Fusao Hirata

1. Hirata, F . Role of lipocortins in cellular function as a second messenger of glucocorticoids. in Anti-inflammatory Steroid Action: Basic and Clinical Aspects , LM Lichtenstein, H Claman, A Oronsky and R Schleimer, eds, pp 67-95, Academic Press, San Diego, 1989.
2. Lee, J.Y. et al. Alteration of G protein levels in antigen challenged guinea pigs, J Pharm Exp Therap 1994;271:1713-1720.
3. Sakamoto, T. et al . Modulation of cell death pathways to apoptosis and necrosis of H 2 O 2 -treated rat thymocytes by lipocortin I. Biochem Biophys Res Commun 1996;220:643-647.
4. Pompeo, A. et al . Neutrophil extraced lipocortin inhibits corticotropin secretion in the AtT-20D 16:16 clonal mouse pituitary cell line. Lipocrotin inhibition of ACTH releae in vitro . Regulatory Peptides 1997;72:169-177.
5. Hirata, F . Annexins (Lipocortins). Encyclopedia of Immunology, 2 nd ed, IM Roitt and PJ Delves, eds, Academic Press Ltd, pp 111-115, 1998.
6. Hirata, A. and Hirata, F . Lipoocrtin (Annexin) I heterotetramer binds to purine RNA and Pyrimidine DNA. Biochem Biophys Res Commun 1999;265;200-204.

Mechanisms of action of glucocorticoids

    Glucocorticoids are widely used in clinic for the treatments of various inflammatory and immunological diseases such as asthma and rheumatoid arthritis. However, their use is restricted because of serious side effects. Since glucocorticoids exert their effects by inducing the syntheses of proteins, it is possible to isolate second messenger proteins that mimick the actions of glucocorticoids without side effects. Our laboratory was the first to discover lipocortin (also termed annexin) I as a second messenger protein of anti-inflammatory action of glucocorticoids. Its anti-inflammatory and immunosuppressive actions have been characterized in both in vivo and in vitro (animal models of asthma and rheumatoid arthritis) studies. Along this line of efforts, our laboratory is currently dealing with on genomic and nongenomic mechanisms of apoptosis in immature lymphocytes by glucocorticoids, since these steroids are used for the treatment of acute lymphomas.

Medicated through nuclear lipocortins DNA replication and mutagenesis

    Lipocortin/Annexin I and II are also used as biomarkers of proliferating cells (cancer cells), and are major substrate proteins of oncogenic tyrosine kinases such as met and src. To study the signal transduction of growth factors including EGF and IGF, our present focus is on nuclear functions of lipocortin/annexin heterotetramers. They not only stimulate DNA replication but also promote mutagenesis, a key step leading to cancer. Since the lipocortin/annexin family are capable of binding various heavy metals, categorized as carcinogens, their DNA binding, DNA unwinding and stimulatory action on replicative and nonreplicative DNA polymerases are being studied in the light of heavy metal-induced cancer