DNA障害による癌細胞応答からみた新規分子標的の探索

• 研究課題/領域番号: 13218132
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 産業医科大学
• 研究代表者: 河野 公俊 産業医科大学, 医学部, 教授 (00153479)
• 研究期間 (年度): 2001 – 2004
• 研究課題ステータス: 完了 (2004年度)
• 配分額: 36,500千円 (直接経費: 36,500千円); 2004年度: 9,500千円 (直接経費: 9,500千円); 2003年度: 9,500千円 (直接経費: 9,500千円); 2002年度: 9,000千円 (直接経費: 9,000千円); 2001年度: 8,500千円 (直接経費: 8,500千円)
• キーワード: DNA損傷 / シグナル伝達 / 遺伝子発現制御 / p300 / Sp1 / TAS-103 / シスプラチン / 固形癌 / 薬剤耐性 / YB-1 / mtTFA / ATF4 / CTF2 / p53 / アポトーシス / 遺伝子 / 癌 / 発現制御 / 薬剤感受性 / DNAダメージ

研究概要

DNA障害による癌細胞応答からみた新規分子標的の探索を目指して、1.DNA障害で発現誘導される遺伝子群の解析と2.損傷DNA認識分子の解析を進めている。平成16年度の解析からDNA障害で発現誘導される転写因子としてYB-1を始め、ATF4、ZNF143を見いだした。これらの分子は、相互に発現を制御するだけでなく、自身がDNA損傷を認識できることも証明した。これらの転写因子の解析から、その標的遺伝子がアポトーシスや耐性に関与することも見いだした。そのメカニズムとして、細胞内pHの制御やレドック分子の制御、さらに細胞内グルタチオン量の制御やABCトランスポーターの発現を介していることが示唆された。また、トポイソメラーゼ阻害剤である抗癌剤TAS-103がSp1を介した転写系を亢進することを見いだした。この分子機序として、Sp1とp300の分子会合を介したSp1のアセチル化が重要であった。p300は癌抑制遺伝子と考えており、消化器癌ではしばしば欠失や変異が見られる。TAS-103に対する消化器癌細胞株の感受性にp300の発現の有無が密接に関わることを見いだしている。一方、p53と細胞内RNAとの結合の意義についても報告した。

研究成果

• [雑誌論文] Cisplatin resistance and transcription factors (2005)
  • 著者名/発表者名: Torigoe, T.
  • 雑誌名: Curr.Med.Chem.Anti-Canc.Agents 5・1 ページ: 15-27
• [雑誌論文] DNA topoisomerase II poison TAS-103 transactivates GC-box-dependent transcription via acetylation of Sp1 (2005)
  • 著者名/発表者名: Torigoe, T.
  • 雑誌名: J.Biol.Chem. 280・2 ページ: 1179-1185
• [雑誌論文] The broad-range cyclin-dependent kinase inhibitor UCN-01 induces apoptosis in colon carcinoma cells through transcriptional suppression of the Bcl-x_L protein (2005)
  • 著者名/発表者名: Bhonde, M.R.
  • 雑誌名: Oncogene 24・1 ページ: 148-156
• [雑誌論文] Transcriptional regulation of multidrug resistance-1 gene by interleukin-2 in lymphocytes (2004)
  • 著者名/発表者名: Tsujimura, S.
  • 雑誌名: Genes Cells 9・12 ページ: 1265-1273
• [雑誌論文] The role of nuclear Y-box binding protein 1 as a global marker in drug resistance (2004)
  • 著者名/発表者名: Kuwano, M.
  • 雑誌名: Mol.Cancer Ther. 3・11 ページ: 1485-1492
• [雑誌論文] 4-[3,5-bis (trimethylsilyl) benzamido] Benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor (2004)
  • 著者名/発表者名: Minagawa, N.
  • 雑誌名: Oncol.Res. 14・9 ページ: 407-414
• [雑誌論文] ZNF143 activates gene expression in response to DNA damage and binds to cisplatin-modified DNA (2004)
  • 著者名/発表者名: Ishiguchi, H.
  • 雑誌名: Int.J.Cancer 111・6 ページ: 900-909
• [雑誌論文] Interleukin-1β represses MRP2 gene expression through inactivation of interferon regulatory factor 3 in HepG2 cells (2004)
  • 著者名/発表者名: Hisaeda, K.
  • 雑誌名: Hepatology 39・6 ページ: 1574-1582
• [雑誌論文] Bifunctional properties of peroxisome proliferator-activated receptor γ1 in KDR gene regulation mediated via interaction with both Sp1 and Sp3 (2004)
  • 著者名/発表者名: Sassa, Y.
  • 雑誌名: Diabetes 53・5 ページ: 1222-1229
• [雑誌論文] Co-expression of Y box-binding protein-1 and P-glycoprotein as a prognostic marker for survival in epithelial ovarian cancer (2004)
  • 著者名/発表者名: Huang, X.
  • 雑誌名: Gynecol.Oncol. 93・2 ページ: 287-291
• [雑誌論文] Binding of RNA to p53 regulates its oligomerization and DNA-binding activity (2004)
  • 著者名/発表者名: Yoshida, Y.
  • 雑誌名: Oncogene 23・25 ページ: 4371-4379
• [雑誌論文] Targeted disruption of one allele of the Y-box binding protein-1 (YB-1) gene in mouse embryonic stem cells and increased sensitivity to cisplatin and mitomycin C (2004)
  • 著者名/発表者名: Shibahara, K.
  • 雑誌名: Cancer Sci. 95・4 ページ: 348-353
• [雑誌論文] The expression pattern of UDP-N-acetyl-α-d-galactosamine : polypeptide N-acetylgalactosaminyl transferase-3 in early gastric carcinoma (2004)
  • 著者名/発表者名: Ishikawa, M.
  • 雑誌名: J.Surg.Oncol. 86・1 ページ: 28-33
• [雑誌論文] Expression of UDP-N-acetyl-α-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase isozyme 3 in the subserosal layer correlates with postsurgical survival of pathological tumor stage 2 carcinoma of the gallbladder (2004)
  • 著者名/発表者名: Miyahara, N.
  • 雑誌名: Clin.Cancer Res. 10・6 ページ: 2090-2099
• [文献書誌] Y.Oda: "Nuclear expression of Y-box-binding Protein-1 correlates with P-glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma"J.Pathol.. 199・2. 251-258 (2003)
• [文献書誌] H.Saji: "Nuclear expression of YB-1 protein corerlates with P-glycoprotein expression in human breast carcinoma"Cancer Lett.. 190・2. 191-197 (2003)
• [文献書誌] H.Uramoto: "Physical interaction of tumour suppressor p53/p73 with CCAAT-binding transcription factor 2 (CTF2) and differential regulation of human high-mobility group 1 (HMG1) gene expression"Biochem.J.. 371・Pt2. 301-310 (2003)
• [文献書誌] M.Kuwano: "The basic and clinical implications of ABC transporters, Y-box-binding protein-1 (YB-1) and angiogenesis-related factors in human malignancies"Cancer Sci.. 94・1. 9-14 (2003)
• [文献書誌] K.Onitsuka: "Prognostic significance of UDP-N-acetyl-α-D-galactosamine : polypeptide N-acetylgalactosaminyltransferase-3(GalNAc-T3) expression in patients with gastric carcinoma"Cancer Sci.. 94・1. 32-36 (2003)
• [文献書誌] K.Kohno: "The pleiotropic functions of the Y-box-binding Protein, YB-1"Bioessays. 25・7. 691-698 (2003)
• [文献書誌] Y.Yoshida: "p53 physically interacts with mitochondrial transcription factor A and differentially regulates binding to damaged DNA"Cancer Res.. 63・13. 3729-3734 (2003)
• [文献書誌] H.Izumi: "Structural and functional characterization of two human V-ATPase subunit gene promoters"Biochim.Biophys.Acta. 1628・2. 97-104 (2003)
• [文献書誌] H.Izumi: "p300/CBP-associated factor (P/CAF) interacts with nuclear respiratory factor-1 to regulate the UDP-N-acetyl-α-D-galactosamine : polypeptide N-acetylgalactosaminyltransferase-3 gene"Biochem.J.. 373・Pt3. 713-722 (2003)
• [文献書誌] T.Torigoe: "Low pH enhances Sp1 DNA binding activity and interaction with TBP"Nucleic Acids Res.. 31・15. 4523-4530 (2003)
• [文献書誌] H.Izumi: "Cellular pH regulators : potentially promising molecular targets for cancer chemotherapy"Cancer Treat.Rev.. 29・6. 541-549 (2003)
• [文献書誌] M.Tanabe: "Activating transcription factor 4 increases the cisplatin resistance of human cancer cell lines"Cancer Res.. 63・24. 8592-8595 (2003)
• [文献書誌] S.Yamamoto: "Expression of uridine diphosphate N-acetyl-α-D-galactosamine : polypeptide N-acetylgalactosaminyl transferase 3 in adenocarcinoma of the pancreas"Pathobiology. 71・1. 12-18 (2004)
• [文献書誌] C.Gu: "Low expression of polypeptide GalNAc N-acetylgalactosaminyl transferase-3 in lung adenocarcinoma : impact on poor prognosis and early recurrence"Br.J.Cancer. 90・2. 436-442 (2004)
• [文献書誌] T.Fukuda: "Characterization of the 5'-untranslated region of YB-1 mRNA and autoregulation of translation by YB-1 protein"Nucleic Acids Res.. 32・2. 611-622 (2004)
• [文献書誌] Y.Yoshida: "Human mitochondrial transcription factor A binds preferentially to oxidatively damaged DNA"Biochem.Biophys.Res.Commun.. 295・4. 945-951 (2002)
• [文献書誌] H.Uramoto: "p73 interacts with c-Myc to regulate Y-box-binding protein-1 expression"J.Biol.Chem.. 277・35. 31694-31702 (2002)
• [文献書誌] M.Ashizuka: "Novel translational control through an iron-responsive element by interaction of multifunctional protein YB-1 and IRP2"Mol.Cell.Biol.. 22・18. 6375-6383 (2002)
• [文献書誌] H.Dosaka-Akita: "N-acetylgalactosaminyl transferase-3 is a potential new marker for non-small cell lung cancers"Br.J.Cancer. 87・7. 751-755 (2002)
• [文献書誌] T.Torigoe: "Enhanced expression of the human vacuolar H+-ATPase c subunit gene (ATP6L) in response to anticancer agents"J.Biol.Chem.. 277・39. 36534-36543 (2002)
• [文献書誌] A.Hackzell: "p73 independently of c-Myc represses transcription of platelet-derived growth factor β-receptor through interaction with NF-Y"J.Biol.Chem.. 277・42. 39769-39776 (2002)
• [文献書誌] H.Hayakawa: "Binding capacity of human YB-1 protein for RNA containing 8-oxoguanine"Biochemistry. 41・42. 12739-12744 (2002)
• [文献書誌] H.Yahata: "Increased nuclear localization of transcription factor YB-1 in acquired cisplatin-resistant ovarian cancer"J.Cancer Res.Clin.Oncol.. 128・11. 621-626 (2002)
• [文献書誌] M.Kuwano: "The basic and clinical implications of ABC transporter, Y-box-binding protein-1 (YB-1) and angiogenesis-related factors in human malignancies"Cancer Sci.. 94・1. 9-14 (2003)
• [文献書誌] K.Onitsuka: "Prognostic significance of UDP-N-acetyl-α-D-galactosamine : polypeptide N-acetylgalactosaminyltransferase-3 (GalNAc-T3) expression in patients with gastric carcinoma"Cancer Sci.. 94・1. 32-36 (2003)
• [文献書誌] Y.Oda: "Nuclear expression of Y-box-binding protein-1 correlates with P-glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma"J.Pathol.. 199・2. 251-258 (2003)
• [文献書誌] H.Uramoto: "Physical interaction of tumor suppressor p53/p73 with CTF2 and differential regulation of human HMG1 gene expression"Biochem.J.. (in press). (2003)
• [文献書誌] H.Izumi: "Y box-binding protein-1 binds preferentially to single-stranded nucleic acids and exhibits 3'→5' exonuclease activity"Nucleic Acids Research. 29・5. 1200-1207 (2001)
• [文献書誌] K.Shibahara: "Nuclear expression of the Y-box binding protein, YB-I, as a novel marker of disease progression in non-small cell lung cancer"Clinical Cancer Research. 7・10. 3151-3155 (2001)
• [文献書誌] A.Inokuchi: "Enhanced expression of the human multidrug resistance protein 3 by bile salt in human enterocytes : Atranscriptional control of a plausible bile acid transporter"The Journal of Biological Chemistry. 276・50. 46822-46829 (2001)
• [文献書誌] M.Okamoto: "Up-regulation of thrombospondin-1 gene by epidermal growth factor and transforming growth factor β in human cancer cells -transcriptional activation and messenger RNA stabilization"Biochimica et Biophysica Acta. (in press).
• [文献書誌] K.Shibao: "Expression of UDP-N-acetyl-α-D-galactosamine : polypeptide GaINAc N-acetylgalactosaminyltransferase-3 in relation to differentiation and prognosis in human colorectal carcinoma"Cancer. (in press).
• [文献書誌] T.Torigoe: "Vaculoar H^+-ATPase : Functional mechanisms and potential as a target for cancer chemotherapy"Anti-cancer Drugs. (in press).