2003 Fiscal Year Annual Research Report

傷害察知と連携したMet/HGF受容体シグナル変換能の調節を介した再生制御の研究

Research Project

Project/Area Number	13470037
Research Institution	Osaka University
Principal Investigator	松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)
Co-Investigator(Kenkyū-buntansha)	町出充大阪大学, 医学系研究科, 助手 (90346198) 中村敏一大阪大学, 医学系研究科, 教授 (00049397)
Keywords	HGF / c-Met / トランスジェニックマウス / 肝細胞 / 再生・修復 / 細胞接着 / チロシンキナーゼ / 肝再生
Research Abstract	HGFは肝再生をはじめ、様々な組織・臓器の再生・修復に関与する内因性因子である。臓器傷害にともないHGFのレベルは各種組織、血中で上昇するものの、HGFは傷害臓器において特異的に再生促進作用を発揮する。さらに、外因的に投与したHGFも傷害臓器特異的に生理作用を発揮することから、傷害にともなうc-Met/HGF受容体シグナル変換能のON⇔OFF制御がHGFによる傷害組織特異的再生促進作用に関与すると考えられる。本研究はc-Met/HGF受容体シグナル変換能のON⇔OFF制御のメカニズムならびにその生理的意義を明らかにすることを目的とし、本年度は以下の研究成果を得た。 1.c-Metのjuxtamembrane Ser985リン酸化とc-Met活性化制御:c-Metのjuxtamembrane Ser985リン酸化とHGFによるc-Metチロシンリン酸化(活性化)は相反的であり、Ser985のリン酸化状態ではHGFによって引き起こされるc-Metチロシンリン酸化能は低下することを明らかにした。 2.c-Met juxtamembrane Ser985のリン酸化制御とSer985リン酸化を介した細胞応答性の制御:c-Met Ser985はPKCによってリン酸化される一方、PP2Aプロテインフォスファターゼによって脱リン酸化されることを明らかにした。また、PKCに依存したSer985のリン酸化が酸化ストレス(H202ストレス)によっで引き起こされるとともに、酸化ストレス下にある培養細胞(A549細胞)ではHGFに対する応答能を失っていることを明らかにした。一方、初代培養肝細胞を用いた解析から、Ser985のリン酸化が細胞間接着によって制御されることを明らかにした。したがって、Ser985リン酸化はc-Met/HGF受容体シグナル変換能のON⇔OFF制御機構の一つであると考えられる。 3.遺伝子改変動物を用いたc-Metシグナル変換能の生理的意義の解析:Ser985を含むjuxtamembrane領域を欠くc-Met variantが天然にも存在するが、その生理的機能は不明である。Juxtamembrane領域の機能を明らかにすべく、juxtamemrnaeを欠くc-Metのみを発現するノックインマウスの作成を進めた。現在まで、ノックインマウス作成用ES細胞を樹立し、キメラマウスの作成まで完了した。

Research Products

(43 results)

All Other

All Publications (43 results)

[Publications] K.Matsumoto, et al.: "Hepatocyte growth factor"Encyclopedia of Endocrinology and Endocrine Diseases. In press. (2004)
[Publications] S.Yoshoda, et al.: "Recombinant hepatocyte growth factor accerelates cutaneous wound healing in diabetic mouse model"Growth factors. In press. (2004)
[Publications] K.Ohuchida, et al.: "Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions"Cancer Res.. In press. (2004)
[Publications] Y.Ueda, et al.: "Skeletal muscle targeting in vivo electroporation-mediated HGF gene therapy of bleomycin-induced pulmonary fibrosis in mice"Lab.invest.. In press. (2004)
[Publications] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy"AM.J.physiol.. 286. F134-F143 (2004)
[Publications] J.Wen, Et al.: "Hepatic gene expression of NK4, an HGF-antagonist/angio-genesis inhibitor supprcsses liver metastasis and invasive growth of colon cancer in mice"Cancer Gene Therapy. In press. (2004)
[Publications] J.Wen, Et al.: "Hydrocortisone potentiates hepatocyte growth factor expression in vascular endothelial cells"Biomed.Res.. In press. (2004)
[Publications] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats"FASEB J. 18. 212-214 (2004)
[Publications] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism"Am.J Pathol.. In press. (2004)
[Publications] H.Takahashi, Et al.: "LIM-kinase as a regulator of actin dynamics in sperm atogenesis"Cytogenic and Genome Research. In press. (2004)
[Publications] K.Matsumoto, et al.: "NK4(HGF-antagonist and angiogenesis inhibitor) in cancer biology and therapeutics"Cancer Sci.. 94. 321-327 (2003)
[Publications] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis"Am.J Physiol.. 284. F1171-F1180 (2003)
[Publications] S.Yoshida, et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation"J.Invest.Dermatol. 120. 335-343 (2003)
[Publications] K.Kitajima, et al.: "A newly identified AMSH-family protein is specifically expressed in haploid stages of testicular germ cells"Biochem.Biophys.Res.Commun.. 309. 135-142 (2003)
[Publications] K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol.Dial.Transplant.. 17. 135-142 (2003)
[Publications] T.Inoue, et al.: "Hepatocyte growth factor counteracts transforming growth factor-β1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6-nephrectomized mice"FASEB J.. 17. 268-270 (2003)
[Publications] H.Koike, et al.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene"FASEB J.. 103. 36-48 (2003)
[Publications] Tomita, N, et al.: "Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1"Circulation. 107. 1411-1417 (2003)
[Publications] Y.Matsuno, et al.: "Hepatocyte growth factor gene transfer into liver via the portal vein using electroporation attenuates the rat liver cirrhosis"Gene Therapy. 10. 1559-1566 (2003)
[Publications] M.Nakabayashi, et al.: "HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model"Diabetologia. 46. 115-123 (2003)
[Publications] T.Manabe, et al.: "Cell-based protein delivery system for pancreatic cancer therapy : NK4 gene-transduced oral mucosal epithelial cell sheet"Clin Cancer Res.. 9. 3158-3166 (2003)
[Publications] K.Nishimura, et al.: "Effects of hepatocyte growth factor on urokinase-type plasm in ogen activator(uPA)and uPA receptor in Du145 prostate cancer cells"Intern.J.Androl.. 26. 175-179 (2003)
[Publications] S.Kato, et al.: "Expression of hepatocyte growth factor and c-Met in the anterior horn cells of the spinal cord in the patients with amyotrophic lateral sclerosis(ALS) : immunohisto chemical studies on sporadic ALS and familial ALS with superoxide dismutase 1 gene mutation"Acta Neuropathol.. 106. 112-120 (2003)
[Publications] L.W.Qian., et al.: "Co-cultivation of pancreatic cancer cells with orthotopic tumor derived fibroblasts : fibroblasts stimulate tumor cell invasion via HGF secret ion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production"Canser Lett.. 190. 105-112 (2003)
[Publications] L.W.Qian., et al.: "Radiation stimulates HGF receptor/c-met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and map kinase activity in pancreatic cancer cells"intern.J.Cancer. 104. 542-549 (2003)
[Publications] R.Pai, et al.: "Prostaglandins promote colon cancer cell invasion ; signaling by cross-talk between two distinct growth factor receptors"FASEB-J.. 17. 640-1647 (2003)
[Publications] T.A.Martin, et al.: "Growth and angiogenesis of human breast cancer in a nude mouse tumor model is reduced by NK4, the HGF/SF antagonist"Carcirogenesis. 24. 1317-1323 (2003)
[Publications] G.Davies, et al.: "The HGF/SF antagonist NK4 reverses fibroblast-and HGF-induced prostate tumor growth and angiogenesis in vivo"Intern.J.Cancer. 106. 348-354 (2003)
[Publications] P.Netzer, et al.: "Interaction between hepatocyte growth factor and non-steroidal anti-inflammatory drugs during gastric epithelial wound healing"Digestion. 67. 118-128 (2003)
[Publications] 松本邦夫, 吉富秀幸: "Medical Science Digest"北隆館. 2 (2003)
[Publications] 水野信哉他: "医学のあゆみ"医歯薬出版. 3 (2003)
[Publications] 水野信哉他: "臨床免疫2003"科学論評社. 9 (2003)
[Publications] 水野信哉, 中村敏一: "The Lung Perspective"メディカルレビュー社. 11 (2003)
[Publications] 橋ガ迫敦子他: "血液・免疫・腫瘍"メディカルレビュー社. 8 (2003)
[Publications] 中村敏一: "日本医師会雑誌"日本医師会. 5 (2003)
[Publications] 田村隆彦他: "Biotherapy"癌と化学療法社. 8 (2003)
[Publications] 松本邦夫, 中村敏一: "BIO Clinica"北隆館. 7 (2003)
[Publications] 町出充, 中村敏一: "現代医療"現代医療社. 9 (2003)
[Publications] 福田一弘他: "遺伝子医学別"メディカルドゥ. 9 (2003)
[Publications] 松本邦夫, 中村敏一: "日本内科学雑誌"日本内科学学会. 5 (2003)
[Publications] 船越洋, 中村敏一: "神経治療学"日本神経治療学会. 8 (2003)
[Publications] 町出充, 中村敏一: "G.I.Research"先端医学社. 6 (2003)
[Publications] 船越洋, 中村敏一: "肺と神経"医学書院. 5 (2003)

2003 Fiscal Year Annual Research Report

傷害察知と連携したMet/HGF受容体シグナル変換能の調節を介した再生制御の研究

Principal Investigator

松本 邦夫 大阪大学, 医学系研究科, 助教授 (90201780)

Research Products

[Publications] K.Matsumoto, et al.: "Hepatocyte growth factor"Encyclopedia of Endocrinology and Endocrine Diseases. In press. (2004)

[Publications] S.Yoshoda, et al.: "Recombinant hepatocyte growth factor accerelates cutaneous wound healing in diabetic mouse model"Growth factors. In press. (2004)

[Publications] K.Ohuchida, et al.: "Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions"Cancer Res.. In press. (2004)

[Publications] Y.Ueda, et al.: "Skeletal muscle targeting in vivo electroporation-mediated HGF gene therapy of bleomycin-induced pulmonary fibrosis in mice"Lab.invest.. In press. (2004)

[Publications] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy"AM.J.physiol.. 286. F134-F143 (2004)

[Publications] J.Wen, Et al.: "Hepatic gene expression of NK4, an HGF-antagonist/angio-genesis inhibitor supprcsses liver metastasis and invasive growth of colon cancer in mice"Cancer Gene Therapy. In press. (2004)

[Publications] J.Wen, Et al.: "Hydrocortisone potentiates hepatocyte growth factor expression in vascular endothelial cells"Biomed.Res.. In press. (2004)

[Publications] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats"FASEB J. 18. 212-214 (2004)

[Publications] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism"Am.J Pathol.. In press. (2004)

[Publications] H.Takahashi, Et al.: "LIM-kinase as a regulator of actin dynamics in sperm atogenesis"Cytogenic and Genome Research. In press. (2004)

[Publications] K.Matsumoto, et al.: "NK4(HGF-antagonist and angiogenesis inhibitor) in cancer biology and therapeutics"Cancer Sci.. 94. 321-327 (2003)

[Publications] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-induced mesangial cell proliferation in a rat model of glomerulonephritis"Am.J Physiol.. 284. F1171-F1180 (2003)

[Publications] S.Yoshida, et al.: "Neutralization of hepatocyte growth factor leads to retarded cutaneous wound healing associated with decreased neovascularization and granulation tissue formation"J.Invest.Dermatol. 120. 335-343 (2003)

[Publications] K.Kitajima, et al.: "A newly identified AMSH-family protein is specifically expressed in haploid stages of testicular germ cells"Biochem.Biophys.Res.Commun.. 309. 135-142 (2003)

[Publications] K.Matsumoto, et al.: "Renotropic role and therapeutic potential of HGF in the kidney"Nephrol.Dial.Transplant.. 17. 135-142 (2003)

[Publications] T.Inoue, et al.: "Hepatocyte growth factor counteracts transforming growth factor-β1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6-nephrectomized mice"FASEB J.. 17. 268-270 (2003)

[Publications] H.Koike, et al.: "Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene"FASEB J.. 103. 36-48 (2003)

[Publications] Tomita, N, et al.: "Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1"Circulation. 107. 1411-1417 (2003)

[Publications] Y.Matsuno, et al.: "Hepatocyte growth factor gene transfer into liver via the portal vein using electroporation attenuates the rat liver cirrhosis"Gene Therapy. 10. 1559-1566 (2003)

[Publications] M.Nakabayashi, et al.: "HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model"Diabetologia. 46. 115-123 (2003)

[Publications] T.Manabe, et al.: "Cell-based protein delivery system for pancreatic cancer therapy : NK4 gene-transduced oral mucosal epithelial cell sheet"Clin Cancer Res.. 9. 3158-3166 (2003)

[Publications] K.Nishimura, et al.: "Effects of hepatocyte growth factor on urokinase-type plasm in ogen activator(uPA)and uPA receptor in Du145 prostate cancer cells"Intern.J.Androl.. 26. 175-179 (2003)

[Publications] L.W.Qian., et al.: "Co-cultivation of pancreatic cancer cells with orthotopic tumor derived fibroblasts : fibroblasts stimulate tumor cell invasion via HGF secret ion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production"Canser Lett.. 190. 105-112 (2003)

[Publications] L.W.Qian., et al.: "Radiation stimulates HGF receptor/c-met expression that leads to amplifying cellular response to HGF stimulation via upregulated receptor tyrosine phosphorylation and map kinase activity in pancreatic cancer cells"intern.J.Cancer. 104. 542-549 (2003)

[Publications] R.Pai, et al.: "Prostaglandins promote colon cancer cell invasion ; signaling by cross-talk between two distinct growth factor receptors"FASEB-J.. 17. 640-1647 (2003)

[Publications] T.A.Martin, et al.: "Growth and angiogenesis of human breast cancer in a nude mouse tumor model is reduced by NK4, the HGF/SF antagonist"Carcirogenesis. 24. 1317-1323 (2003)

[Publications] G.Davies, et al.: "The HGF/SF antagonist NK4 reverses fibroblast-and HGF-induced prostate tumor growth and angiogenesis in vivo"Intern.J.Cancer. 106. 348-354 (2003)

[Publications] P.Netzer, et al.: "Interaction between hepatocyte growth factor and non-steroidal anti-inflammatory drugs during gastric epithelial wound healing"Digestion. 67. 118-128 (2003)

[Publications] 松本邦夫, 吉富秀幸: "Medical Science Digest"北隆館. 2 (2003)

[Publications] 水野信哉他: "医学のあゆみ"医歯薬出版. 3 (2003)

[Publications] 水野信哉他: "臨床免疫2003"科学論評社. 9 (2003)

[Publications] 水野信哉, 中村敏一: "The Lung Perspective"メディカルレビュー社. 11 (2003)

[Publications] 橋ガ迫敦子他: "血液・免疫・腫瘍"メディカルレビュー社. 8 (2003)

[Publications] 中村敏一: "日本医師会雑誌"日本医師会. 5 (2003)

[Publications] 田村隆彦他: "Biotherapy"癌と化学療法社. 8 (2003)

[Publications] 松本邦夫, 中村敏一: "BIO Clinica"北隆館. 7 (2003)

[Publications] 町出充, 中村敏一: "現代医療"現代医療社. 9 (2003)

[Publications] 福田一弘他: "遺伝子医学別"メディカルドゥ. 9 (2003)

[Publications] 松本邦夫, 中村敏一: "日本内科学雑誌"日本内科学学会. 5 (2003)

[Publications] 船越洋, 中村敏一: "神経治療学"日本神経治療学会. 8 (2003)

[Publications] 町出充, 中村敏一: "G.I.Research"先端医学社. 6 (2003)

[Publications] 船越洋, 中村敏一: "肺と神経"医学書院. 5 (2003)

松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)