1993 Fiscal Year Annual Research Report

微生物由来がん遺伝子機能抑制物質の研究

Research Project

Project/Area Number	04253243
Research Institution	国立予防衛生研究所
Principal Investigator	上原至雅国立予防衛生研究所, 生物活性物質部, 室長 (50160213)
Co-Investigator(Kenkyū-buntansha)	深澤秀輔国立予防衛生研究所, 生物活性物質部, 研究員 (10218878) 村上裕子国立予防衛生研究所, 生物活性物質部, 主任研究官 (00142133)
Keywords	がん遺伝子 / ハービマイシン / EGFレセプター / エンジェルマイシン / チロシンキナーゼ
Research Abstract	1.新規がん遺伝子機能抑制物質angelmicin:正常細胞とSrcがん細胞間の血清要求性の差を指標にしたスクリーニングから、分子量が約1700、アントラキノン骨格に6つ糖が結合した新規物質angelmicinを見いだした。選択性が高いチロシンキナーゼ阻害剤で、HL-60をきれいに顆粒球に分化誘導するが、チロシンキナーゼ阻害活性との関連については今のところ不明。invivoでの効果は弱く、P388でのILSは30-40%程度であった。 2.ハービマイシンによるA431細胞の増殖促進:erbB1(EGFレセプター)の過剰発現が知られるヒト偏平上皮がんA431細胞を用い、ハービマイシンの作用を調べた。この細胞は高濃度のEGF(100ng/ml)で増殖抑制(DNA合成阻害)を受けるが、ハービマイシンを共存させるとEGF刺激(10,100ng/ml)によるDNA合成は逆に促進した。ハービマイシン処理によりEGFレセプターのキナーゼ活性が低下したが、これは予想されたキナーゼ活性の直接の阻害によるのではなく、レセプターが生合成途上に分解の促進を受け、その結果、レセプター蛋白量が低下したことに起因することが判明した。ハービマイシン処理により、増殖抑制に働く低親和性のレセプターが減少し、EGF刺激のDNA合成を促進する高親和性のレセプター数が減少しなかったことが、増殖のphenotypeを正常細胞様に変化させたことの説明となる。erbB1やerbB2が過剰発現した癌細胞に対して、レセプターの発現量を低下させる薬剤が、抗がん効果を示すのか今後の検討課題である。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] Mihiro Okabe: "New insight into oncoprotein-tageted antitumor effect:Herbimycin A asan antagonist of protein tyrosine kinase against Ph^1-positive leukemiacells." Leuk.Lymph. in press. (1994)
[Publications] Mihiro Okabe: "Mamoru Shoji,William Ralph Vogler,Keisuke Sakurada,Yoshimasa Uehara and Tamotsu Miyazaki.Effect of herbimycin A,an inhibitor of tyrosine kinase,on protein tyrosine kinase activity andphosphotyrosyl6 proteins of Ph1-positive eukemia cells." Leuk.Res. in press. (1994)
[Publications] Toshie Kanbe: "Use of transcriptional enhancerelements responsive to Ras,protein kinase A and protein kinase C to evaluate inhibitors of specific signal transduction pathways." Biol.Pharm.Bull. in press. (1994)
[Publications] Hidesuke Fukazawa: "Labeling of v-Src and BCR-ABL tyrosine kinases with [14C]herbimycin Aand its use in the elucidation of kinase inactivation mechanism." FEBS Lett. in press. (1994)
[Publications] Yuko Murakami: "Accelerated degration of 160 kDa EGF receptor precursor by the tyrosine kinase inhibitor herbimycin A in the endoplasmic reticulum of A431 human epidermoid carcinoma cells." Biochem.J.in press. (1994)
[Publications] Pei-ming Li: "Evaluation of protein kinase inhibitors in an assay system containingmultiple protein kinase activities." Anticancer Res.13. 1957-1964 (1993)
[Publications] Tadahide Furuno: "Confocal fluorescence microscopy for studying the effects of a tyrosine kinase inhibitor on the nuclear calcium signals in B cells." Bioinages. 1. 175-180 (1993)
[Publications] Kayoko S.Tuchiya: "Distinct effects of clinically used anthracycline antibiotics on ras oncogene-expressed cells." Biol.Pharm.Bull.16. 908-911 (1993)
[Publications] Masahiko Taniguchi: "Inhibition of ret tyrosine kinase activity by herbimycin A." Biochem.Biophy.Res.Comnun.195. 208-214 (1993)
[Publications] Yoshimasa Uehara: "New evaluation systems for inhibitors of oncogenic signal transductions." Acti〓omyatologica. 7. s9-10 (1993)
[Publications] Yoshimasa Uehara: "Angelmicins,new inhibitors of oncogenic src signal transduction." J.Antibiotics. 46. 1306-1308 (1993)
[Publications] Hidesuke Fukuzawa: "Method for simultaneos detection of protein kinase A,protein kinase C,protein tyrosine kinase,and calmodulin-dependent protein kinase activities." Anal.Biochem. 212. 106-110 (1993)
[Publications] Pei-ming Li: "Method of identifying inhibitors of oncogenic transformation:selective inhibition of cell growth in serum-free medium." Oncogene. 8. 1731-17354:Toshiyuki Yoneda (1993)
[Publications] "Herbimycin A,a pp60^<c-src>tyrosine kinase inhibitor,inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo." J,Clin.Invest.91. 2791-2795 (1993)
[Publications] Michinari Hamaguchi: "Herbimycin A inhibits the association of p60v-src with the cytoskeletal structure and with phophatidylinositol 3'kinase." Oncogene. 8. 559-564 (1993)
[Publications] 上原至雅: "がん遺伝子産物を標的とした抗がん剤の開発" 癌と化学療法. 20. 1885-1891 (1993)
[Publications] 上原至雅: "チロシンキナーゼ阻害剤" 実験医学. 11. 2130-2135 (1993)
[Publications] 上原至雅: "チロシンキナーゼ阻害剤、ハービマイシン" 蛋白質・核酸・酵素. 38. 1950-1959 (1993)
[Publications] 上原至雅: "腫瘍学(佐藤昇志、菊地浩吉編)" 中外医学社, (1994)
[Publications] 上原至雅: "医学微生物学の新しい展開1993(加藤延夫編)" 菜根出版, P234-241 (1993)

1993 Fiscal Year Annual Research Report

微生物由来がん遺伝子機能抑制物質の研究

Principal Investigator

上原 至雅 国立予防衛生研究所, 生物活性物質部, 室長 (50160213)

Research Products

[Publications] Mihiro Okabe: "New insight into oncoprotein-tageted antitumor effect:Herbimycin A asan antagonist of protein tyrosine kinase against Ph^1-positive leukemiacells." Leuk.Lymph. in press. (1994)

[Publications] Mihiro Okabe: "Mamoru Shoji,William Ralph Vogler,Keisuke Sakurada,Yoshimasa Uehara and Tamotsu Miyazaki.Effect of herbimycin A,an inhibitor of tyrosine kinase,on protein tyrosine kinase activity andphosphotyrosyl6 proteins of Ph1-positive eukemia cells." Leuk.Res. in press. (1994)

[Publications] Toshie Kanbe: "Use of transcriptional enhancerelements responsive to Ras,protein kinase A and protein kinase C to evaluate inhibitors of specific signal transduction pathways." Biol.Pharm.Bull. in press. (1994)

[Publications] Hidesuke Fukazawa: "Labeling of v-Src and BCR-ABL tyrosine kinases with [14C]herbimycin Aand its use in the elucidation of kinase inactivation mechanism." FEBS Lett. in press. (1994)

[Publications] Yuko Murakami: "Accelerated degration of 160 kDa EGF receptor precursor by the tyrosine kinase inhibitor herbimycin A in the endoplasmic reticulum of A431 human epidermoid carcinoma cells." Biochem.J.in press. (1994)

[Publications] Pei-ming Li: "Evaluation of protein kinase inhibitors in an assay system containingmultiple protein kinase activities." Anticancer Res.13. 1957-1964 (1993)

[Publications] Tadahide Furuno: "Confocal fluorescence microscopy for studying the effects of a tyrosine kinase inhibitor on the nuclear calcium signals in B cells." Bioinages. 1. 175-180 (1993)

[Publications] Kayoko S.Tuchiya: "Distinct effects of clinically used anthracycline antibiotics on ras oncogene-expressed cells." Biol.Pharm.Bull.16. 908-911 (1993)

[Publications] Masahiko Taniguchi: "Inhibition of ret tyrosine kinase activity by herbimycin A." Biochem.Biophy.Res.Comnun.195. 208-214 (1993)

[Publications] Yoshimasa Uehara: "New evaluation systems for inhibitors of oncogenic signal transductions." Acti〓omyatologica. 7. s9-10 (1993)

[Publications] Yoshimasa Uehara: "Angelmicins,new inhibitors of oncogenic src signal transduction." J.Antibiotics. 46. 1306-1308 (1993)

[Publications] Hidesuke Fukuzawa: "Method for simultaneos detection of protein kinase A,protein kinase C,protein tyrosine kinase,and calmodulin-dependent protein kinase activities." Anal.Biochem. 212. 106-110 (1993)

[Publications] Pei-ming Li: "Method of identifying inhibitors of oncogenic transformation:selective inhibition of cell growth in serum-free medium." Oncogene. 8. 1731-17354:Toshiyuki Yoneda (1993)

[Publications] "Herbimycin A,a pp60^<c-src>tyrosine kinase inhibitor,inhibits osteoclastic bone resorption in vitro and hypercalcemia in vivo." J,Clin.Invest.91. 2791-2795 (1993)

[Publications] Michinari Hamaguchi: "Herbimycin A inhibits the association of p60v-src with the cytoskeletal structure and with phophatidylinositol 3'kinase." Oncogene. 8. 559-564 (1993)

[Publications] 上原至雅: "がん遺伝子産物を標的とした抗がん剤の開発" 癌と化学療法. 20. 1885-1891 (1993)

[Publications] 上原至雅: "チロシンキナーゼ阻害剤" 実験医学. 11. 2130-2135 (1993)

[Publications] 上原至雅: "チロシンキナーゼ阻害剤、ハービマイシン" 蛋白質・核酸・酵素. 38. 1950-1959 (1993)

[Publications] 上原至雅: "腫瘍学(佐藤昇志、菊地浩吉編)" 中外医学社, (1994)

[Publications] 上原至雅: "医学微生物学の新しい展開1993(加藤延夫編)" 菜根出版, P234-241 (1993)

上原至雅国立予防衛生研究所, 生物活性物質部, 室長 (50160213)