2001 年度実績報告書

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

研究課題

研究課題/領域番号	13470037
研究機関	大阪大学
研究代表者	松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)
研究分担者	中村敏一大阪大学, 医学系研究科, 教授 (00049397)
キーワード	HGF / c-Met / トランスジェニックマウス / チロシンキナーゼ / ノックアウトマウス / 再生・修復 / 細胞増殖因子 / 肝再生
研究概要	傷害の察知と連携するc-Met/HGFレセプターのunfunctional(無傷)⇔functional(傷害)の機能変換機構の解明は、傷害組織特異的な再生駆動ならびに停止機構の解明につながるものと考えられる。本研究はc-Metレセプターの負の制御域(juxtamembrane領域)の欠失や領域内アミノ酸変異を導入したc-Metレセプター発現細胞を用いて、c-Metレセプター機能のON⇔OFF変換機構を生化学的に解明するとともに、傷害察知を介したc-MetレセプターのON⇔OFF変換の意義を遺伝子改変動物を用いて解明することを目的としている。 1.c-Metレセプターのjuxtamembraneドメインを介した機能制御: c-Met/HGFレセプターのjuxtamembrane領域がc-MetのON⇔OFF機能変換に関与するものと推察した。そこで、1)リン酸化されたSer1002を認識する特異抗体の作成、2)Ser1002をAlaなどに置換したものやjuxtamembraneを欠質したc-Metを発現する細胞の樹立、3)HGF刺激による変異c-Metの活性化制御などの研究を行った。その結果、通常のc-MetはHGF刺激により急速な分解、一過的なチロシンリン酸化が引き起こされるのに対して、juxtamembraneを欠くc-MetではHGF刺激による分解が認められず、c-Metの活性化が長期に及ぶことが明らかとなり、これら結果から、juxtamembrane領域がc-Metの負の調節機能に関与する領域であることが示唆された。 2.遺伝子改変動物を用いたc-MetのON⇔OFF機能変換の生理的意義の解析: juxtamembraneを欠くc-Metを組織特異的に発現するノックインマウスを用いてON⇔OFF機能変換の生理的意義を明らかにする目的で、juxtamembrane領域をコードするexon14を欠質したc-Met遺伝子を相同組み換えにより導入されたES細胞を得た。現在、ノックインマウスの作成を急いでいる。 3.HGFによる肝細胞増殖制御の細胞間接着依存性:細胞間接着のルーズな低細胞密度ではHGFは強力にDNA合成を誘導する一方、細胞間接着の密な高細胞密度ではHGFはほとんどDNA合成を促進しない。高細胞密度(組織化状態)ならびに低細胞密度(脱組織化状態)はそれぞれ正常肝組織ならびに傷害を受けた肝組織における肝細胞の増殖制御を反映するものと考えられ、HGFによるc-Metの活性化は細胞間接着や細胞間相互作用を介した組織化状態によって制御されていることが示唆された。

研究成果

(32件)

すべてその他

すべて文献書誌 (32件)

[文献書誌] Matsumoto, K., et al.: "Liver organogenesis promoted by endothelial cells prior to vascular function"Science. 294. 559-563 (2001)
[文献書誌] Tomioka, D., et al.: "Inhibition of Growth, Invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res.. 61. 7518-7524 (2001)
[文献書誌] Sumi, T., et al.: "Specific activation of LIM-kinase 2 via phosphorylation of the threonine-505 by ROCK, a Rho-dependent protein kinase"J.Biol.Chem.. 276. 670-676 (2001)
[文献書誌] Matsumoto, K., et al.: "Hepatocyte growth factor. renotropic role and potential therapeutics for renal diseases"Kid.Intem.. 59. 2023-2038 (2001)
[文献書誌] Sumi, T., et al.: "Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha"J Biol Chem.. 276. 23092-23096 (2001)
[文献書誌] Kuroiwa, T., et al.: "Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function"J Clin Invest. 107. 1365-1373 (2001)
[文献書誌] Maehara, N., et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br.J.Cancer. 84. 864-873 (2001)
[文献書誌] Mizuno, S., et al.: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy"Kidney Intern. 59. 1304-1314 (2001)
[文献書誌] Nakamura, T., et al.: "Malecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein"Biochim.Biophys.Acta. 1518. 63-72 (2001)
[文献書誌] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models : preclinical study for treatment of peripheral arterial disease"Gene Therapy. 8. 181-189 (2001)
[文献書誌] Azuma, H., et al.: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an experimental rat transplant model"J.Am.Soc.Nephrol. 12. 12180-12920 (2001)
[文献書誌] Matsumoto, K., et al.: "Inhibition of neointima by angiotensin-converting enzyme inhibitor in porcine coronary artery balloon-injury model"Hypertension. 37. 270-264 (2001)
[文献書誌] Nakagami, H., et al.: "Mitogenic and antiapoptotic actions of hepatocyte growth factor through ERK, STAT3, and AKT in endothelial cells"Hypertension. 37. 581-586 (2001)
[文献書誌] Yamamoto, K., et al.: "Contribution of bcl-2, but not bcl-xl and bax, to antiapoptotic actions of hepatocyte growth factor hypoxia-conditioned human endothelial cells"Hypertension. 37. 1341-1348 (2001)
[文献書誌] Ueda, H., et al.: "A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats"Cardiovascular Res.. 51. 41-50 (2001)
[文献書誌] Tsuzuki, N., et al.: "Hepatocyte growth factor reduces the infarct volume after transient focal cerebral ischemia in rats"Neurol Res.. 51. 417-424 (2001)
[文献書誌] Parr, C., et al.: "The HGF/SF-induced phosphorylation of paxillin, matrix adhesion, and invasion of prostate cancer cells were suppressed by NK4, an HGF/SF variant"Biochem Biophys Res Commun.. 285. 1330-1337 (2001)
[文献書誌] Beppu, K., et al.: "Hepatocyte growth factor production by peripheral blood mononuclear cells of recurrent cancer patients"Anticancer Res.. 21. 2195-2200 (2001)
[文献書誌] Aoki, M., et al.: "Inhibition of neointimal formation after balloon injury by cilostazol, accompanied by improvement of endothelial dysfunction and induction of hepatocyte growth factor in rat diabetes model"Diabetologia. 44. 1034-1042 (2001)
[文献書誌] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model : molecular mechanisms of delayed angiogenesis in diabetes"Circulation. 104. 2344-2350 (2001)
[文献書誌] Hayashi, K., et al.: "Gene therapy for preventing neuronal death using hepatocyte growth factor : in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons"Gene Therpy. 8. 1167-1173 (2001)
[文献書誌] Shibuki, H., et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemia-reperfusion injury"Invest. Ophthalmol. Vis. Sci.. 43. 528-536 (2002)
[文献書誌] Maemondo, M., et al.: "Targeting angiogenesis and HGF function using an adenovirul vector expressing the HGF-antagonist NK4 for cancer therapy"Mol. Therapy. 5. 177-185 (2002)
[文献書誌] Sumi, T., et al.: "Mitosis-dependent phosphorylation and activation of LIM-kinase-1"Biochem.Biophys.Res.Commun.. (印刷中). (2002)
[文献書誌] Sakamaki, Y., et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postneumonectomy compensatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. (印刷中). (2002)
[文献書誌] Funakoshi, H., et al.: "Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neurosci.Res.. (印刷中). (2002)
[文献書誌] Kishi, A.Y., et al.: "Molecular cloning, expression and partial characterization of Kksy, a novel Xenopus member of Sky receptor tyrosine kinase"Gene. (印刷中). (2002)
[文献書誌] 松本邦夫, 中村敏一: "増殖因子による再生医学の展開-HGFを中心にして-"Biotherapy. 15. 95-104 (2001)
[文献書誌] 松本邦夫, 他: "HGFによる肺の再生と繊維化の阻止"呼吸. 20. 935-939 (2001)
[文献書誌] 富岡大策, 他: "NK4/malignostatinによる腫瘍血管新生阻止作用とその制がん効果"最新医学. 56. 1799-1807 (2001)
[文献書誌] 松本邦夫: "肝臓の初期発生を支える血管内皮細胞"実験医学. 20. 468-471 (2002)
[文献書誌] Matsumoto, K., et al.: "分担: HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4 書名: Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher. 35 (2001)

2001 年度 実績報告書

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

研究代表者

松本 邦夫 大阪大学, 医学系研究科, 助教授 (90201780)

研究成果

[文献書誌] Matsumoto, K., et al.: "Liver organogenesis promoted by endothelial cells prior to vascular function"Science. 294. 559-563 (2001)

[文献書誌] Tomioka, D., et al.: "Inhibition of Growth, Invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res.. 61. 7518-7524 (2001)

[文献書誌] Sumi, T., et al.: "Specific activation of LIM-kinase 2 via phosphorylation of the threonine-505 by ROCK, a Rho-dependent protein kinase"J.Biol.Chem.. 276. 670-676 (2001)

[文献書誌] Matsumoto, K., et al.: "Hepatocyte growth factor. renotropic role and potential therapeutics for renal diseases"Kid.Intem.. 59. 2023-2038 (2001)

[文献書誌] Sumi, T., et al.: "Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha"J Biol Chem.. 276. 23092-23096 (2001)

[文献書誌] Kuroiwa, T., et al.: "Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function"J Clin Invest. 107. 1365-1373 (2001)

[文献書誌] Maehara, N., et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br.J.Cancer. 84. 864-873 (2001)

[文献書誌] Mizuno, S., et al.: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy"Kidney Intern. 59. 1304-1314 (2001)

[文献書誌] Nakamura, T., et al.: "Malecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein"Biochim.Biophys.Acta. 1518. 63-72 (2001)

[文献書誌] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models : preclinical study for treatment of peripheral arterial disease"Gene Therapy. 8. 181-189 (2001)

[文献書誌] Azuma, H., et al.: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an experimental rat transplant model"J.Am.Soc.Nephrol. 12. 12180-12920 (2001)

[文献書誌] Matsumoto, K., et al.: "Inhibition of neointima by angiotensin-converting enzyme inhibitor in porcine coronary artery balloon-injury model"Hypertension. 37. 270-264 (2001)

[文献書誌] Nakagami, H., et al.: "Mitogenic and antiapoptotic actions of hepatocyte growth factor through ERK, STAT3, and AKT in endothelial cells"Hypertension. 37. 581-586 (2001)

[文献書誌] Yamamoto, K., et al.: "Contribution of bcl-2, but not bcl-xl and bax, to antiapoptotic actions of hepatocyte growth factor hypoxia-conditioned human endothelial cells"Hypertension. 37. 1341-1348 (2001)

[文献書誌] Ueda, H., et al.: "A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats"Cardiovascular Res.. 51. 41-50 (2001)

[文献書誌] Tsuzuki, N., et al.: "Hepatocyte growth factor reduces the infarct volume after transient focal cerebral ischemia in rats"Neurol Res.. 51. 417-424 (2001)

[文献書誌] Parr, C., et al.: "The HGF/SF-induced phosphorylation of paxillin, matrix adhesion, and invasion of prostate cancer cells were suppressed by NK4, an HGF/SF variant"Biochem Biophys Res Commun.. 285. 1330-1337 (2001)

[文献書誌] Beppu, K., et al.: "Hepatocyte growth factor production by peripheral blood mononuclear cells of recurrent cancer patients"Anticancer Res.. 21. 2195-2200 (2001)

[文献書誌] Aoki, M., et al.: "Inhibition of neointimal formation after balloon injury by cilostazol, accompanied by improvement of endothelial dysfunction and induction of hepatocyte growth factor in rat diabetes model"Diabetologia. 44. 1034-1042 (2001)

[文献書誌] Taniyama, Y., et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model : molecular mechanisms of delayed angiogenesis in diabetes"Circulation. 104. 2344-2350 (2001)

[文献書誌] Hayashi, K., et al.: "Gene therapy for preventing neuronal death using hepatocyte growth factor : in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons"Gene Therpy. 8. 1167-1173 (2001)

[文献書誌] Shibuki, H., et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemia-reperfusion injury"Invest. Ophthalmol. Vis. Sci.. 43. 528-536 (2002)

[文献書誌] Maemondo, M., et al.: "Targeting angiogenesis and HGF function using an adenovirul vector expressing the HGF-antagonist NK4 for cancer therapy"Mol. Therapy. 5. 177-185 (2002)

[文献書誌] Sumi, T., et al.: "Mitosis-dependent phosphorylation and activation of LIM-kinase-1"Biochem.Biophys.Res.Commun.. (印刷中). (2002)

[文献書誌] Sakamaki, Y., et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postneumonectomy compensatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. (印刷中). (2002)

[文献書誌] Funakoshi, H., et al.: "Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neurosci.Res.. (印刷中). (2002)

[文献書誌] Kishi, A.Y., et al.: "Molecular cloning, expression and partial characterization of Kksy, a novel Xenopus member of Sky receptor tyrosine kinase"Gene. (印刷中). (2002)

[文献書誌] 松本邦夫, 中村敏一: "増殖因子による再生医学の展開-HGFを中心にして-"Biotherapy. 15. 95-104 (2001)

[文献書誌] 松本邦夫, 他: "HGFによる肺の再生と繊維化の阻止"呼吸. 20. 935-939 (2001)

[文献書誌] 富岡大策, 他: "NK4/malignostatinによる腫瘍血管新生阻止作用とその制がん効果"最新医学. 56. 1799-1807 (2001)

[文献書誌] 松本邦夫: "肝臓の初期発生を支える血管内皮細胞"実験医学. 20. 468-471 (2002)

[文献書誌] Matsumoto, K., et al.: "分担: HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4 書名: Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher. 35 (2001)

2001 年度実績報告書

松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)