2003 Fiscal Year Annual Research Report

腫瘍関連抗原4F2重鎖(CD98)のmTORを介するシグナル機構の解明

Research Project

Project/Area Number	15024258
Research Institution	Kyorin University
Principal Investigator	金井好克杏林大学, 医学部, 教授 (60204533)
Co-Investigator(Kenkyū-buntansha)	入部雄司杏林大学, 医学部, 助手 (20348618) 安西尚彦杏林大学, 医学部, 助手 (70276054)
Keywords	4F2hc / CD98 / シグナル伝達 / 酵母two-hybrid法 / トランスポーター / 細胞増殖 / mTOR / PI3kinase
Research Abstract	4F2hc(4F2抗原重鎖)は、リンパ球の活性化抗原及び腫瘍抗原として同定され、細胞の形質転換及び増殖制御との関わりが想定されている1回膜貫通型のII型膜糖タンパク質である。本研究は、4F2hcのmTORを介するシグナリング機構を明らかにする目的で、mTOR系のシグナル分子の解析と、4F2hcの細胞内ドメインに連結するタンパク質の探索を行った。本年度の研究により、4F2hcの過剰発現によりTSC2のリン酸化が抑制されることが示され、4F2hcによるAktの活性化、TSC2の抑制、mTORの活性化、それに引き続くp70 S6kinase、4E-BP1の活性化により4F2hcのシグナルが伝達されることが示唆された。加えて、4F2hc細胞内ドメイン結合タンパク質として、annexinIIが同定され、そのsiRNAによるノックダウンにより4F2hcによるmTOR経路の活性化における重要性が示唆された。すでに複数同定されている4F2hc細胞内ドメイン結合タンパク質が、Aktを介するmTOR活性化経路、及びAktを介さずにmTORを活性化する経路とどのように関わっているかを明らかにすることが今後の課題である。また、Aktを介さないmTOR活性化経路と未同定のアミノ酸センサーとの関わりが、4F2hcシグナリングの解析から明らかになる可能性があり、この点も平行して研究を進める必要がある。本研究の成果は、4F2hcを介するシグナリング機構の研究の端緒を開くとともに、mT0R経路の上流因子に関する新たな示唆を与えるものである。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] Shikano, N, Kanai, Y, Kawai, K, Ishikawa, N, Endou, H.: "Characterization of 3-[(125)I]iodo-alpha-methyl-L-tyrosine transport via human"Nucl.Med.Biol.. 30. 31-37 (2003)
[Publications] Shikano, N, Kanai, Y, Kawai, K, Inatomi, J, Kim, DK, Ishikawa, N, Endou, H.: "Isoform selectivity of 3-125I-iodo-alpha-methyl-L-tyrosine membrane transport in human L-type amino acid transporters."J.Nucl.Med.. 44. 244-246 (2003)
[Publications] Muto, T, Takasaki, S, Takahashi, T, Hano, H, Kanai, Y, Wakui, S, Endou, H, Furusa: "Initial changes of hepatic glycogen granules and glycogen phosphorylase a after exposure to 7,12-dimethylbenz[a]anthracene in"J.Toxicol.Pathol.. 16. 153-160 (2003)
[Publications] Jutabha, P, Kanai, Y, Hosoyamada, M, Chairoungdua, A, Kim, DK, Iribe, Y, Babu, E, Kim, JY, Anzai, N: "Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule."J.Biol.Chem.. 278. 27930-27938 (2003)
[Publications] Babu, E, Kanai, Y, Chairoungdua, A, Kim, DK, Iribe Y, Tangtrongsup, S, Jutabha, P, Li, Y, Ahmed, N, Sakamoto, S, Anzai, N, Endou, H: "Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters."J.Biol.Chem.. 278. 43838-43845 (2003)
[Publications] Yoon, JH, Kim, YB, Kanai, Y, Endou, H, Kim, DK: "Sequential increases in 4F2hc expression during DMBA-induced hamster buccal pouch carcinogenesis."Anticancer Res.. 28. 1-17 (2003)
[Publications] Muto, T, Watanabe, T, Moto, M, Okamura, M, Kashida, Y, Kanai, Y, Mitsumori, K, Endou, H: "Time course of expression of 7,12-dimethylbenz[a]anthracene-induced CYP1A1 and CYP1B1 mRNA and protein in rat liver"J.Toxicol.Pathol.. 16. 287-290 (2003)
[Publications] Sakata, T, Anzai, N, Shin, HJ, Noshiro, R, Hirata, T, Yokoyama, H, Kanai, Y, Endou, H: "Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions."Biochem.Biophys.Res.Commun.. 313. 789-793 (2004)
[Publications] Shikano N, Kanai Y, Kawai k, Ishikawa N, Endou H: "Transport of 99mTc-MAG3 via rat renal organic anion transporter 1."J Nucl Med.. 45. 80-85 (2004)
[Publications] Matsuo, H, Kanai, Y, Tokunaga, M, Nakata, T, Chairoungdua, A, Ishimine, H, Tsukada, S, Ooigawa, H: "High affinity D-and L-serine transporter Asc-1 : Cloning and dendritic localization in the rat cerebral and cerebellar cortices."Neurosci.Lett. 358(2). 123-126 (2004)
[Publications] Yoon JH, Kim YB, Kim MS, Park JC, Kook JK, Jung HM, Kim SG, Yoo H, Ko YM, Lee SH, Kim BY, Chun HS, Kanai Y, Endou H, Kim do K: "Expression and functional characterization of the system L amino acid transporter in KB human oral epidermoid carcinoma cells."Cancer Lett.. 205. 215-226 (2004)
[Publications] Park JC, Kim YB, Yoon JH, Kim HJ, Kim SM, Kanai Y, Endou H, Kim DK: "Preferential Expression of L-type Amino Acid Transporter 1 in Ameloblasts During Rat Tooth Development."Anat Histol Embryol.. 33. 119-124 (2004)
[Publications] Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M, Kanai Y, Sophasan S, Endou H: "Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules."J.Pharmacol.Sci.. 94. 297-304 (2004)
[Publications] Kanai, Y, Endou, H: "Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity."J.Toxicol.Sci.. 28. 1-17 (2003)
[Publications] 金井好克: "アミノ酸輸送体の多様性:アミノ酸代謝異常症の分子基盤"Molecular Medicine. 40. 782-790 (2003)
[Publications] Verrey, F, Closs, EI, Wagner, CA, Palacin, M, Endou, H, Kanai, Y: "CATs and HATs : the SLC7 family of amino acid transporters."Pflugers Arch.. 447. 532-542 (2004)
[Publications] Palacin, M, Kanai, Y: "The ancillary proteins of HATs : SLC3 family of amino acid transporters."Pflugers Arch.. 447. 490-494 (2004)
[Publications] Kanai, Y, Heidiger, MA: "The Glutamate and Neutral Amino Acid Transporter Family : Physiological and Pharmacological Implications."Pflugers Arch.. 447. 469-479 (2004)
[Publications] Kanai, Y, Heidiger, MA: "The glutamate and neutral amino acid transporter family : physiological and pharmacological implications."Eur.J.Pharmacol.. 479. 237-247 (2003)
[Publications] Kanai Y, Endou H: "Molecular characteristics and physiological and pharmacological implications of heterodimeric amino acid transporters. In Topics in Current Genetics : Molecular Mechanisms Controlling Transmembrane Tr"Springer, Heidelberg (in press).

2003 Fiscal Year Annual Research Report

腫瘍関連抗原4F2重鎖(CD98)のmTORを介するシグナル機構の解明

Principal Investigator

金井 好克 杏林大学, 医学部, 教授 (60204533)

Research Products

[Publications] Shikano, N, Kanai, Y, Kawai, K, Ishikawa, N, Endou, H.: "Characterization of 3-[(125)I]iodo-alpha-methyl-L-tyrosine transport via human"Nucl.Med.Biol.. 30. 31-37 (2003)

[Publications] Shikano, N, Kanai, Y, Kawai, K, Inatomi, J, Kim, DK, Ishikawa, N, Endou, H.: "Isoform selectivity of 3-125I-iodo-alpha-methyl-L-tyrosine membrane transport in human L-type amino acid transporters."J.Nucl.Med.. 44. 244-246 (2003)

[Publications] Muto, T, Takasaki, S, Takahashi, T, Hano, H, Kanai, Y, Wakui, S, Endou, H, Furusa: "Initial changes of hepatic glycogen granules and glycogen phosphorylase a after exposure to 7,12-dimethylbenz[a]anthracene in"J.Toxicol.Pathol.. 16. 153-160 (2003)

[Publications] Jutabha, P, Kanai, Y, Hosoyamada, M, Chairoungdua, A, Kim, DK, Iribe, Y, Babu, E, Kim, JY, Anzai, N: "Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule."J.Biol.Chem.. 278. 27930-27938 (2003)

[Publications] Yoon, JH, Kim, YB, Kanai, Y, Endou, H, Kim, DK: "Sequential increases in 4F2hc expression during DMBA-induced hamster buccal pouch carcinogenesis."Anticancer Res.. 28. 1-17 (2003)

[Publications] Muto, T, Watanabe, T, Moto, M, Okamura, M, Kashida, Y, Kanai, Y, Mitsumori, K, Endou, H: "Time course of expression of 7,12-dimethylbenz[a]anthracene-induced CYP1A1 and CYP1B1 mRNA and protein in rat liver"J.Toxicol.Pathol.. 16. 287-290 (2003)

[Publications] Sakata, T, Anzai, N, Shin, HJ, Noshiro, R, Hirata, T, Yokoyama, H, Kanai, Y, Endou, H: "Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions."Biochem.Biophys.Res.Commun.. 313. 789-793 (2004)

[Publications] Shikano N, Kanai Y, Kawai k, Ishikawa N, Endou H: "Transport of 99mTc-MAG3 via rat renal organic anion transporter 1."J Nucl Med.. 45. 80-85 (2004)

[Publications] Matsuo, H, Kanai, Y, Tokunaga, M, Nakata, T, Chairoungdua, A, Ishimine, H, Tsukada, S, Ooigawa, H: "High affinity D-and L-serine transporter Asc-1 : Cloning and dendritic localization in the rat cerebral and cerebellar cortices."Neurosci.Lett. 358(2). 123-126 (2004)

[Publications] Park JC, Kim YB, Yoon JH, Kim HJ, Kim SM, Kanai Y, Endou H, Kim DK: "Preferential Expression of L-type Amino Acid Transporter 1 in Ameloblasts During Rat Tooth Development."Anat Histol Embryol.. 33. 119-124 (2004)

[Publications] Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M, Kanai Y, Sophasan S, Endou H: "Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules."J.Pharmacol.Sci.. 94. 297-304 (2004)

[Publications] Kanai, Y, Endou, H: "Functional properties of multispecific amino acid transporters and their implications to transporter-mediated toxicity."J.Toxicol.Sci.. 28. 1-17 (2003)

[Publications] 金井好克: "アミノ酸輸送体の多様性:アミノ酸代謝異常症の分子基盤"Molecular Medicine. 40. 782-790 (2003)

[Publications] Verrey, F, Closs, EI, Wagner, CA, Palacin, M, Endou, H, Kanai, Y: "CATs and HATs : the SLC7 family of amino acid transporters."Pflugers Arch.. 447. 532-542 (2004)

[Publications] Palacin, M, Kanai, Y: "The ancillary proteins of HATs : SLC3 family of amino acid transporters."Pflugers Arch.. 447. 490-494 (2004)

[Publications] Kanai, Y, Heidiger, MA: "The Glutamate and Neutral Amino Acid Transporter Family : Physiological and Pharmacological Implications."Pflugers Arch.. 447. 469-479 (2004)

[Publications] Kanai, Y, Heidiger, MA: "The glutamate and neutral amino acid transporter family : physiological and pharmacological implications."Eur.J.Pharmacol.. 479. 237-247 (2003)

[Publications] Kanai Y, Endou H: "Molecular characteristics and physiological and pharmacological implications of heterodimeric amino acid transporters. In Topics in Current Genetics : Molecular Mechanisms Controlling Transmembrane Tr"Springer, Heidelberg (in press).

金井好克杏林大学, 医学部, 教授 (60204533)