Analysis of ERK2 roles in immunoregulation by ERK2 mutant mice

• Project/Area Number: 15590435
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Mie University
• Principal Investigator: OGATA Masato Mie University, Faculty of Medicine, Professor, 医学部, 教授 (60224094)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: T lymphocyte / MAP kinase / ERK2 / mutant mice / Tリンパ球分化

Research Abstract

Mitogen-activated protein kinases(MAPKs) are activated in response to various extracellular stimuli. Extracellular signal-regulated kinase(ERK), a MAPK family, has been implicated in T cell differentiation, proliferation and cytokine production. The ERK family consists of two members, ERK1 and ERK2. Recently, defective thymocyte maturation has been reported in ERK1-deficient mice. However, roles of ERK2 in the regulation of immune system remain to be determined. Here we show that the targeted disruption of the mouse ERK2 gene results in embryonic lethality by E11.5 and severe abnormality of the placenta. In these animals, the labyrinthine layer of the placenta is very thin and few fetal blood vessels are observed. ERK2 mutants can be rescued by the transgenic expression of ERK2, demonstrating that these abnormalities are caused by ERK2-deficiency. Although ERK2-deficient fetuses are much smaller than wild-type littermates, this seems to be secondary to malfunction of the placenta. When the placental defect is rescued by tetraploid-aggregation, ERK2-deficient fetuses grow as well as littermate controls.
As described above, ERK2-deficient mice were embryonic lethal due to placental defect. So we generated ERK2 conditional knockout mice to study the physiological role of ERK2 in the immune system. We generated T cell-specific ERK2-deficient mice using LCK-Cre transgenic mice. These mice were viable and more than 95% ERK2 gene was disrupted in the thymocytes. ERK2 protein was undetectable in the thymocytes. In the thymus, CD3^<high> CD4^+ or CD8^+ mature T cells were significantly decreased. Thus, ERK2 is essential for development of T cells.

Research Products

• [Journal Article] Prolactin prevents acute stress-induced hypocalcemia and ulcerogenesis by acting in the brain of rat (2004)
  • Author(s): Fujikawa, T.
  • Journal Title: Endocrinology. 15 Pages: 2006-2013
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of promoter region of ghrelin gene in human medullary thyroid carcinoma cell line (2004)
  • Author(s): Nakai, N.
  • Journal Title: Life Sci 75 Pages: 2193-2201
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prolactin prevents acute stress-induced hypocalcemia and ulcerogenesis by acting in the brain of rat. (2004)
  • Author(s): Fujikawa, T., Soya, H., Tamashiro, K.L., Sakai, R.R., McEwen, B.S., Nakai, N., Ogata, M., Suzuki, I., Nakashima, K.
  • Journal Title: Endocrinology. 145 Pages: 2006-2013
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of promoter region of ghrelin gene in human medullary thyroid carcinoma cell line. (2004)
  • Author(s): Nakai, N., Kaneko, M., Nakao, N., Fujikawa, T., Nakashima, K., Ogata, M., Tanaka, M.
  • Journal Title: Life Sci. 75 Pages: 2193-2201
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prolactin prevents acute stress-induced hypocalcemia and ulcerogenesis by acting in the brain of rat (2004)
  • Author(s): Fujikawa, T.
  • Journal Title: Endocrinology. 145 Pages: 2006-2013
• [Journal Article] Essential role for ERK2 mitogen-activated protein kinase in placental development (2003)
  • Author(s): Hatano, N.
  • Journal Title: Genes to Cells. 8 Pages: 847-856
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation (2003)
  • Author(s): Tanimura, N.
  • Journal Title: J Cell Biol. 160 Pages: 12-5135
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Follicle stimulating hormone activates extracellular signal regulated kinases but not extracellular signal regulated kinase kinase through a 100 kDa phosphotyrosine pliosphatase. (2003)
  • Author(s): Cottom, J.
  • Journal Title: J.Biol.Chem. 278 Pages: 7167-7179
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] PTHrP Induces Insulin Expression though Activation of MAP Kinase specific Phosphatase-1 that Dephosphorylates c-Jun N-terminal Kinase in Pancreatic β-Cells (2003)
  • Author(s): Zhang, B.
  • Journal Title: Diabetes. 52 Pages: 2720-2730
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Essential role for ERK2 mitogen-activated protein kinase in placental development. (2003)
  • Author(s): Hatano, N., Mori, Y., Oh-hora, M., Kosugi, A., Fujikawa, T., Nakai, N., Niwa, H., Miyazaki, J., Hamaoka, T., Ogata, M.
  • Journal Title: Genes to Cells 8 Pages: 847-856
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation. (2003)
  • Author(s): Tanimura, N., Nagafuku, M., Minaki, Y., Umeda, Y., Hayashi, F., Sakakura, J., Kato, A., Liddicoat, D.R., Ogata, M., Hamaoka, T., Kosugi, A.
  • Journal Title: J Cell Biol. 160 Pages: 125-135
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Follicle stimulating hormone activates extracellular signal regulated kinases but not extracellular signal regulated kinase kinase through a 100 kDa phosphotyrosine phosphatase. (2003)
  • Author(s): Cottom, J., Salvador, L.M., Maizels, E.T., Reierstad, S., Park, Y., Horvat, R., Carr, D.W., Davare, M.A., Hell, J.W., Palmer, S.S., Dent, P., Kawakatsu, H., Ogata, M., Hunzicker-Dunn, M.
  • Journal Title: J.Biol.Chem. 278 Pages: 7167-7179
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PTHrP Induces Insulin Expression through Activation of MAP Kinasespecific Phosphatase-1 that Dephosphorylates c-Jun N-terminal Kinase in Pancreatic b-Cells. (2003)
  • Author(s): Zhang, B., Hosaka, M., Sawada, Y., Seiji Torii, S., Mizutani, S., Ogata, M., Izumi, T., Takeuchi, T.
  • Journal Title: Diabetes. 52 Pages: 2720-2730
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hatano, N.: "Essential role for ERK2 mitogen-activated protein kinase in placental development"Genes to Cells. 8. 847-856 (2003)
• [Publications] Tanimura, N.: "Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation"J Cell Biol.. 160. 125-135 (2003)
• [Publications] Cottom, J.: "Follicle stimulating hormone activates extracellular signal regulated kinases but not extracellular signal regulated kinase kinase through a 100kDa phosphotyrosine phosphotase"J.Biol.Chem.. 278. 7167-7179 (2003)
• [Publications] Zhang, B.: "PTHrP Induces Insulin Expression through Activation of MAP Kinasespecific Phosphatase-1 that Dephosphorylates c-Jun N-terminal Kinase in Pancreatic β-Cells"Diabetes. 52. 2720-2730 (2003)
• [Publications] Fujikawa, T.: "Prolactin prevents acute stress-induced hypocalcemia and ulcerogenesis by acting in the brain rat"Endocrinology. 145. 2006-2013 (2004)