1996 Fiscal Year Annual Research Report

ホルモンによるがん増殖制御機構とその臨床応用

Research Project

Project/Area Number	08265106
Research Category	Grant-in-Aid for Scientific Research on Priority Areas
Research Institution	Japanese Foundation For Cancer Research
Principal Investigator	尾形悦郎財団法人癌研究會, 癌研究所, 部長 (70013761)
Co-Investigator(Kenkyū-buntansha)	大薗恵一大阪市立母子保健総合医療センター, 研究所, 部長 (20270770) 名和田新九州大学, 医学部, 教授 (10038820) 首藤紘一東京大学, 薬学部, 教授 (50012612) 加藤茂明東京大学, 分生研, 助教授 (60204468) 梅園和彦奈良先端科学技術大学院大, バイオサイエンス研, 助教授 (50183752)
Keywords	核受容体 / 共役因子 / ステロイド・ホルモン / レチノイド / 乳癌 / 前立腺癌 / 白血病 / PTHrP
Research Abstract	ホルモン療法における作用機序及び耐性化の機序につき検討し、以下の結果を得た。 1.(1)ビタミンD受容体(VDR)分子のC端域にリガンド依存性転写調節領域(AF2)を同定。この領域の変異VDRは、dominant negativeである。ラット・VD24水酸化酵素プロモーター上に存在する2つのVDREは相加的に機能的にする(大薗)。(2)VDRと特異的に相互作用する転写共役因子を同定(加藤)。(3)U937(白血病細胞)及びLNCaP(前立腺癌細胞)において、VDは主としてp27誘導を介し増殖抑制・分化誘導効果を発揮する。VDは、PTHrP遺伝子を抑制。この責任DNA配列にVDRとKu抗原とが結合する(尾形)。 2.リガンド結合により惹起されるエストロゲン受容体の構造変化を検討。N末端とC末端とがリガンド依存性に相互作用をするようになる(加藤)。 3.(1)RXRヘテロ2量体とこれに関連する転写介在因子(co-activator,co-repressor)との間の核内におけるリガンド依存性の結合・解離をモニターする系を確立(梅園)。(2)前骨髄急性白血病株HL60の分化誘導活性を著しく増強するretinoidagonist・HX600を合成。これはRAR・RXRheterodimerのRXRと結合、転写活性を高める(首藤)。 4.白血病細胞におけるglucocorticoid(G)不応の機序として、G受容体(GR)アイソマ-(GRβ)発現が関与する可能性がある(名和田)。 5.ヒト11番染色体よりKAI1前立腺癌転移抑制遺伝しをクローニング。前立腺癌におけるホルモン不応に関連し、8番染色体短腕にLOHが80%に認められる(市川)。 6.乳癌に対する化学療法で、3ヶ月で血中E2が極端に低下。antiestrogenはin vitroの系でadriamycin細胞障害性を増強(堀越)。

Research Products
(19 results)

All Other

All Publications (19 results)

[Publications] Chung,U.,et.al.: "The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium." J.Biol.Chem.271. 8593-8598 (1996)
[Publications] Chen,J.D.,et.al.: "SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers." Proc.Natl.Acad.Sci.USA. 93. 7567-7571 (1996)
[Publications] Perlmann,T.,et.al.: "Two distinct dimerization interfaces differentially modulate target gene specificity of nuclear hormone receptors." Mol.Endocrinol.10. 958-966 (1996)
[Publications] Ebihara,K.,et.al.: "Intron retention generates a novel isoform of the murine vitamin D receptor that acts in a dominant negative way on the vitamin D signaling pathway." Mol.Cell.Biol.16. 3393-3400 (1996)
[Publications] Arao,Y.,et.al.: "A synthetic estrogen antagonist inhibits estrogen-induced transcriptional,but not post-transcriptional regulation of gene expression." Biochem.J.313. 269-274 (1996)
[Publications] Takeyama,K.,et.al.: "Retinoic acid differentially up-regulates the gene expression of retinoic acid alpha and gamma isoforms in embryos and adult rats." Biochem.Biophys.Res.Commun.222. 395-400 (1996)
[Publications] Arao,Y.,et.al.: "Steroid hormones differentially induce transcription of the chicken ovalbumin gene,but stabilize the mRNA with the same half-life." J.Biochem.120. 710-715 (1996)
[Publications] Ninomiya,Y.,et.al.: "Vitamin A is involved in estrogen-induced cell proliferation,but not in cytodifferentiation of the chicken oviduct." J.Endocrinol.148. 257-265 (1996)
[Publications] Arao,Y.,et.al.: "Steroid hormone-induced expression of the chicken ovalbumin gene and the levels of nuclear steroid hormone receptors in chick oviduct." Biosci.Biotech.Biochem.60. 493-495 (1996)
[Publications] Hashimoto,Y.,et.al.: "Evaluation of differentiation inducing activity of retinoids on human leukemia cells Hl60 and NB4." Biol.Pharm.Bull.19. 1322-1328 (1996)
[Publications] Takeshita,A.,et.al.: "Successful treatment of relapse of acute promyelocytic leukemia with a new synthetic retinoid,Am80." Ann.Intl.Medicine. 124. 893-896 (1996)
[Publications] Oba,K.,et.al.: "Structual characterization of human Ad4BP (SF-1) gene." Biochem.Biophys.Res.Commun.226. 261-267 (1996)
[Publications] Ichikawa,T.,et.al.: "Metastasis Suppressor Genes for Prostatic Cancer." Prostate. Suppl.6. 31-35 (1996)
[Publications] Dong,J.-T.,et.al.: "Prostate cancer-Biology of metastasis and its clinical implications." World J.Urol.14. 182-189 (1996)
[Publications] Ueda,T.,et.al.: "Expression of the KAI1 protein in genign prostatic hyperplasia and prostate cancer." Am.J.Pathol.149(5). 1435-1440 (1996)
[Publications] Nihei,N.,et.al.: "Mapping of metastasis suppressor gene (s) for rat prostate cancer on the short arm of human chromosome 8 by irradiated microcell-mediated chromosome transfer." Genes Chromosom.Cancer. 17(4). 260-268 (1996)
[Publications] Tomioka,S.,et.al.: "Characteristics of androgen-independent growth of androgen-responsive shionogi carcinoma 115." Intl.J.Urol.3(4). 286-291 (1996)
[Publications] Ohyama,Y.,et.al.: "Function of two vitamin D-responsive elements in the rat 25-hydroxyvitamin D_324-Hydroxylase gene." J.Biol.Chem.271. 30381-30385 (1996)
[Publications] Uchida,M.,et.al.: "In vitro binding of vitamin D receptor occupied by 24R,25-dihydroxyvitamin D_3 to vitamin D responsive element of human osteocalcin gene." J.Steroid Biochem.Mol.Biol.(in press).

1996 Fiscal Year Annual Research Report

ホルモンによるがん増殖制御機構とその臨床応用

Principal Investigator

尾形 悦郎 財団法人癌研究會, 癌研究所, 部長 (70013761)

Research Products

[Publications] Chung,U.,et.al.: "The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium." J.Biol.Chem.271. 8593-8598 (1996)

[Publications] Chen,J.D.,et.al.: "SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers." Proc.Natl.Acad.Sci.USA. 93. 7567-7571 (1996)

[Publications] Perlmann,T.,et.al.: "Two distinct dimerization interfaces differentially modulate target gene specificity of nuclear hormone receptors." Mol.Endocrinol.10. 958-966 (1996)

[Publications] Ebihara,K.,et.al.: "Intron retention generates a novel isoform of the murine vitamin D receptor that acts in a dominant negative way on the vitamin D signaling pathway." Mol.Cell.Biol.16. 3393-3400 (1996)

[Publications] Arao,Y.,et.al.: "A synthetic estrogen antagonist inhibits estrogen-induced transcriptional,but not post-transcriptional regulation of gene expression." Biochem.J.313. 269-274 (1996)

[Publications] Takeyama,K.,et.al.: "Retinoic acid differentially up-regulates the gene expression of retinoic acid alpha and gamma isoforms in embryos and adult rats." Biochem.Biophys.Res.Commun.222. 395-400 (1996)

[Publications] Arao,Y.,et.al.: "Steroid hormones differentially induce transcription of the chicken ovalbumin gene,but stabilize the mRNA with the same half-life." J.Biochem.120. 710-715 (1996)

[Publications] Ninomiya,Y.,et.al.: "Vitamin A is involved in estrogen-induced cell proliferation,but not in cytodifferentiation of the chicken oviduct." J.Endocrinol.148. 257-265 (1996)

[Publications] Arao,Y.,et.al.: "Steroid hormone-induced expression of the chicken ovalbumin gene and the levels of nuclear steroid hormone receptors in chick oviduct." Biosci.Biotech.Biochem.60. 493-495 (1996)

[Publications] Hashimoto,Y.,et.al.: "Evaluation of differentiation inducing activity of retinoids on human leukemia cells Hl60 and NB4." Biol.Pharm.Bull.19. 1322-1328 (1996)

[Publications] Takeshita,A.,et.al.: "Successful treatment of relapse of acute promyelocytic leukemia with a new synthetic retinoid,Am80." Ann.Intl.Medicine. 124. 893-896 (1996)

[Publications] Oba,K.,et.al.: "Structual characterization of human Ad4BP (SF-1) gene." Biochem.Biophys.Res.Commun.226. 261-267 (1996)

[Publications] Ichikawa,T.,et.al.: "Metastasis Suppressor Genes for Prostatic Cancer." Prostate. Suppl.6. 31-35 (1996)

[Publications] Dong,J.-T.,et.al.: "Prostate cancer-Biology of metastasis and its clinical implications." World J.Urol.14. 182-189 (1996)

[Publications] Ueda,T.,et.al.: "Expression of the KAI1 protein in genign prostatic hyperplasia and prostate cancer." Am.J.Pathol.149(5). 1435-1440 (1996)

[Publications] Nihei,N.,et.al.: "Mapping of metastasis suppressor gene (s) for rat prostate cancer on the short arm of human chromosome 8 by irradiated microcell-mediated chromosome transfer." Genes Chromosom.Cancer. 17(4). 260-268 (1996)

[Publications] Tomioka,S.,et.al.: "Characteristics of androgen-independent growth of androgen-responsive shionogi carcinoma 115." Intl.J.Urol.3(4). 286-291 (1996)

[Publications] Ohyama,Y.,et.al.: "Function of two vitamin D-responsive elements in the rat 25-hydroxyvitamin D_324-Hydroxylase gene." J.Biol.Chem.271. 30381-30385 (1996)

[Publications] Uchida,M.,et.al.: "In vitro binding of vitamin D receptor occupied by 24R,25-dihydroxyvitamin D_3 to vitamin D responsive element of human osteocalcin gene." J.Steroid Biochem.Mol.Biol.(in press).

尾形悦郎財団法人癌研究會, 癌研究所, 部長 (70013761)