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研究内容(Publication)

1. CDK阻害タンパク質遺伝子のエピジェネティックな発現制御機構の研究

  1. Kotake Y, Zeng Y, Xiong Y. DDB1-CUL4 and MLL1 mediate oncogene-induced p16INK4a activation.Cancer Res., 69(5):1809-14, 2009.
  2. Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene.Genes Dev., 21(1):49-54, 2007.

2. ユビキチンリガーゼSCF-Skp2および-Fbw7の機能の探索

  1. Isobe T, Hattori T, Kitagawa K, Uchida C, Kotake Y, Kosugi I, Oda T, Kitagawa M. Adenovirus E1A inhibits SCFFbw7 ubiquitin ligase. J Biol Chem. 284(41): 27766-27779, 2009.
  2. Kitagawa, K., Hiramatsu, Y., Uchida, C., Isobe, T., Hattori, T., Oda, T., Shibata, K., Nakamura, S., Kikuchi, A. and Kitagawa, M. Fbw7 promotes ubiquitin-dependent degradation of c-Myb involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb. Oncogene 28, 2383-2405, 2009.
  3. Suzuki, S., Fukasawa, H., Kitagawa, K., Uchida, C., Hattori, T., Isobe, T., Oda, T., Misaki, T., Ohashi, N., Nakayama, K., Nakayama, K.I., Hishida, A., Yamamoto, T. and Kitagawa, M.: Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice. Am. J. Pathol. 171:473-483, 2007.
  4. Hiramatsu, Y., Kitagawa, K., Suzuki, T., Uchida, C., Hattori, T., Hirotoshi K., Oda, T. Hatakeyama, S., Nakayama K.I., Yamamtoto, T., Konno, H. and Kitagawa, M.: Degradation of Tob1 mediated by SCFSkp2-dependent ubiquitination. Cancer Research 66: 8477-8483, 2006.
  5. Nakayama, K., Nagahama, H., Minamishima, Y. A., Miyake S., Matsumoto, M., Ishida, N., Hatakeyama S., Kitagawa, M., Iemura, S.-i., Natsume, T., and Nakayama, K.-i.: Skp2-mediated degradation of p27 regulates progression into Mitosis. Dev. Cell, 6 :661-672, 2004.
  6. Hattori, T., Kitagawa, K., Uchida, C., Oda, T., and Kitagawa, M.: Cks1 is degraded via the ubiquitin-proteasome pathway in a cell cycle-dependent manner. Genes to Cells 8: 889-896, 2003.
  7. Imaki, H., Nakayama, K., Delehouzee, S., Handa, H., Kitagawa, M., Kamura, T. and Nakayama, K.-I.: Cell Cycle-dependent Regulation of the Skp2 Promoter by GA-binding Protein. Cancer Res. 63(15): 4607-4613, 2003.
  8. Inui, N., Kitagawa, K., Miwa, S., Hattori, T., Chida, K., Nakamura, H. and Kitagawa, M.: High expression of Cks1 in human non-small cell lung carcinomas. Biochem. Biophys. Res. Commun. 303: 978-984, 2003.
  9. Nakayama, K., Nagahama, H., Minamishima, Y. A., Matsumoto, M., Nakamichi, I., Kitagawa, K., Shirane, M., Tsunematsu, R., Tsukiyama, T., Ishida, N., Kitagawa, M., Nakayama, K.-i., and Hatakeyama7. S.: Targeted disruption of Skp2 result in accumulation of Cyclin E and p27Kip1, polyploidy, and centrosome overdeplication. EMBO J. 19(9): 2069-2081, 2000.
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3. CDK阻害タンパク質p27Kip1の分解と細胞周期制御機構の研究 †

  1. Shimada, M., Kitagawa, K., Dobashi, Y., Isobe, T., Hattori, T., Uchida, C., Abe, K., Kotake, Y., Oda, T, Suzuki, H, Hashimoto, K., Kitagawa, M. High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers. Cancer Sci. 100, 866-872, 2009.
  2. Hattori, T., Isobe, T., Abe, K., Kikuchi, H., Kitagawa, K., Oda, T., Uchida, C. and Kitagawa, M.: Pirh2 Promotes Ubiquitin-Dependent Degradation of the CDK Inhibitor p27Kip1. Cancer Research 67:10789-10795, 2007.
  3. Suzuki, S., Fukasawa, H., Kitagawa, K., Uchida, C., Hattori, T., Isobe, T., Oda, T., Misaki, T., Ohashi, N., Nakayama, K., Nakayama, K.I., Hishida, A., Yamamoto, T. and Kitagawa, M.: Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice. Am. J. Pathol. 171:473-483, 2007
  4. Gao, Y., Kitagawa, K., Hiramatsu, Y., Kikuchi, H., Isobe, T., Shimada, M., Uchida, C., Hattori, T., Oda, T., Nakayama, K., Nakayama, K.I., Tanaka, T., Konno, H. and Kitagawa, M.: Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Research 66(24):11623-11631, 2006.
  5. Nakayama, K., Nagahama, H., Minamishima, Y. A., Miyake S., Matsumoto, M., Ishida, N., Hatakeyama S., Kitagawa, M., Iemura, S.-i., Natsume, T., and Nakayama, K.-i.: Skp2-mediated degradation of p27 regulates progression into Mitosis. Dev. Cell, 6 :661-672, 2004.
  6. Hattori, T., Kitagawa, K., Uchida, C., Oda, T., and Kitagawa, M.: Cks1 is degraded via the ubiquitin-proteasome pathway in a cell cycle-dependent manner. Genes to Cells 8: 889-896, 2003.
  7. Inui, N., Kitagawa, K., Miwa, S., Hattori, T., Chida, K., Nakamura, H. and Kitagawa, M.: High expression of Cks1 in human non-small cell lung carcinomas. Biochem. Biophys. Res. Commun. 303: 978-984, 2003.
  8. Tsukiyama, T., Ishida, N., Shirane, M., Minamishima, Y. A., Hatakeyama S., Kitagawa, M., Nakayama, K. and Nakayama, K.-i.: Down-regulation of p27Kip1 expression is required for development and function of T cells. J. Immunl. 66: 304-312, 2001.
  9. Ishida, N., Kitagawa, M., Hatakeyama, S. and Nakayama, K.-i.: Phosphorylation at Ser10 a major phosphorylation site of p27Kip1 , increases its protein stability. J Biol. Chem. 275: 25146-25154, 2000.
  10. Nakayama, K., Nagahama, H., Minamishima, Y. A., Matsumoto, M., Nakamichi, I., Kitagawa, K., Shirane, M., Tsunematsu, R., Tsukiyama, T., Ishida, N., Kitagawa, M., Nakayama, K.-i., and Hatakeyama S.: Targeted disruption of Skp2 result in accumulation of Cyclin E and p27Kip1, polyploidy, and centrosome overdeplication. EMBO J. 19(9): 2069-2081, 2000.
  11. Shirane, M., Harumiya, Y., Ishida, N., Miyamoto, C., Hirai, A., Hatakeyama, S., Nakayama, K.-i. and Kitagawa, M.: Down-regulation of p27Kip1 by two mechanizms, ubiquitin-mediated degradation and site-specific cleavage. J. Biol. Chem. 274(20): 13886-13893, 1999.
  12. Kawana, H., Tamaru, J.-i., Tanaka, T., Hirai, A., Saito, Y., Kitagawa, M., Mikata, A., Harigaya, K. and Kuriyama, T.: Role of p27Kip1 and cyclin-dependent kinase 2 in proliferation of non-small cell lung cancer. Am. J. Pathol. 153: 505-513, 1998.
  13. Hirai, A., Nakamura, S., Noguchi, Y., Yasuda, T., Kitagawa, M., Tatsuno, I., Oeda, T., Tahara, K., Terano,T., Narumiya, S., Kohn, L. D. and Saito, Y. : Geranylgeranylated Rho small GTPase(s) are essential for the degradation of p27Kip1 and facilitate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells. J. Biol. Chem. 272: 13-16, 1997.
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4. RBおよびp53経路の全容の解明 †

  1. Kitagawa, K., Kotake, Y. and Kitagawa, M. Ubiquitin-mediated control of oncogene and tumor suppressor gene products. Cancer Sci. 100, 1374-1381, 2009.
  2. Inoue, Y., Kitagawa, M. and Taya, Y.: Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage. EMBO J., 26:2083-2093, 2007.
  3. Uchida, C., Miwa, S., Isobe, T., Kitagawa, K., Hattori, T., Oda, T., Yasuda, H. and Kitagawa, M.: Effect of MdmX on Mdm2-mediated downregulation of pRB. FEBS Letters 580:1753-1758, 2006.
  4. Miwa, S., Uchida, C., Kitagawa, K., Hattori, T., Oda, T., Sugimura, H., Yasuda, H., Nakamura, H. Chida K. and Kitagawa, M.: Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner. Biochem Biophys Res Commun. 340: 54-61, 2006.
  5. Takemura, M., Yoshida, S., Akiyama, T., Kitagawa, M., Yamada, Y.: Role of the second-largest subunit of DNA polymerase α in the interaction between the catalytic subunit and hyperphosphorylated retinoblastoma protein in late S phase. Biochem. Biophys. Acta 1764: 1447-1453, 2006.
  6. Uchida, C., Miwa, S., Kitagawa, K., Hattori, T., Isobe, T., Otani, S., Oda, T., Sugimura, H., Kamijo, T., Ookawa, K., Yasuda, H., and Kitagawa, M.: Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation. EMBO J. 24: 160-169, 2005.
  7. Takaki, T., Fukasawa, K., Suzuki-Takahashi, I., Semba, K., Kitagawa, M., Taya, Y. and Hirai, H: Preferences for phosphorylation sites in the retinoblastoma protein of D-Type cyclin-dependent kinases, Cdk4 and Cdk6 in vitro. J. Biochem. 137: 381-386, 2005.
  8. Takemura, M., Yamamoto, T., Kitagawa, M., Taya Y., Akiyama, T., Asahara, H., Linn S., Suzuki, S., Tamai, K. and Yoshida, S.: Stimulation of DNA polymerase α activity by cdk2-phosphorylated Rb Protein. Biochem. Biophys. Res. Commun. 282: 984-990, 2001.
  9. Kitagawa, M., Higashi, H., Jung, H.-K., Suzuki-Takahashi, I., Ikeda, M., Tamai, K., Kato, J., Segawa, K., Yoshida, E., Nishimura, S. and Taya, Y.: Consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J. 15: 7060-7069, 1996.
  10. Kitagawa, M., Higashi, H., Takahashi, -S.I., Segawa, K. Hanks, S.K., Taya, Y., Nishimura, S. & Okuyama, A.: Phosphorylation of E2F-1 by cyclin A-cdk2. Oncogene, 10 : 229-236, 1995.
  11. Suzuki-Takahashi, I., Kitagawa, M., Saijo, M., Higashi, H., Ogino, H., Matsumoto, H., Taya, Y., Nishimura, S. & Okuyama, A.: The interaction of E2F with pRB and with p107 are regulated via the phosphorylation of pRB and p107 by cyclin-dependent kinases. Oncogene, 10 : 1691-1698, 1995.
  12. Kitagawa, M., Higashi, H., Takahashi, -S.I., Okabe, T., Ogino, H., Taya, Y., Nishimura, S. & Okuyama, A.: A cyclin dependent kinase inhibitor, butyrolactone I, inhibits phosphorylation of RB protein and cell cycle progression. Oncogene, 9 : 2549-2557, 1994.
  13. Kitagawa, M., Saitoh, S., Ogino, H., Okabe, T., Matsumoto, H., Okuyama, A., Tamai, K., Ohba, Y., Yasuda, H., Nishimura, S. & Taya, Y.: cdc2-like kinase is associated with the retinoblastoma protein. Oncogene, 7 : 1067-1074, 1992.
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5. 癌化および癌の予後不良化のメカニズムの研究 †

  1. Shimada, M., Kitagawa, K., Dobashi, Y., Isobe, T., Hattori, T., Uchida, C., Abe, K., Kotake, Y., Oda, T, Suzuki, H, Hashimoto, K., Kitagawa, M. High expression of Pirh2, an E3 ligase for p27, is associated with low expression of p27 and poor prognosis in head and neck cancers. Cancer Sci. 100, 866-872, 2009.
  2. Yamamoto, M., Kikuchi, H., Ohta, M., Kawabata, T., Hiramatsu, Y., Kondo, K., Baba, M,. Kamiya, K., Tanaka, T., Kitagawa M. and Konno H. TSU68 prevents liver metastasis of colon cancer xenografts by modulating the pre-metastatic niche. Cancer Res. 68: 9754-9762, 2008.
  3. Gao, Y., Kitagawa, K., Hiramatsu, Y., Kikuchi, H., Isobe, T., Shimada, M., Uchida, C., Hattori, T., Oda, T., Nakayama, K., Nakayama, K.I., Tanaka, T., Konno, H. and Kitagawa, M.: Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res. 66(24):11623-11631, 2006.
  4. Gao, Y., Kitagawa, K., Shimada, M., Uchida, C., Hattori, T., Oda, T. and Kitagawa, M.: Generation of a constitutively active mutant of human GPR48/LGR4, a G-protein-coupled receptor. Hokkaido. J. Med. Sci. 81:101-105, 2006.
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6. サイクリンD1の発現および活性制御機構の研究 †

  1. Kikuchi, H., Uchida, C., Hattori, T., Isobe, T., Hiramatsu, Y., Kitagawa, K., Oda, T., Konno, H. and Kitagawa, M.:　 ARA54 is involved in transcriptional regulation of the cyclin D1 gene in human cancer cells. Carcinogenesis in press.
  2. Hiramatsu, Y., Kitagawa, K., Suzuki, T., Uchida, C., Hattori, T., Hirotoshi K., Oda, T. Hatakeyama, S., Nakayama K.I., Yamamtoto, T., Konno, H. and Kitagawa, M.: Degradation of Tob1 mediated by SCFSkp2-dependent ubiquitination. Cancer Research 66: 8477-8483, 2006.
  3. Natsume, H., Sasaki, S., Kitagawa, M., Kashiwabara, Y., Matsushita, A., Nakano, K., Nishiyama, K., Nagayama, K., Misawa, H., Masuda H. and Nakamura, H.: β-Catenin/Tcf-1-mediated transactivation of cyclin D1 promoter is negatively regulated by thyroid hormone. Biochem. Biophys. Res. Commun. 309: 408-413, 2003.
  4. Katayama, K., Dobashi, Y., Kitagawa, M., Kawai, M., Kadoya, Y. and Kameya, T.: Cdk4/cyclin D1 kinase, a universal and critical regulator of apoptosis. Anticancer Res. 23: 235-244, 2003.
  5. Katayama, K., Dobashi Y., Kitagawa, M., Kamekura, S., Kawai, M., Kadoya Y., and Kameya T.: Overexpression of Cdk4/Cyclin D1 induces apoptosis in PC12 cells in the presence of trophic support. FEBS Let. 509: 382-388, 2001.
  6. Kitagawa, M., Higashi, H., Jung, H.-K., Suzuki-Takahashi, I., Ikeda, M., Tamai, K., Kato, J., Segawa, K., Yoshida, E., Nishimura, S. and Taya, Y.: Consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J. 15: 7060-7069, 1996.
  7. Yamamoto, K., Hirai, A., Ban, T., Saito, J., Tahara, K., Terano, T., Tamura, Y., Saito, Y. and Kitagawa, M.: Tyrotropin induces G1 cyclin expression and accelerates G1 phase after insulin-like growth factor I stimulation in FRTL-5 cells. Endocrinology 137: 2036-2042, 1996.
  8. Higashi, H., Suzuki-Takahashi, I., Saitoh, S., Segawa, K., Taya, Y., Okuyama, A., Nishimura, S. and Kitagawa, M.: Cyclin-depemdent kinase 2 (Cdk2) forms an inactive complex with cyclin D1 since Cdk2 associated with cyclin D1 is not phosphorylated by Cdk7-cyclin-H. Eur. J. Biochem. 237: 460-467, 1996.
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7. TGFbeta/Smad系および腎障害に関与するユビキチンシステムの研究 †

  1. Fukasawa, H., Yamamoto, T., Fujigaki, Y., Misaki, T., Ohashi, N., Takayama, T., Mugiya, S., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Hayashi, H., Ozono, S., Kitagawa, M. and Akira Hishida : Reduction of transforming growth factor-s type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma. Int. J Cancer in press.
  2. Misaki, T., Yamamoto, T., Suzuki, S., Fukasawa, H., Togawa, A., Ohashi, N., Suzuki, H., Fujigaki, Y., Oda, T, Uchida, C., Kitagawa, K., Hattori, T., Kitagawa, M., Hishida, A., Decrease in TRADD resulted from ubiquitin-dependent degradation in the obstructive renal injury in rats. Am J Pathol 175, 74-83, 2009.
  3. Ohashi, N., Yamamoto, T., Huang, Y., Misaki, T., Fukasawa, H., Suzuki, H., Togawa, A., Suzuki, S., Fujigaki, Y., Nakagawa, T., Nakamura, Y., Suzuki, F., Kitagawa, M., Hishida, A., Intrarenal RAS activity and urinary angiotensinogen excretion in anti-thymocyte serum nephritis rats. Am J. Physiol Renal Physiol.295: F1512-1518, 2008.
  4. Suzuki, S., Fukasawa, H., Kitagawa, K., Uchida, C., Hattori, T., Isobe, T., Oda, T., Misaki, T., Ohashi, N., Nakayama, K., Nakayama, K.I., Hishida, A., Yamamoto, T. and Kitagawa, M.: Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice. Am. J. Pathol. 171:473-483, 2007.
  5. Fukasawa, H., Yamamato, T., Kitagawa, M. and Hishida, A.: Regulation of TGF-beta signaling by Smads and its roles in tissue fibrosis. Current signal transduction therapy (review article) in press.
  6. Fukasawa, H., Yamamoto, T., Togawa, A. Ohashi, N., Fujigaki, Y., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M. and Hishida, A.: Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury. Kidney Int. 69, 1733-1740, 2006.
  7. Ohashi, N., Yamamoto, T., Uchida, C., Togawa, A., Fukasawa, H., Fujigaki, Y., Suzuki, S., Kitagawa, K., Hattori, T., Oda, T., Hayashi, H., Hishida, A. and Kitagawa, M.: Transcriptional induction of Smurf2 ubiquitin ligase by TGF-β. FEBS Letters 579: 2557-2563, 2005.
  8. Fukasawa, H., Yamamoto, T., Togawa, A. Ohashi, N., Fujigaki, Y., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M. and Hishida, A.: Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in mice obstructive nephropathy. Proc. Nathl. Acad. Sci. USA 101 (23): 8687-8692, 2004.
  9. Inoue, Y., Kitagawa, M., Onozaki, K, and Hayashi, H.: Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-β signaling. J. Interferon & Cytokine Research, 24: 43-54, 2004
  10. Fukasawa, H., Yamamoto, T., Suzuki, H., Togawa, A. Ohashi, N., Fujigaki, Y., Uchida, C., Aoki, M., Hosono, M., Kitagawa, M. and Hishida, A.: Treatment with anti-TGF-s antibody ameliorates progressive nephritis by inhibiting Smad/TGF-s signaling. Kidney Int. 65: 63-74, 2004.
  11. Togawa, A., Yamamoto, T., Suzuki, S., Fukasawa, H., Ohashi, N., Fujigaki, Y., Kitagawa, K., Hattori, T., Kitagawa, M. and Hishida, A.: Ubiquitin-dependent degradation of Smad2 is increased in the glomeruli of rats with anti-thymocyte serum nephritis. Am. J. Pathol. 163, 1645-1652, 2003.
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8. ユビキチンリガーゼの活性制御の研究 †

  1. Isobe, T., Hattori, T., Kitagawa, K., Uchida, C., Kotake, Y., Kosugi, I., Oda, T., Kitagawa, M. Adenovirus E1A inhibits SCFFbw7 ubiquitin ligase. J Biol Chem. 284(41): 27766-27779, 2009.
  2. Uchida, C., Miwa, S., Isobe, T., Kitagawa, K., Hattori, T., Oda, T., Yasuda, H. and Kitagawa, M.: Effect of MdmX on Mdm2-mediated downregulation of pRB. FEBS Letters 580:1753-1758, 2006.
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9. タンパク質の凝集・異局在化の研究 †

  1. Kono, S., Suzuki, H., Oda, T., Takahashi, Y., Shirakawa, K., Takahashi, Y., Kitagawa, M. and Miyajima, H.: Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia. J. Hepatology 47:844-850, 2007.
  2. Kono, S., Suzuki, H., Oda, T., Miyajima, H., Takahashi, Y., Shirakawa, K., Ishikawa, K., and Kitagawa, M.: Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia. Neuromolecular Med. 8(3):361-374, 2006.
  3. Mizuno, T., Ito, K., Uchida, C., Kitagawa, M., Ichiyama, A., Miura, S., Fujita, K. and Oda, T.: Analyses in transfected cells and in vitro of a putative peroxisomal targeting signal of rat liver serine:pyruvate aminotransferase. Histochem. Cell Biol. 118: 321-328 2002.
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10. 細胞周期制御に関する研究 †

  1. Ohoka, N., Hattori, T., Kitagawa, M., Onozaki, K. and Hayashi H.: Critical and functional regulation of CHOP (C/EBP homologous protein) through the N-terminal portion. J Biol Chem. 282: 35687-35694, 2007.
  2. Arakawa, T., Yamamura, T., Hattori, T., Hayashi H., Mori, A., Yoshida, A., Uchida, C., Kitagawa, M. and Onozaki, K.: Contribution of Extracellular Signal-Regulated Kinases to the IL-1-induced Growth Inhibition of Human Melanoma Cells A375. International Immunopharmacology 8: 80-89, 2007.
  3. Takemura, M., Yoshida, S., Akiyama, T., Kitagawa, M., Yamada, Y.: Role of the second-largest subunit of DNA polymerase a in the interaction between the catalytic subunit and hyperphosphorylated retinoblastoma protein in late S phase. Biochem. Biophys. Acta 1764: 1447-1453, 2006.
  4. Kimura M, Uchida C, Takano Y, Kitagawa M, Okano Y.:Cell cycle-dependent regulation of the human aurora B promoter. Biochem Biophys Res Commun. 316(3): 930-6, 2004.
  5. Tahara, K., Tsuchimoto, D., Tominaga, Y., Asoh, S., Ohta, S., Kitagawa, M., Horie, H., Kadoya. T. and Nakabeppu, Y.:ΔFosB but not FosB induces delayed apoptosis independent of cell proliferation in the Rat1a embryo cell line. Cell Death and Diff. 10: 496-507, 2003.
  6. Katayama, K., Dobashi Y., Kitagawa, M., Kamekura, S., Kawai, M., Kadoya Y., and Kameya T.: Overexpression of Cdk4/Cyclin D1 induces apoptosis in PC12 cells in the presence of trophic support. FEBS Let. 509: 382-388, 2001.
  7. Sugiyama, T., Uchida, C., Oda, T., Kitagawa, M., Hayashi, H. and Ichiyama, A.: Involvement of CCAAT/enhancer-binding protein in regulation of the rat serine:pyruvate/alanine:glyoxylate aminotransferase gene expression. FEBS Let. 508: 16-22, 2001.
  8. Takemura, M., Yamamoto, T., Kitagawa, M., Taya Y., Akiyama, T., Asahara, H., Linn S., Suzuki, S., Tamai, K. and Yoshida, S.: Stimulation of DNA polymerase a activity by cdk2-phosphorylated Rb Protein. Biochem. Biophys. Res. Commun. 282: 984-990, 2001.
  9. Yamanaka, A., Hatakeyama, S., Kominami, K.-i., Kitagawa, M., Matsumoto, M. and Nakayama, K.-i. : Cell-cycle dependent expression of mammalian E2-C regulated by the anaphase promoting complex/cyclosome. Mol. Biol. Cell 11: 2821-2831, 2000.
  10. Ishimi, Y., Komamura, Y., You, Z., Omori, A. and Kitagawa, M.: Inhibition of Mcm4,6,7 helicase activity by phosphorylation with cyclin A-Cdk2. J. Biol. Chem. 275: 16235-16241, 2000.
  11. Dobashi, Y., Shoji, M., Kitagawa, M., Noguchi, T. and Kameya, T.: Simultaneous suppression of Cdc2/Cdk2 activity is necessary and sufficient for neuronal differentiation of PC12. J. Biol. Chem. 275: 12572-12580, 2000.
  12. Tanaka, T., Tatsuno, I., Uchida, D., Moroo, I., Morio, H., Nakamura, S., Noguchi, Y., Yasuda, T., Kitagawa, M., Saito, Y. and Hirai, A.: Geranylgeranyl-pyrophosphate(GGPP), an isoprenoid of mevalonate cascade, is a critical compound for rat primary cultured cortical neurons to protect the cell death induced by HMG-CoA reductase inhibition. J. Neurosci. 20: 2852-2859, 2000.
  13. Watanabe Y,. Watanabe, T., Kitagawa, M., Taya Y., Nakayama, K.-i., and Motoyama, N.: pRb phosphorylation is regulated differentially by cyclin-dependent kinase Cdk2 and Cdk4 in retinoic acid-induced neuronal differentiation of P19 cells. Brain Res. 842: 342-350, 1999.
  14. Terano, T., Shiina, T., Noguchi, Y., Tanaka, T., Tatsuno, I., Saito, Y., Yasuda, T., Kitagawa, M. and Hirai, A.: Geranylgeranyl-pyrophosphateplays a key role for the G1 to S transition in vascular smooth muscle cells. Journal of Atherosclerosis & Thrombosis 5: 1-6, 1999
  15. Terano, T., Tanaka, T., Tamura, Y., Kitagawa, M., Higashi, H., Saito, Y. and Hirai, A.: Eicosapentaenoic acid and docosahexaenoic acid inhibit vascular smooth muscle cell proliferation by inhibiting phosphorylation of Cdk2-cyclin E, Biochem. Biophys. Res. Commun. 252: 502-506, 1999.
  16. Noguchi, Y., Nakamura, S., Yasuda, T., Kitagawa, M., Kohn, L.D., Saito, Y. and Hirai, A.: Newly synthesized Rho A, not Ras is isoprenylated and translocated to membranes coincident with progression of the G1 to S phase of growth stimulated rat FRTL-5 cells. J. Biol. Chem. 273: 3649-3653, 1998.
  17. Tanaka, T., Tatsuno, I., Noguchi, Y., Uchida, D., Oeda, T., Narumiya, S., Yasuda, T., Higashi, H., Kitagawa, M., Nakayama, K., Saito, Y. and Hirai, A.: Activation of Cyclin dependent kinase 2 (Cdk2) in growth-stimulated rat astrocytes. - Geranylgeranylated-Rho-small GTPase(s) are essential for the induction of cyclin E gene expression. J. Biol. Chem. 273: 26772-26778, 1998.
  18. Higashi, H., Suzuki-Takahashi, I., Yoshida, E., Nishimura, S. and Kitagawa, M.: Expression of p16 suppresses the unbounded and anchorage dependent growth of a glioblastoma cell line that lacks p16ink4a. Biochem. Biophys. Res. Commun. 231: 743-750, 1997.
  19. Suzuki-Takahashi, I., Higashi, H., Yoshida, E., Nishimura, S. and Kitagawa, M.: Effect of exogenous p16ink4a.on growth of cells with various status of cell-cycle regulators. Biochem. Biophys. Res. Commun. 234: 386-392, 1997.
  20. Dobashi, Y., Chigira, M., Shoji, M., Wakata, Y., Kitagawa, M., Tamauchi, H., Akiyama, T. and Kameya, T.: Cell cycle control with minimal participation of Cdk2 in a murine fibrosarcoma clone cultured in protein-free medium. Biochem. Biophys. Res. Commun. 232: 622-625, 1997.
  21. Terano, T., Shiina, T., Yamamoto, K., Ban, T., Hirai, A., Tamura, Y., Saito, Y. and Kitagawa, M.: Eicosapentaenoic acid and docosahexaenoic acid inhibit DNA synthesis through inhibiting cdk2 kinase in vascular smooth muscle cells. Ann. N Y Acad. Sci., 811: 369-377, 1997.
  22. Tatsuno, I., Tanaka, T., Oeda, T., Yasuda, T., Kitagawa, M., Saito Y. and Hirai. A.: Geranylgeranyl-pyrophosphate, a metabolite of mevalonate, regulates the cell cycle progression and DNA synthesis in human lymphocytes. Biochem. Biophys. Res. Commun. 241: 376-382, 1997.
  23. Kikuchi, J., Furukawa, Y., Iwase, S., Terui, Y., Kitagawa, M., Komatsu, N., Miura, Y. and Kitagawa, S.: Polyploidization and functional maturation are two distinct processes during megakaryocystec differentiation: Involvement of cyclin-dependent kinase inhibitor p21 in polyploidization. Blood 89: 3980-3990, 1997.
  24. Furukawa, Y., Iwase, S., Terui, Y., Kikuchi, J., Nakamura, M., Kitagawa, S., and Kitagawa, M.: Transcriptional activation of the cdc2 gene is associated with Fas-induced apoptosis of human hematopoietic cells. J. Biol. Chem. 271: 28469-28477, 1996.
  25. Yamamoto, K., Hirai, A., Ban, T., Saito, J., Tahara, K., Terano, T., Tamura, Y., Saito, Y. and Kitagawa, M.: Tyrotropin induces G1 cyclin expression and accelerates G1 phase after insulin-like growth factor I stimulation in FRTL-5 cells. Endocrinology 137: 2036-2042, 1996.
  26. Higashi, H., Suzuki-Takahashi, I., Saitoh, S., Segawa, K., Taya, Y., Okuyama, A., Nishimura, S. and Kitagawa, M.: Cyclin-depemdent kinase 2 (Cdk2) forms an inactive complex with cyclin D1 since Cdk2 associated with cyclin D1 is not phosphorylated by Cdk7-cyclin-H. Eur. J. Biochem. 237: 460-467, 1996.
  27. Matsukawa, T., Kitagawa, M., Katayama, K., Nagai, Y., Hayashi, T., Yasuda, H. and Ohba Y.: The existence of thyroid hormone responsive element, TRE, was confirmed in the first intron of rat a1-acid glycoprotein gene. J. Biochem. 119: 934-939, 1996.
  28. Kitagawa, M., Higashi, H., Takahashi, -S.I., Segawa, K. Hanks, S.K., Taya, Y., Nishimura, S. & Okuyama, A.: Phosphorylation of E2F-1 by cyclin A-cdk2. Oncogene, 10 : 229-236, 1995.
  29. Kotani, S., Endo, T., Kitagawa, M., Higashi, H. & Onaya, T.: A variant form of cyclin-dependent kinase 2(Cdk2) in a malignantly transformed rat thyroid (FRTL-Tc) cell line. Oncogene, 10 : 663-669, 1995.
  30. Higashi, H., Suzuki-Takahashi, I., Taya, Y., Segawa, K., Nishimura, S. & Kitagawa, M.: Differencies in substrate specificity between Cdk2-cyclinA and Cdk2-cyclin E in vitro. Biochem. Biophys. Res. Commun., 216 : 520-525, 1995.
  31. Suzuki-Takahashi, I., Kitagawa, M., Saijo, M., Higashi, H., Ogino, H., Matsumoto, H., Taya, Y., Nishimura, S. & Okuyama, A.: The interaction of E2F with pRB and with p107 are regulated via the phosphorylation of pRB and p107 by cyclin-dependent kinases. Oncogene, 10 : 1691-1698, 1995.
  32. Ueno, Y., Makino, S., Kitagawa, M., Nishimura, S., Taya, Y. & Hata, T.: Chemical synthesis of phosphopeptides using arylthio group for protection of phosphate : Application to identification of cdc2 kinase phosphorylation sites. Int. J. Peptide Prot. Res., 46 : 106-112, 1995.
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11. タンパク分解に関する研究 †

  1. Hayakawa, M., Matsushima, M., Hagiwara, H., Oshima, T., Fujino, T., Ando, K., Kikugawa, K., Tanaka, H., Miyazawa,K. and Kitagawa, M. Novel insights into FGD3, a putative GEF for Cdc42, that undergoes SCFFWD1/b-TrCP-mediated proteasomal degradation analogous to that of its homologue FGD1 but regulates cell morphology and motility differently from FGD1. Genes to Cells 13: 329-442, 2008.
  2. Abe, K., Hattori, T., Isobe, T., Kitagawa, K., Oda, T., Uchida, C., Kitagawa, M. Pirh2 interacts with and ubiquitylates signal recognition particle receptor beta subunit. Biomed Res. 29:53-60, 2008.
  3. Isobe, T., Uchida, C., Hattori, T., Kitagawa, K., Oda, T. and Kitagawa, M.: Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69. Biochem Biophys Res Commun. 339: 367-374, 2006.
  4. Hayakawa, M., Kitagawa, H., Miyazawa, K., Kitagawa, M., and Kikugawa, K.: The FWD1/b-TrCP-mediated degradation pathway establishes a turning off switch of a Cdc42 guanine nucleotide exchange factor, FGD1. Genes to Cells 10: 241-251, 2005.
  5. Naito, M., Katayama, R., Ishioka, T., Suga, A., Takubo, K., Nanjyo, M., Hashimoto, C., Taira, M., Takada S., Takada, R., Kitagawa, M., Matsuzawa, S.-i., Reed, J. C. and Tsuruo, T.: Cellular FLIP inhibits b-catenin ubiquitylation and enhances Wnt signaling. Mol. Cell. Biol. 24:8418-8427, 2004.
  6. Matsumoto,M., Yada, M., Hatakeyama, S., Ishimoto, H., Tanimura, T., Tsuji, S., Kakizuka, A., Kitagawa, M. and Nakayama K-I : Molecular clearance of ataxin-3 is regulated by a mammalian E4. EMBO J 23: 659-669, 2004.
  7. Inoue, Y., Kitagawa, M., Onozaki, K, and Hayashi, H.: Contribution of the constitutive and inducible degradation of Smad3 by the ubiquitin-proteasome pathway to transforming growth factor-b signaling. J. Interferon & Cytokine Research, 24: 43-54, 2004
  8. Hayakawa, M., Miyashita, H., Sakamoto, I., Kitagawa, M., Tanaka, H., Yasuda, H., Karin, M. and Kikugawa, K.: Evidence that reactive oxygen species do not mediate NF-kB activation. EMBO J. 22: 3356-3366, 2003.
  9. Nishida, T., Kaneko, F., Kitagawa, M. and Yasuda, H.: Characterization of a novel mammalian SUMO-1/Smt3-specific isopeptidase, a homologue of rat Axam, which is an Axin-binding protein promoting b-catenin degradation. J. Biol. Chem. 276: 39060-39066, 2001
  10. Kitagawa, M., Hatakeyama S., Shirane, M., Matsumoto, M., Ishida, N., Hattori, K., Nakamichi, I., Kikuchi, A., Nakayama, K.-i. and Nakayama, K. : An F-box protein FWD1 mediates ubiquitin-dependent proteolysis of β-catenin. EMBO J. 18: 2401-2410, 1999.
  11. Hatakeyama S., Kitagawa, M., Nakayama, K., Shirane, M., Matsumoto, M., Hattori, K., Higashi, H., Nakao, H., Okumura, K., Onoe, K., Good, R. A. and Nakayama, K.-i. (Hatakeyama, S. and Kitagawa, M. equally contributed to this report): Ubiquitin-dependent degradation of IkBa is mediated by a ubiquitin ligase Skp1/Cul1/F-box protein FWD1. Proc. Nathl. Acad. Sci. USA 96: 3859-3863, 1999.
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12. 癌に関する研究 †

  1. Kikuchi, H., Yamamoto, M., Hiramatsu, Y., Baba, M., Ohta, M., Kamiya, K., Tanaka, T., Suzuki, S., Sugimura, H., Kitagawa, M., Kanai, T., Kitayama, Y., Kanda, T., Nishikura, K. and Konno, H.:Effect of loss of heterozygosity of the c-kit gene on prognosis after hepatectomy for metastatic liver gastrointestinal stromal tumors. Cancer Sci. 98: 1734-1739, 2007.
  2. Li, S., Gao, Y., Tokuyama, T., Yamamoto, J., Yokota, N., Yamamoto, S., Terakawa, S., Kitagawa, M. and Namba, H.: Genetically engineered neural stem cells migrate and suppress glioma cell growth at distant intracranial sites. Cancer Letters, 251(2): 220-227, 2007.
  3. Kikuchi, H., Yamashita, K., Kawabata, T., Yamamoto, M., Hiramatsu, Y., Kondo, K., Baba, M., Ohta, M., Kamiya, K., Tanaka, T., Suzuki, S., Kitagawa, K., Kitagawa, M., Sugimura, H. and Konno, H.:Immunohistochemical and genetic features of gastric and the metastatic liver GISTs, sequential analyses. Cancer Sci. 97, 127-132, 2006.