1998 年度実績報告書

ホルモンによるがん増殖制御機構とその臨床応用

研究課題

研究課題/領域番号	08265106
研究機関	(財)癌研究会
研究代表者	尾形悦郎癌研究会, 癌研究所, 部長 (70013761)
研究分担者	柳澤純東京大学, 分子細胞生物学研究所, 助手 (50301114) 市川智彦千葉大学, 医学部, 講師 (20241953) 名和田新九州大学, 医学部, 教授 (10038820) 首藤紘一東京大学, 大学院薬学系, 教授 (50012612) 梅園和彦京都大学, ウィルス研究所, 教授 (50183752)
キーワード	乳癌 / 前立腺癌 / 白血病 / レチノイド / TGFβ / VDR / ER / AR
研究概要	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.ステロイド・ホルモンによる遺伝子抑制の機序をVDとPTHrP遺伝子とを例に検討し、PTHrP遺伝子上の責任promoter構造を決定。ついでそこにVDRとKu抗原が結合すること、Ku抗原によるVDRのリン酸化が抑制の作用機序である可能性を示した(尾形)。 2.オーファン・レセプターとしてTixを新たに単離・同定した。Tixが神経芽細胞腫や結腸癌に発現すること、これの過剰発現が細胞増殖を強く誘導することを示した(梅園)。 3.RAR・RXRに比較的特異的に結合・作用する薬物を合成し、それによりRAR・RXRの機能の解析を行った(首藤)。 4.白血病細胞のグルココルチコイド抵抗性との関係で、PPARγの発現が極めて高いこと,増加が認められるGRβは核内で機能することを観察した(名和田)。 5.ホルモン療法抵抗性前立腺癌の14%にAR遺伝子codon877の点突然変異を見出しこの変異を持つ癌細胞がアンチアンドロゲンによっても増殖刺激を受けることを示した(市川)。 6.ビタミンD作用に拮抗する新規化合物(TEI9647)について検討し、これがVDRと結合し、そのco-activatorとの作用を阻害する可能性を示した(大薗)。 7.乳癌患者に化療を施した場合のestrogenレベルの動態を明らかにした(堀越)。 8.核受容体をめぐるステロイド・ホルモンと成長因子・サイトカインとの間のクロス・トークの例としてERがMAP-kinaseによりリン酸化され、AF1の転写活性が高まることを示し、このためのco-activatorの候補として68KD蛋白を見出した。また、TGFβの作用に関与するSmad蛋白がVDRと相互作用し、VDRの転写活性を増強することを見出した(柳澤)。

研究成果

(21件)

すべてその他

すべて文献書誌 (21件)

[文献書誌] Nishishita,Y., Ogata,E.: "A negative vitamin D responsive DNA element in the human parathyroid hormone-related peptide gene binds to vitamin D receptor along with Ku antigen to mediate negative gene regulation by vitamin D." J.Boil.Chem.273. 10901-10907 (1998)
[文献書誌] Menjo,M., Ogata,E.: "Critical role for p27 kip1 in cell cycle arrest after androgen depletion in mouse mammary carcinoma cells (SC-3)." Oncogene. 17. 2619-2627 (1998)
[文献書誌] Blumberg,B.M., Umesono,K.: "Transcriptional activation induced by aminobenzoates through a novel nuclear receptor." Gene.Dev.12. 1269-1277 (1998)
[文献書誌] Ogawa,H., Umesono,K.: "Intracellular localization and transcriptional activation by the human glucocorticoid receptor-green fluorescent protein (GFP) fusion proteins." Acta.Histochem.Cytochem.31. 303-308 (1998)
[文献書誌] Ohta,K., Shudo,K.: "Potent Retinoid Synergists with A Diphenylamine Skeleton." Bio.Pharm.Bull.21. 544-546 (1998)
[文献書誌] Ebisawa,M., Shudo,K.: "Novel Thiazolidinedione Derivatives with Retinoid Synergistic Activity." Bio.Pharm.Bull.21. 547-549 (1998)
[文献書誌] Luu,H., Ichikawa,T.,: "Identification of a novel metastasis-suppressor region on human chormosone 12." Cancer Res.58(16). 3561-3565 (1998)
[文献書誌] Nihei,N., Ichikawa,T.: "Metastasis suppressor gene(s) for rat prostate cancer on the long arm of human chromosome 7." Genes Chromosomes Cancer. 24(1). 1-8 (1999)
[文献書誌] Ueda,T., Ichikawa,T.: "Identification of a 1-cM region of common deletion on 13q14 associated with metastasis of human prostate cancer." Genes Chromosomes Cancer. in press.
[文献書誌] Nakajima,S., Ozono,K.: "Characterization of the activation function-2 domail of the human 1, 25-dihydroxyvitamin D3 receptor." Mol Cell Endocrinol. 139. 15-24 (1998)
[文献書誌] Ozono,K.: "Direct repeat 3-type element lacking the ability to bind to the vitamin D receptor enhances the function of a vitaminD-responsive element." J.Steroid Biochem Mol Bio.166. 263-269 (1998)
[文献書誌] Nakajima,S., Ozono,K.: "Effect of cyclic adenosine 3, 5-monophosphate and protein kinase A on ligand-dependent transactivation via the Vitamin D receptor." Mol Cell Endocrinol. in press.
[文献書誌] Tanaka,Y., Horikoshi,N.: "Gonadotropins stimulate growth of breast cancer MCF-7 cells by stimulating intracellular synthesis of estra-diol from DHEA." Breast Cancer Res.Treat.50(3). 367 (1998)
[文献書誌] Takeyama,K., Yanagisawa,J.: "Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog." Mol.Cell.Biol.in press.
[文献書誌] Yanagisawa,J.: "Convergence of TGFβ and vitamin D signaling pathways on SMAD proteins acting as common transcrip-tional co-activators." Science. in press.
[文献書誌] Watanabe,M., Yanagisawa,J.: "A putative tumor suppressor, TSG101, acts as a transcriptional suppressor through its coiled-coil domain." Biochem.Biophys.Res.Commun.245. 900-905 (1998)
[文献書誌] Nishihara,A., Yanagisawa,J.: "Role of p300, a transcriptional coactivator, in signalling of TGF-β." Genes to Cells. 3. 613-623 (1998)
[文献書誌] Tanimoto,K., Hayashi,S.: "Regulation of Estrogen Receptor α Gene Mediated by Promoter B Responsible for Its Enhanced Expres-sion in Human Breast Cancer." Nucl.Acids Res.27. 903-909 (1999)
[文献書誌] Saji,S., Hayashi,S.: "MDM2, a Regulator for Estradiol Induced p53 Up-regulation in Breast Cancer Cells." Jpn.J.Cancer Res.in press. (1999)
[文献書誌] Okamoto,K., Hayashi,S.: "Redox-dependent Modulation of Nuclear Import of the Glucocorticoid Receptor." J.Biol.Chem.in press. (1999)
[文献書誌] Shimoike,T., Nawata,H.: "Subcutaneous or visceral adipose expression of the PPAR γ gene is not altered in the fatty (fa/fa) Zucker rat." Metabolism. 47. 1494-1498 (1998)

1998 年度 実績報告書

ホルモンによるがん増殖制御機構とその臨床応用

研究代表者

尾形 悦郎 癌研究会, 癌研究所, 部長 (70013761)

研究成果

[文献書誌] Nishishita,Y., Ogata,E.: "A negative vitamin D responsive DNA element in the human parathyroid hormone-related peptide gene binds to vitamin D receptor along with Ku antigen to mediate negative gene regulation by vitamin D." J.Boil.Chem.273. 10901-10907 (1998)

[文献書誌] Menjo,M., Ogata,E.: "Critical role for p27 kip1 in cell cycle arrest after androgen depletion in mouse mammary carcinoma cells (SC-3)." Oncogene. 17. 2619-2627 (1998)

[文献書誌] Blumberg,B.M., Umesono,K.: "Transcriptional activation induced by aminobenzoates through a novel nuclear receptor." Gene.Dev.12. 1269-1277 (1998)

[文献書誌] Ogawa,H., Umesono,K.: "Intracellular localization and transcriptional activation by the human glucocorticoid receptor-green fluorescent protein (GFP) fusion proteins." Acta.Histochem.Cytochem.31. 303-308 (1998)

[文献書誌] Ohta,K., Shudo,K.: "Potent Retinoid Synergists with A Diphenylamine Skeleton." Bio.Pharm.Bull.21. 544-546 (1998)

[文献書誌] Ebisawa,M., Shudo,K.: "Novel Thiazolidinedione Derivatives with Retinoid Synergistic Activity." Bio.Pharm.Bull.21. 547-549 (1998)

[文献書誌] Luu,H., Ichikawa,T.,: "Identification of a novel metastasis-suppressor region on human chormosone 12." Cancer Res.58(16). 3561-3565 (1998)

[文献書誌] Nihei,N., Ichikawa,T.: "Metastasis suppressor gene(s) for rat prostate cancer on the long arm of human chromosome 7." Genes Chromosomes Cancer. 24(1). 1-8 (1999)

[文献書誌] Ueda,T., Ichikawa,T.: "Identification of a 1-cM region of common deletion on 13q14 associated with metastasis of human prostate cancer." Genes Chromosomes Cancer. in press.

[文献書誌] Nakajima,S., Ozono,K.: "Characterization of the activation function-2 domail of the human 1, 25-dihydroxyvitamin D3 receptor." Mol Cell Endocrinol. 139. 15-24 (1998)

[文献書誌] Ozono,K.: "Direct repeat 3-type element lacking the ability to bind to the vitamin D receptor enhances the function of a vitaminD-responsive element." J.Steroid Biochem Mol Bio.166. 263-269 (1998)

[文献書誌] Nakajima,S., Ozono,K.: "Effect of cyclic adenosine 3, 5-monophosphate and protein kinase A on ligand-dependent transactivation via the Vitamin D receptor." Mol Cell Endocrinol. in press.

[文献書誌] Tanaka,Y., Horikoshi,N.: "Gonadotropins stimulate growth of breast cancer MCF-7 cells by stimulating intracellular synthesis of estra-diol from DHEA." Breast Cancer Res.Treat.50(3). 367 (1998)

[文献書誌] Takeyama,K., Yanagisawa,J.: "Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog." Mol.Cell.Biol.in press.

[文献書誌] Yanagisawa,J.: "Convergence of TGFβ and vitamin D signaling pathways on SMAD proteins acting as common transcrip-tional co-activators." Science. in press.

[文献書誌] Watanabe,M., Yanagisawa,J.: "A putative tumor suppressor, TSG101, acts as a transcriptional suppressor through its coiled-coil domain." Biochem.Biophys.Res.Commun.245. 900-905 (1998)

[文献書誌] Nishihara,A., Yanagisawa,J.: "Role of p300, a transcriptional coactivator, in signalling of TGF-β." Genes to Cells. 3. 613-623 (1998)

[文献書誌] Tanimoto,K., Hayashi,S.: "Regulation of Estrogen Receptor α Gene Mediated by Promoter B Responsible for Its Enhanced Expres-sion in Human Breast Cancer." Nucl.Acids Res.27. 903-909 (1999)

[文献書誌] Saji,S., Hayashi,S.: "MDM2, a Regulator for Estradiol Induced p53 Up-regulation in Breast Cancer Cells." Jpn.J.Cancer Res.in press. (1999)

[文献書誌] Okamoto,K., Hayashi,S.: "Redox-dependent Modulation of Nuclear Import of the Glucocorticoid Receptor." J.Biol.Chem.in press. (1999)

[文献書誌] Shimoike,T., Nawata,H.: "Subcutaneous or visceral adipose expression of the PPAR γ gene is not altered in the fatty (fa/fa) Zucker rat." Metabolism. 47. 1494-1498 (1998)

1998 年度実績報告書

尾形悦郎癌研究会, 癌研究所, 部長 (70013761)