ヒトcMOATの遺伝疾病と癌への関与

• Project/Area Number: 10217209
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyushu University
• Principal Investigator: 内海 健 九州大学, 大学院・医学研究院, 助手 (80253798)
• Co-Investigator(Kenkyū-buntansha): 和田 守正 九州大学, 大学院・医学研究院, 助教授 (20220965)
• Project Period (FY): 1998 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥42,800,000 (Direct Cost: ¥42,800,000); Fiscal Year 2002: ¥7,000,000 (Direct Cost: ¥7,000,000); Fiscal Year 2001: ¥7,100,000 (Direct Cost: ¥7,100,000); Fiscal Year 2000: ¥9,400,000 (Direct Cost: ¥9,400,000); Fiscal Year 1999: ¥9,500,000 (Direct Cost: ¥9,500,000); Fiscal Year 1998: ¥9,800,000 (Direct Cost: ¥9,800,000)
• Keywords: MRP2 / プロモーター / 遺伝病 / 肝炎 / ABC / 分化度 / C型肝炎 / Dubin-Johnson症候群 / 腸肝循環 / ABCトランスポーター / 抗がん剤感受性 / 大腸癌 / グルタチオン / 肝炎ウイルス / cMUAT / MRP3 / Dubin Johnson 疾病群

Research Abstract

ABC蛋白のMRP2に関する遺伝疾病の生化学的解析、及び肝、大腸での発現様式について明らかにしてきた。
(1)MRP2遺伝子変異とDubin-Johnson症候群
MRP2/cMOAT遺伝子がDubin-Johnson症候群の責任遺伝子であることを明らかにした。R768W変異によりMRP2蛋白質は合成後の修飾、成熟過程が進行できず、プロテアゾームで分解されていることを明らかにし、このアルギニンがMRP2/cMOAT成熟蛋白質の形成と三次元構造を維持するために必須の領域であることが示唆された。一方、Q1382R変異の蛋白質は合成後の修飾、膜への移行は正常であるが基質輸送活性が低下していることが観察された。
(2)C型肝炎感染者症例では、肝臓でのMRP2の発現レベルが著しく低下する事を見いだした。また、炎症性サイトカインによりMRP2の発現レベルが低下することをmRNAレベルで観察した。炎症性サイトカインIL-1betaによりMRP2プロモーターの活性低下が認められ、ISRE領域がこの活性に関与する事を明らかにした。

Research Products

• [Publications] Hashimoto, K., et al.: "Trafficking-defect and functional-defect by mutations of the ATP-binding domains in multidrug resistance protein 2 (MRP2,ABCB2) in patients with Dubin-Johnson syndrome"Hepatology. 36. 1246-1252 (2002)
• [Publications] Yamamoto, C., et al.: "Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier"J Pharm Pharmacol. 54. 1055-1063 (2002)
• [Publications] Inokuchi, A. et al.: "Enhanced expression of Human Multidrug resistance protein 3 by bile salt in human enterocytes : a transcriptional control of plausible bile acid transporter"J. Biol. Chem.. 276. 46822-46829 (2001)
• [Publications] Hinoshita, E. et al.: "Decreased expression of an ATP-binding cassette transporter, MRP2, in human livers with hepatitis C virus infection"J. Hepatology. 35. 765-773 (2001)
• [Publications] Izumi,H.,Uchiumi,T.and et.al.: "YB-1 binds preferentially to single-stranded nucleic acid and exhibit 3'-5' exonuclease activity."Nucl.Acids Res.. 29(in press). (2001)
• [Publications] Haga,S.,Uchiumi,T.and et.al: "The involvement of the multidrug resistance protein 3 in drug sensitivity and its expression in human glioma."Jpn.J.Cancer Res.. 92. 211-219 (2001)
• [Publications] Ushigome,F.,Uchiumi,T.,and et.al.: "Human placental transport of vinblastine, vincristine, digoxin and progesterone : contribution of P-glycoprotein."Eur.J.Pharmacol.. 408. 1-10 (2000)
• [Publications] Okamoto,T.,Uchiumi,T.,and et.al.: "Direct interaction of p53 with the Y-box binding protein, YB-1 : a mechanism for regulation of human gene expression."Oncogene. 19. 6194-6202 (2000)
• [Publications] Hinoshita,E.,Uchiumi,T.,and et.al.: "Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas."Clinical Cancer Res.. 6. 2401-2407 (2000)
• [Publications] Uchiumi,T.,et.al.: "Isolation of a novel human canalicular multispecific organic anion transporter,cMOAT2/MRP3,and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport."Biochem.Biophys.Res.Commun.. 252. 103-110 (1998)
• [Publications] Toh,S.,et.al.: "Genomic structure of the canalicular multispecitic organic anion transporter(cMOAT)gene and mutations in the ATP binding cassette region in Dubin-Johnson syndrome."Am.J.Human Genet.. 64. 739-746 (1999)
• [Publications] Tanaka,T.,et.al.: "Cellular balance of glutathione levels through the expression of γ-glutamylcysteine synthetase and glutathione thiol transferase gene in human hepatic cells resistant to a glutathione poison."Biochim.Biophys.Acta. 1427. 367-377 (1999)
• [Publications] Kawabe,T.,et.al.: "Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter(cMOAT/MRP2)."FEBS Lett.. 456. 327-331 (1999)
• [Publications] Tanaka,T.,et.al.: "The Human Multispecific Resistance Protein2 Gene:Functional Characterization of 5'-Flanking Region and Expression in Hepatic Cells."Hepatology. 30. 1507-1512 (1999)
• [Publications] Uchiumi,T.,et.al.: "Isolation of a novel human canalicular multispecific organic anion transporter,cMOAT2/MRP3,and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport" Biochem. Biophys.Res.Commun.252. 103-110 (1998)
• [Publications] Toh,S.,et.al.: "Genomic structure of the canalicular multispecific organic anion tranporter (cMOAT)gene and mulations in the ATP binding cassette region in Dubin-Johnson syndrome." Am.J.Human Genet.in press. (1999)
• [Publications] Ise,T.,et.al.: "Transcription factor YB-1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen." Cancer Res.59. 342-346 (1999)
• [Publications] Tanaka,T.,et.al.: "Cellular balance of glutathione levels through the expression of γ-glutamylcysteine synthetase and glutathione thiol transferase gene in human hepatic cells resistant to a glutathione poison" Biochem.Biophys.Acta.in press. (1999)