Ubiquitination of overexpressed protein and enclosure by inducible ER membrane

• Project/Area Number: 17590244
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: ODA Toshiaki Hamamatsu Univ. 8ch. Medi., Associate Prot., 医学部, 准教授 (90126805)
• Co-Investigator(Kenkyū-buntansha): KITAGAWA Masatoshi Hamamatsu Univ. Sch. Med., Prof, 医学部, 教授 (50294971) ; UCHIDA Chiharu Hamamatsu Univ. Sch. Med., Assistant Prof, 医学部, 助教授 (60223567)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: protein overexpression / crystalloid endoplasmic reticulum / organelle targeting signal / inducible ER / cell response / タンパク質過剰発現 / タンパク質過剰産生ストレス / タンパク質の質と量の制御 / ユビキチン化

Research Abstract

It has been reported that overexpression in the culture cells of endoplasmic reticulum (ER) membrane proteins, such as microsomal aldehyde dehydrogenase (ALDH), causes the induction of a specific ER membrane structure (crystalloid ER, cER). We recently found for the first time that overexpression of an ER-unrelated, mitochondrial precursor for serine : pyruvate aminotransferase (SPT45K) induced the generation of cER, and overexpressed pOTC and pAd, other mitochondrial precursor proteins, also induced the ER aggregates. We also found that the chimeric fluorescent protein having the C terminal ER targeting sequence of ALDH at the C terminus had the remarkable ER aggregating activity by the overexpression. Because these cER (or ER aggregates) inducing activities were not observed in the cases of proteins (SPT43K, ALDHdC, EYFP) lacking organelle targeting signals, the activities is dependent on their structures. It was further indicated that the cER (ER aggregates) inducing activities was dependent on their expression levels in the cell. These data suggest that the cell has a novel system for the detection of the quality (structure) and the quantity of proteins expressed in the cytoplasm by inducing the new ER membrane structure.

Research Products

• [Journal Article] Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice. (2007)
  • Author(s): 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., Kitagawa M.
  • Journal Title: Am. J. Pathol. (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice. (2007)
  • Author(s): 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., Kitagawa, M.
  • Journal Title: Am. J. Pathol. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors : Sequential analyses (2006)
  • Author(s): 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., Konon, H.
  • Journal Title: Cancer Sci 97 Pages: 127-132
  • NAID: 10020388517
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia (2006)
  • Author(s): Kono, S., Suzuki, H., Oda, T., Miyajima, H., Takahashi, Y., Shirakawa, K., Ishikawa, K., Kitagawa, M.
  • Journal Title: Neuromol. Med. 8 Pages: 361-374
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Up-regulation of GPR48 induced by down-regulation of p27^<Kip1> enhances carcinoma cell invasiveness and metastasis (2006)
  • Author(s): 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., Kitagawa, M.
  • Journal Title: Cancer Res 66 Pages: 11623-11631
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Degradation of Tob1 Mediated by SCF^<ska2>-Dependent Ubiquitination (2006)
  • Author(s): Hiramatsu, Y., Kitagawa, K., Suzuki, T., Uchida, C., Hattori, T., Kikuchi, H., Oda, T., Hatakeyama, S., Nakayama, KI., Yamamoto, T., Konno, H., Kitagawa M.
  • Journal Title: Cancer Res 66 Pages: 8477-8483
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury (2006)
  • Author(s): Fukasawa, H., Yamamoto, T., Togawa, A., Ohashi, N., Fujigaki, Y., Oda T., Uchida C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M., Hishida
  • Journal Title: Kidney Int 69 Pages: 1733-1740
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of MdmX on Mdm2-mediated downregulation of pRB. (2006)
  • Author(s): Uchida, C., Miwa, S., Isobe, T., Kitagawa, K., Hattori, T., Oda, T., Yasuda, H., Kitagawa, M.
  • Journal Title: FEBS Letters 560 Pages: 1753-1758
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69. (2006)
  • Author(s): Isobe, T., Uchida, C., Hattori T., Kitagawa, K., Oda, T., Kitagawa, M.
  • Journal Title: Biochem Biophys Res Commun 339 Pages: 367-374
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner (2006)
  • Author(s): Miwa, S., Uchida, C., Kitagawa, K., Hattori, T., Oda, T., Sugimura, H., Yasuda, H., Nakamura, H., Chida K., Kitagawa, M.
  • Journal Title: Biochem Biophys Res Commun 340 Pages: 54-61
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Generation of a constitutively active mutant of human GPR48/LGR4, a G-protein-coupled receptor (2006)
  • Author(s): Gao, Y., Kitagawa, K., Shimada, M., Uchida, C., Hattori, T., Oda, T., Kitagawa.M.
  • Journal Title: H. J. Med. Sci.(北海道医誌). 81 Pages: 101-109
  • NAID: 10029919292
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors : Sequential analyses (2006)
  • Author(s): 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., Konno, H
  • Journal Title: Cancer Sci. 97 Pages: 127-132
  • NAID: 10020388517
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia (2006)
  • Author(s): Kono, S., Suzuki, H., Oda T., Miyajima, H., Takahashi, Y., Shirakawa, K., Ishikawa, K., Kitagawa, M
  • Journal Title: Neuromol. Med. 8 Pages: 361-374
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Up-regulation of GPR48 induced by down-regulation of p27kip1 enhances carcinoma cell invasiveness and metastasis (2006)
  • Author(s): 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., Kitagawa, M
  • Journal Title: Cancer Res. 66 Pages: 11623-11631
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Degradation of Tobl Mediated by SkP2-Dependent Ubiquitination (2006)
  • Author(s): Hiramatsu, Y., Kitagawa, K., Suzuki, T., Uchida, C., Hattori, T., Kikuchi, H., Oda T., Hatakeyama, S., Nakayama, KI., Yamamoto, T., Konno, H., Kitagawa M.
  • Journal Title: Cancer Res. 66 Pages: 8477-8483
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ubiqui tin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury (2006)
  • Author(s): Fukasawa, H., Yamamoto, T., Togawa, A., Ohashi, N., Fujigaki, Y., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M., Hishida
  • Journal Title: Kidney Int. 69 Pages: 1733-1740
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of MdmX on Mdm2-ediated downregulation of pRB (2006)
  • Author(s): Uchida, C., Miwa, S., Isobe, T., Kitagawa, K., Hattori, T., Oda, T., Yasuda, H., Kitagawa, M.
  • Journal Title: FEBS Letters 560 Pages: 1753-1758
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69. (2006)
  • Author(s): Isobe, T., Uchida, C., Hattori, T., Kitagawa, K., Oda, T., Kitagawa, M
  • Journal Title: Biochem Biophys Res Commun. 339 Pages: 367-374
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner (2006)
  • Author(s): Miwa, S., Uchida C., Kitagawa, K., Hattori, T., Oda, T., Sugimura, H., Yasuda, H., Nakamura, H.Chida K., Kitagawa, M
  • Journal Title: Biochem Biophys Res Commun 340 Pages: 54-61
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of a constitutively active mutant of human GPR48/LGR4, a G-protein-coupled receptor (2006)
  • Author(s): Gao, Y., Kitagawa, K., Shimada, M., Uchida, C., Hattori, T., Oda, T., Kitagawa, M.
  • Journal Title: H.J.Med.Sci(北海道医誌). 81 Pages: 101-109
  • NAID: 10029919292
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors : Sequential analyses (2006)
  • Author(s): 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., Konno, H
  • Journal Title: Cancer Sci 97 Pages: 127-132
  • NAID: 10020388517
• [Journal Article] Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia (2006)
  • Author(s): Kono, S., Suzuki, H., Oda, T., Miyajima, H., Takahashi, Y., Shirakawa, K., Ishikawa, K., Kitagawa.M
  • Journal Title: Neuromol. Med. 8 Pages: 361-374
• [Journal Article] Up-regulation of GPR48 induced by down-regulation of p27^<Kip1> enhances carcinoma cell invasiveness and metastasis (2006)
  • Author(s): 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., Kitagawa.M
  • Journal Title: Cancer Res 66 Pages: 11623-11631
• [Journal Article] Degradation of Tobl Mediated by SCF^<Skp2>-Dependent Ubiquitination (2006)
  • Author(s): Hiramatsu, Y., Kitagawa, K., Suzuki, T., Uchida, C., Hattori, T., Kikuchi, H., Oda, T., Hatakeyama, S., Nakayama, KI., Yamamoto, T., Konno, H., Kitagawa M.
  • Journal Title: Cancer Res 66 Pages: 8477-8483
• [Journal Article] Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury (2006)
  • Author(s): Fukasawa, H., Yamamoto, T., Togawa, A., Ohashi, N., Fujigaki, Y., Oda, T., Uchida C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M., Hishida
  • Journal Title: Kidney Int 69 Pages: 1733-1740
• [Journal Article] Effects of MdmX on Mdm2-mediated downregulation of pRB. (2006)
  • Author(s): Uchida, C., Miwa, S., Isobe, T., Kitagawa, K., Hattori, T., Oda.T., Yasuda, H., Kitagawa.M.
  • Journal Title: FEBS Letters 560 Pages: 1753-1758
• [Journal Article] Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69. (2006)
  • Author(s): Isobe, T., Uchida.C., Hattori, T., Kitagawa, K., Oda, T., Kitagawa, M
  • Journal Title: Biochem Biophys Res Commun 339 Pages: 367-374
• [Journal Article] Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner (2006)
  • Author(s): Miwa, S., Uchida, C., Kitagawa, K., Hattori, T., 0da, T., Sugimura, H., Yasuda, H., Nakamura, H., Chida K., Kitagawa, M
  • Journal Title: Biochem Biophys Res Commun 340 Pages: 54-61
• [Journal Article] Generation of a constitutively active mutant of human GPR48/LGR4, a G-protein-coupled receptor (2006)
  • Author(s): Gao, Y., Kitagawa, K., Shimada, M., Uchida, C., Hattori, T., Oda, T., Kitagawa, M.
  • Journal Title: H. J. Med. Sci(北海道医誌). 81 Pages: 101-109
  • NAID: 10029919292
• [Journal Article] Mdm2-mediated pRB downregulation is involved in carcinogenesis in a p53-independent manner. (2006)
  • Author(s): Miwa, S., Uchida, C., Kitagawa, K., Hattori, T., Oda, T., Sugimura, H., Yasuda, H., Nakamura, H., Chida K., Kitagawa, M.
  • Journal Title: Biochem Biophys Res Commun. 340 Pages: 54-61
• [Journal Article] Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69. (2006)
  • Author(s): Isobe, T., Uchida, C., Hattori, T., Kitagawa, K., Oda, T., Kitagawa, M.
  • Journal Title: Biochem Biophys Res Commun. 339 Pages: 367-374
• [Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by TGF-b. (2005)
  • Author(s): Ohashi, N., Yamamoto, T., Uchida, C., Togawa, A., Fukasawa, H., Fujigaki, Y., Suzuki, S., Kitagawa, K., Hattori, T., Oda, T., Hayashi, H., Hishida, A., Kitagawa, M
  • Journal Title: FEBS Letters 579 Pages: 2557-2563
• [Journal Article] Enhanced Mdm2 activity ibhibits pRB function via ubiquitin-dependent degradation. (2005)
  • Author(s): Uchida C., Miwa S., Kitagawa K., Hattori T., Isobe T., Otani S., Oda T., Sugimura H., Kamijo T., Ookawa K., Yasuda H., Kitagawa M.
  • Journal Title: EMBO J. 24 Pages: 160-169
• [Journal Article] Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury.
  • Author(s): Fukasawa, H., Yamamoto, T., Togawa, A., Ohashi, N., Fujigaki, Y., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Suzuki, S., Kitagawa, M., Hishida, A
  • Journal Title: Kidney Int. (in press)