2001 Fiscal Year Annual Research Report

足場依存増殖センサーとしてのSHPS-1の研究

Research Project

Project/Area Number	13043021
Research Institution	Nagoya University
Principal Investigator	濱口道成名古屋大学, 大学院・医学研究科, 教授 (90135351)
Co-Investigator(Kenkyū-buntansha)	岩本隆司名古屋大学, アイソトープ総合センター, 助手 (60223426)
Keywords	SHPS-1 / v-Src / チロシンリン酸化 / 細胞接着 / 接着斑 / 足場非依存増殖 / 癌化
Research Abstract	癌の本質は、無規律的な細胞増殖にある。この異常な細胞増殖は、培養細胞で「足場に依存しない細胞増殖」として再現される。今日、正常細胞の細胞増殖・細胞周期制御機構はかなりの詳細が明らかになった。しかし残念な事に、正常細胞と癌細胞の増殖の分水嶺となる「足場依存細胞増殖機構」については殆ど分っていない。我々は、数年来「適格な実験系」の開発に取り組み、ついに成功した。この系は、癌遺伝子v-srcで癌化した細胞(SR3Y1)に、細胞膜糖蛋白質SHPS-1を発現する事により樹立できた。SHPS-1発現SR3Y1は、形態はSR3Y1と変わらず癌化しており、通常の接着状態での増殖はSR3Y1と遜色ない。しかし驚く事に、軟寒天培地中での増殖は強く抑制され、ヌードマウスでの造腫瘍性を失っていた。本年は、まず種々の変異型SHPS-1遺伝子の開発に取り組むと共に、その癌細胞への発現と機能解析を行った。作製した主な変異遺伝子は、細胞質側あるいは細胞外側を単純に欠失もの、細胞質側にあるITEMモチーフと呼ばれる部分のリン酸化を受けるチロシン残基をフェニールアラニンに改編したものである。更に、これら変異型SHPS-1発現SR3Y1を用いて、接着に伴う細胞展開の変化を詳細に解析した。その結果、SHPS-1は細胞の接着と展開を制御する蛋白質である事、この機能発現の為にはSHPS-1の細胞質側リン酸化部位が保存されている必要がある事、癌細胞はSHPS-1の発現を失った為に基質への接着が著しく低下した事を発見した。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Yasuyoshi Sohara, Kazuya M., et al.: "Hyaluronan activates cell motility of v-Src-transformed cells via Ras-MAPK and PI3K-Akt in a tumor-specific manner"Mol. Biol. Cell. 12. 1859-1868 (2001)
[Publications] Yuzhen Liu, Yukiko H., et al.: "Suppression of cell spreading by v-Crk requires Ras-MEK-MAP kinase signaling"Oncogene. 20. 5908-5912 (2001)
[Publications] Kazuhiko Hayashi, Satoru M., et al.: "Invasion activating caveolin-1 mutation in human scirrhous breast cancers"Cancer Ras.. 61. 2361-2364 (2001)
[Publications] Chisako Iriyama, Satoru M., et al.: "Clonning and sequencing of a novel human gene encodes a putative hydroxylase"J. Hum. Genet.. 46. 289-292 (2001)
[Publications] Satoru Matsuda, Chisako I., et al.: "Cloning and sequence of a novel human gene that enocodes a putative target protein of Nesh-SH3"J. Hum. Genet.. 46. 483-486 (2001)
[Publications] Tatsuyoshi Yamamoto, Koji O., et al.: "p73 is highly expressed in myoepithelial cells and in carcinomas with metaplasia"Int. J. Onc.. 19. 271-276 (2001)
[Publications] Aye Aye Thant, Akihiro N., et al.: "Fibronectin activates matrix metalloproteinase-9-secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells"Clin. Exp. Metastas.. 18(5). 423-428 (2001)
[Publications] Takeshi Senga, Takashi I., et al.: "JAK/Stat3 dependent activation of RalGDS/Ral in M1 mouse myeloid leukemia cells"J. Biol. Chem.. 276(35). 32678-32681 (2001)
[Publications] Yanying Zhang, Aye Aye T., et al.: "A role for focal adhesion kinase in hyluronan dependent MMP-2 secretion in a human small-cell lung carcinoma cell line, QG90"Biochem Biophys Ras Commun.. 290(3). 1123-1127 (2001)
[Publications] Etsuko Hirayama, Akiko I., et al.: "Ras/MAP kinase pathway is associated with the control of myotube formation but not myofibril assembly in quail myoblasts transformed with Rous sarcoma virus"Cell Struct. Funct.. 26. 253-261 (2002)
[Publications] Masashi Kato, Kozue T., et al.: "Repair by Src kinase of function-impaired RET-MEN2A with mutations at tyrosines in the carboxyterminal kinase domain"Cancer Ras.. (In press).
[Publications] Naoki Itano, Fukiko A., et al.: "Abnormal accumulation of hyaluronan matrix deiminishes contact inhibition of cell growth and promotes cell migration"Proc. Natl. Acad. Sci. U.S.A.. (In press).

2001 Fiscal Year Annual Research Report

足場依存増殖センサーとしてのSHPS-1の研究

Principal Investigator

濱口 道成 名古屋大学, 大学院・医学研究科, 教授 (90135351)

Research Products

[Publications] Yasuyoshi Sohara, Kazuya M., et al.: "Hyaluronan activates cell motility of v-Src-transformed cells via Ras-MAPK and PI3K-Akt in a tumor-specific manner"Mol. Biol. Cell. 12. 1859-1868 (2001)

[Publications] Yuzhen Liu, Yukiko H., et al.: "Suppression of cell spreading by v-Crk requires Ras-MEK-MAP kinase signaling"Oncogene. 20. 5908-5912 (2001)

[Publications] Kazuhiko Hayashi, Satoru M., et al.: "Invasion activating caveolin-1 mutation in human scirrhous breast cancers"Cancer Ras.. 61. 2361-2364 (2001)

[Publications] Chisako Iriyama, Satoru M., et al.: "Clonning and sequencing of a novel human gene encodes a putative hydroxylase"J. Hum. Genet.. 46. 289-292 (2001)

[Publications] Satoru Matsuda, Chisako I., et al.: "Cloning and sequence of a novel human gene that enocodes a putative target protein of Nesh-SH3"J. Hum. Genet.. 46. 483-486 (2001)

[Publications] Tatsuyoshi Yamamoto, Koji O., et al.: "p73 is highly expressed in myoepithelial cells and in carcinomas with metaplasia"Int. J. Onc.. 19. 271-276 (2001)

[Publications] Aye Aye Thant, Akihiro N., et al.: "Fibronectin activates matrix metalloproteinase-9-secretion via the MEK1-MAPK and the PI3K-Akt pathways in ovarian cancer cells"Clin. Exp. Metastas.. 18(5). 423-428 (2001)

[Publications] Takeshi Senga, Takashi I., et al.: "JAK/Stat3 dependent activation of RalGDS/Ral in M1 mouse myeloid leukemia cells"J. Biol. Chem.. 276(35). 32678-32681 (2001)

[Publications] Yanying Zhang, Aye Aye T., et al.: "A role for focal adhesion kinase in hyluronan dependent MMP-2 secretion in a human small-cell lung carcinoma cell line, QG90"Biochem Biophys Ras Commun.. 290(3). 1123-1127 (2001)

[Publications] Etsuko Hirayama, Akiko I., et al.: "Ras/MAP kinase pathway is associated with the control of myotube formation but not myofibril assembly in quail myoblasts transformed with Rous sarcoma virus"Cell Struct. Funct.. 26. 253-261 (2002)

[Publications] Masashi Kato, Kozue T., et al.: "Repair by Src kinase of function-impaired RET-MEN2A with mutations at tyrosines in the carboxyterminal kinase domain"Cancer Ras.. (In press).

[Publications] Naoki Itano, Fukiko A., et al.: "Abnormal accumulation of hyaluronan matrix deiminishes contact inhibition of cell growth and promotes cell migration"Proc. Natl. Acad. Sci. U.S.A.. (In press).

濱口道成名古屋大学, 大学院・医学研究科, 教授 (90135351)