. Schleimer, eds., pp. 67-95, Academic Press, San Diego.
- Hirata, F. and Hirata, A. (1990) Biology of phospholipase inhibitory proteins. in Biochemistry, Molecular Biology, & Physiology of PLA2 & Its Regulatory Factors, ed., A.B. Mukherjee, pp. 81-89, Plenum Pub. Corp., N.Y.
- Uchida, Y., Hamada, M., Kameyama, M., Ohse, H., Nomura, A., Hasegawa, S. and Hirata,F. (1992) ET-1 induced bronchoconstriction in the early phase but not late phase of anesthetized dogs is inhibited by indomethacin and ICI 198615. Biochem. Biophys. Res. Commun. 183:1197-1202.
- Wills-Karp, M., Uchida, Y., Lee, J.Y., Jinot, J., Hirata, A. and Hirata, F. (1993) Organ culture with proinflammatory cytokines reproduces impairment of the �-adrenoceptor-mediated relaxation in tracheas of guinea pig antigen model. Am. J. Respir. Cell Mol. Biol. 8:153-159.
- Hirata, F., Lee, J.Y., Sakamoto, T., Nomura, A., Uchida, Y., Hirata, A. and Hasegawa, S. (1994) IL-1� regulates the expression of the Gi2α gene via lipid mediators in guinea pig tracheal muscle. Biochem. Biophys. Res. Commun. 203:1889-1896.
- Lee, J.Y., Uchida, Y., Sakamoto, T., Hirata, A., Hasegawa, S. and Hirata, F. (1994) Alteration of G protein levels in antigen challenged guinea pigs. J. Pharm. Exp. Therap. 271:1713-1720.
- Sakamoto, T., Repasky, W.T., Chen, J., Hirata, A. and Hirata, F. (1995) Down-regulation of bcl-xS gene expression in rat thymocytes by dexamethasone.. Biochem. Biophys. Res. Commun. 215:511-516.
- Sakamoto, T., Repasky, W.T., Uchida, K., Hirata, A. and Hirata, F. (1996) Modulation of cell death pathways to apoptosis and necrosis of H2O2-treated rat thymocytes by lipocortin I. Biochem. Biophys. Res. Commun. 220:643-647.
- Kaufman, M. and Hirata, F. (1996) Cyclic GMP inhibits phosphoinositide turnover in choroid plexus: Evidence for interactions between second messengers concurrently triggered by 5HT2c receptors. Neuroscience Let. 206(2,3):153-156.
- Uchida, Y., Jun, T., Ninomiya, H., Ohse, H., Hasegawa, S., Nomura, A., Sakamoto, T., Sardessai, M.S. and Hirata, F. (1996) Involvement of endothelins in immediate and late asthmatic responses of guinea pigs. J. Pharm. Exp. Therap. 277:1622-1629.
- Ishii, Y., Yang, H., Sakamoto, T., Nomura, A., Hasegawa, S. Hirata, F. and Bassett, D.J.P. (1997) Rat alveolar macrophage cytokine production and regulation of neutrophil recruitment following acute ozone exposure. Toxicol. Appl. Pharmacol. 147, 214-223.
- Pompeo, A., Luini, A., Hirata, F., Baldassarre, M. and Buccione, R. (1997) Neutrophil extracted lipocortin inhibits corticotropin secretion in the AtT-20 D16:16 clonal mouse pituitary cell line. Lipocortin inhibition of ACTH release in vitro. Regulatory Peptides 72:169-177.
- Hirata, F. (1998) Annexins (Lipocortins). Encyclopedia of Immunology, 2nd ed., Roitt, I.M. and Delves, P.J. eds., Academic Press Ltd., pp.111-115.
- Hirata, A. and Hirata, F. (1999) Lipocortin (Annexin) I heterotetramer binds to purine RNA and pyrimidine DNA. Biochem. Biophys. Res. Commun. 265:200-204.
- Hirata, A. and Hirata, F. (2002) DNA chain unwinding and annealing reactions of lipocortin (annexin) I heterotetramer: regulation by Ca2+ and Mg2+. Biochem. Biophys. Res. Commun. 291:205-209.
- Manickam, D.S., Hirata, A., Putt, D.A., Lash, L.H., Hirata, F. and Oupicky, D. (2008) Overexpression of Bcl-2 as a proxy redox stimulus to enhance activity of non-viral redox-responsive delivery vectors, Biomaterials, 29:2680-2688.
- Bhalla, D.K., Hirata, F., Rishi, A.K. and Gairola, C.G. (2009) Cigarette smoke, inflammation, and lung injury: A mechanistic perspective. J. Toxicol. Environ. Health, B, 12:45-64.
- Bassett, D.J.P., Hirata, F., Gao, X., Kerr, J., M., Kannan, R., Reale, N.D. Wilson, S. and Lieh-Lai, (2010) Reversal of methylprednisoloneffects in allergen-exposed femal balb/c mice. J. Toxicol. Environ. Health. A.73: 711-14
- Hirata, F. Lisa M. Thibodeau and Hirata, A. (2010) In vitro SUMOylation and ubiquitination of annexin A1 and its helicase activities. Biochim. Biophys. Acta (General Subject) 1800: 899-905
- Hirata, A. Corcoran B.G.III, and Hirata, F. (2010): Carcinogenic heavy metals stimulate the DNA binding and helicase activity of monoubiquitinated annexin A1 dimer. Toxicol. Applied Pharmcol. 248: 45-51
- Hirata, A, Corcoran G.B.III and Hirata, F. (2010) Carcinogenic heavy metals, As3+ and Cr6+ increase affinity of nuclear annexin/lipocortin I for DNA containing 8-oxo-guanosine. Toxicol. Applied Pharmcol. submitted.
- Hirata, F., Harada, T., Corcoran G.B.III, and Hirata, A. (2010) Inhibitory effects of flavonoids on annexin/lipocortin I helicase and mutation of the thymidine kinase gene in L5178 tk (+/-) cells. Toxicol. Applied Pharmcol. In preparation.
- Hirata, A., Senanayake, M.D.T., Hou, Y-C, Wooster, P.M. and Hirata, F. (2010) Annexin A1 and cytostatic effects of HDAC inhibitors in breast adenocarcinoma cell line, MCF 7. Cancer Res. In preparation.