Research

Biochemistry

Outline

 Bioactive lipids are produced from membrane phospholipids upon various stimuli, and act on their specific cell-surface receptors (G-protein coupled receptor; GPCR) of neighborhood cells. They are involved in most life activity such as nervous system, respiration, circulation, reproduction, and cell differentiation. In our department, biochemical research on phospholipid metabolism, lipid mediator and DNA-damage signal is conducted.

Members

Title Name
Professor Takashi Izumi, M,D., Ph.D.
Associate Professor Kazuaki Tatei, Ph.D.
Akimitsu Konishi, M,D., Ph.D.
Assiatant Professor Koji Kishimoto, Ph.D.
Noriyasu Ohshima, Ph.D.

Research

 Our research projects aim to clarify turnover of cell membrane phospholipids on various kinds of stimulation, production of bioactive lipids, signal transduction through their GPCRs, and function of these bioactive lipids (figure 1). We identified oxidative free fatty acids such as 9-HODE (a metabolite of linoleic acid) and 11-HETE (a metabolite of arachidonic acid) as ligands of G2A, a stress-inducible GPCR. This is the first report that a linoleic acid metabolite acts on as a ligand of GPCR. Cytokine production and suppression of cell growth occur when 9-HODE was added in cultured cells expressing G2A such as human keratinocytes (figure 2).

 Focusing on the mechanism for production of oxidative free fatty acids, the signal transduction via G2A and the mechanism of induction of G2A, we want to clarify the physiological roles the 9-HODE-G2A system, especially its involvement in development of cancer stem cell. We also want to clarify the molecular mechanism that involves cellular responses caused by DNA damage during oxidative stress.

Publications

Xin X, Tatei K, Ehara H, Kihara Y, Izumi T:
Expression pattern of class I phosphoinositide 3-kinase and distribution of its product, phosphatidylinositol-3,4,5-trisphosphate, during Drosophila embryogenesis.
Gene Expression Patterns (in press) 2014

Kawakami Y, Hirano S, Kinoshita M, Otsuki A, Suzuki-Yamamoto T, Suzuki M, Kimoto M, Sasabe S, Fukushima M, Kishimoto K, Izumi T, Oga T, Narumiya S, Sugahara M, Miyano M, Yamamoto S, Takahashi Y:
Neutralization of leukotriene C4 and D4 activity by monoclonal and single-chain antibodies.
Biochim Biophys Acta 1840:1625-1633, 2014

Ohyama T, Sato K, Kishimoto K, Yamazaki Y, Horiguch N, Ichikawa T, Kakizaki S, Takagi H, Izumi T, and Mori M:
Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence.
Br J Phrmacol 165:1173-1187, 2012

Nagashima T, Ichimiya S, Kikuchi T, Saito Y, Matsumiya H, Ara S, Koshiba S, Zhang J, Hatate C, Tonooka A, Kubo T, Hirose B, Shirasaki H, Izumi T, Takami T, Himi T, Sato N:
Arachidonate 5-Lipoxygenase Establishes Adaptive Humoral Immunity by Controlling Primary B Cells and Their Cognate T Cell Help.
Am J. Pathol 178:222-232, 2011

Okazaki Y, Ohshima N, Yoshizawa I, Kamei Y, Mariggiò S, Okamoto K, Maeda M, Nogusa Y, Fujioka Y, Izumi T, Ogawa Y, Shiro Y, Wada M, Kato N, Corda D, Yanaka N.
A novel glycerophosphodiester phosphodiesterase GDE5 controls skeletal muscle development via a non-enzymatic mechanism.
J Biol Chem 285:27652-27663, 2010

Ishii I, Akahoshi N, Yamada H, Nakano S, Izumi T, Suematsu M.
Cystathionine γ-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury.
J Biol Chem 285: 26358-26368, 2010

Chen K, Obinata H, Izumi T:
Detection of G protein-coupled receptor-mediated cellular response involved in cytoskeletal rearrangement using surface plasmon resonance.
Biosensors and Bioelectronics 25:1675-1680,2010

Ogawa A, Obinata H, Hattori T, Kishi M, Tatei K, Ishikawa O, Izumi T:
Identification and analysis of two splice variants of human G2A generated by alternative splicing.
J. Pharmacol. Exp. Ther. 332: 469-478, 2010

Ogawa A, Obinata H, Hattori T, Kishi M, Tatei K, Ishikawa O, Izumi T:
Identification and analysis of two splice variants of human G2A generated by alternative splicing.
J. Pharmacol. Exp. Ther. 332: 469-478, 2010

Obinata H, Izumi T:
G2A as a receptor for oxidized free fatty acids.
Prostaglandins Other Lipid Mediat. 89:66-72,2009

Okamura K, Yamashita S, Ando H, Horibata Y, Aoyama C, Takagishi K, Izumi T, Vance DE, Sugimoto H:
Identification of Nuclear Localization and Nuclear Export Signals in Ets2, and the Transcriptional Regulation of Ets2 and CTP:Phosphocholine Cytidylyltransferase a in Tetradecanoyl-13-acetate or Macrophage-Colony Stimulating Factor Stimulated RAW264 Cells.
Biochim Biophys Acta 1791:173-182,2009

Kawamura H, Tatei K, Nonaka T, Obinata H, Hattori T, Ogawa A, Kazama H, Hamada N, Funayama T, Sakashita T, Kobayashi Y, Nakano T, Izumi T:
Ceramide induces myogenic differentiation and apoptosis in Drosophila Schneider cells.
J Rad. Res. 50: 161-169, 2009

Akahoshi N, Kobayashi C, Ishizaki Y, Izumi T, Himi T, Suematsu M, Ishii I:
Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine β-synthase-deficient mice, an animal model for hyperhomocysteinemia.
Human Mol Genetics 17:1994-2005,2008

Hattori T, Obinata H, Ogawa A, Kishi M, Tatei K, Ishikawa O, Izumi T:
G2A plays proinflammatory roles in human keratinocytes under oxidative stress as a receptor for 9-hydroxyoctadecadienoic acid.
J Invest Dermatol 128: 1123-1133, 2008

Sugimoto S, Sugimoto H, Aoyama C, Aso C, Mori M, Izumi T:
Purification and characterization of lysophospholipase D from rat brain.
Biochim Biophys Acta 1761: 1410-1418, 2006

Koike D*, Obinata H*, Yamamoto A*, Takeda S, Komori H, Nara F, Izumi T, Haga T (* equal contribution, corresponding authors):
5-Oxo-Eicosatetraenoic Acid-Induced Chemotaxis: Identification of a Responsible Receptor hGPCR48 and Negative Regulation by G Protein G12/13.
J Biochem 139: 543-549, 2006.

Sone H, Ikeuchi A, Izumi T, Okano H, Hosaka S:
Femtogram Mass Biosensor Using a Self-sensing Cantilever for Allergy Check.
Jpn J Appl Phys 45: 2301-2304, 2006

Obinata H, Hattori T, Nakane S, Tatei K, Izumi T:
Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A.
J Biol Chem, 280: 40676-40683, 2005

Sugimoto H, Okamura K, Sugimoto S, Satou M, Hattori T, Vance DE, Izumi, T:
Sp1 is a co-activator with Ets-1, and Net is an important repressor of the transcription of CTP:phosphocholine cytidylyltransferase alpha.
J Biol Chem, 280: 40857-40866, 2005

Hanaka H, Shimizu T, Izumi T:
Stress-induced nuclear export of 5-lipoxygenase.
Biochem Biophys Res Comm, 338: 111-116, 2005.