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G1P3, an interferon inducible gene 6-16, is expressed in gastric cancers and inhibits mitochondrial-mediated apoptosis in gastric cancer cell line TMK-1 cell

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Abstract

Expression of an interferon inducible gene 6-16, G1P3, increases not only in type I interferon-treated cells but also in human senescent fibroblasts. However, the function of 6-16 protein is unknown. Here we report that 6-16 is 34 kDa glycosylated protein and localized at mitochondria. Interestingly, 6-16 is expressed at high levels in gastric cancer cell lines and tissues. One of exceptional gastric cancer cell line, TMK-1, which do not express detectable 6-16, is sensitive to apoptosis induced by cycloheximide (CHX), 5-fluorouracil (5-FU) and serum-deprivation. Ectopic expression of 6-16 gene restored the induction of apoptosis and inhibited caspase-3 activity in TMK-1 cells. Thus 6-16 protein has anti-apoptotic function through inhibiting caspas-3. This anti-apoptotic function is expressed through inhibition of the depolarization of mitochondrial membrane potential and release of cytochrome c. By two-hybrid screening, we found that 6-16 protein interacts with calcium and integrin binding protein, CIB/KIP/Calmyrin (CIB), which interacts with presenilin 2, a protein involved in Alzheimer’s disease. These protein interactions possibly play a pivotal role in the regulation of apoptosis, for which further detailed analyses are need. These results overall indicate that 6-16 protein may have function as a cell survival protein by inhibiting mitochondrial-mediated apoptosis.

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References

  1. Kelly JM, Porter AC, Chernajovsky Y, Gilbert CS, Stark GR, Kerr IM (1986) Characterization of a human gene inducible by alpha- and beta- interferons and its expression in mouse cells. Embo J 5: 1601

    Google Scholar 

  2. Itzhaki JE, Barnett MA, MacCarthy AB, Buckle VJ, Brown WR, Porter AC (1992) Targeted breakage of a human chromosome mediated by cloned human telomeric DNA. Nat Genet 2: 283

    Article  Google Scholar 

  3. Turri MG, Cuin KA, Porter AC (1995) Characterisation of a novel minisatellite that provides multiple splice donor sites in an interferon-induced transcript. Nucleic Acids Res 23: 1854

    Google Scholar 

  4. Porter AC, Chernajovsky Y, Dale TC, Gilbert CS, Stark GR, Kerr IM (1988) Interferon response element of the human gene 6-16. Embo J 7: 85

    Google Scholar 

  5. Tahara H, Hara E, Tsuyama N, Oda K, Ide T (1994) Preparation of a subtractive cDNA library enriched in cDNAs which expressed at a high level in cultured senescent human fibroblasts. Biochem Biophys Res Commun 199: 1108

    Article  Google Scholar 

  6. Tahara H, Kamada K, Sato E, Tsuyama N, Kim JK, Hara E, Oda K, Ide T (1995) Increase in expression levels of interferon-inducible genes in senescent human diploid fibroblasts and in SV40-transformed human fibroblasts with extended lifespan. Oncogene 11: 1125

    Google Scholar 

  7. Rao L, Debbas M, Sabbatini P, Hockenbery D, Korsmeyer S, White E (1992) The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. Proc Natl Acad Sci U S A 89: 7742

    Google Scholar 

  8. De Laurenzi V, Melino G (2000) Apoptosis. The little devil of death. Nature 406: 135

    Article  Google Scholar 

  9. Capaldi RA (2000) The changing face of mitochondrial research. Trends Biochem Sci 25: 212

    Article  Google Scholar 

  10. Loeffler M, Kroemer G (2000) The mitochondrion in cell death control: certainties and incognita. Exp Cell Res 256: 19

    Google Scholar 

  11. Antonsson B, Martinou JC (2000) The Bcl-2 protein family. Exp Cell Res 256: 50

    Article  CAS  PubMed  Google Scholar 

  12. Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Ide T, Ishikawa F (1998) Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet 18: 65

    CAS  PubMed  Google Scholar 

  13. Radinsky R, Bucana CD, Ellis LM, Sanchez R, Cleary KR, Brigati DJ, Fidler IJ (1993) A rapid colorimetric in situ messenger RNA hybridization technique for analysis of epidermal growth factor receptor in paraffin-embedded surgical specimens of human colon carcinomas. Cancer Res 53: 937

    Google Scholar 

  14. Yokozaki H (2000) Molecular characteristics of eight gastric cancer cell lines established in Japan. Pathol Int 50: 767

    Article  Google Scholar 

  15. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407: 770

    Article  CAS  PubMed  Google Scholar 

  16. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479

    Article  CAS  PubMed  Google Scholar 

  17. Bratton SB, MacFarlane M, Cain K, Cohen GM (2000) Protein complexes activate distinct caspase cascades in death receptor and stress-induced apoptosis. Exp Cell Res 256: 27

    Article  CAS  PubMed  Google Scholar 

  18. Cossarizza A, Baccarani-Contri M, Kalashnikova G, Franceschi C (1993) A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochem Biophys Res Commun 197: 40

    Article  CAS  PubMed  Google Scholar 

  19. Cossarizza A, Ceccarelli D, Masini A (1996) Functional heterogeneity of an isolated mitochondrial population revealed by cytofluorometric analysis at the single organelle level. Exp Cell Res 222: 84

    Article  CAS  PubMed  Google Scholar 

  20. Naik UP, Patel PM, Parise LV (1997) Identification of a novel calcium-binding protein that interacts with the integrin alphaIIb cytoplasmic domain. J Biol Chem 272: 4651

    Article  Google Scholar 

  21. Wu X, Lieber MR (1997) Interaction between DNA-dependent protein kinase and a novel protein KIP. Mutat Res 385: 13

    Google Scholar 

  22. Stabler SM, Ostrowski LL, Janicki SM, Monteiro MJ (1999) A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer’s disease presenilin 2 protein. J Cell Biol 145: 1277

    Article  Google Scholar 

  23. Desagher S, Martinou JC (2000) Mitochondria as the central control point of apoptosis. Trends Cell Biol 10: 369

    CAS  PubMed  Google Scholar 

  24. Kaufmann SH, Earnshaw WC (2000) Induction of apoptosis by cancer chemotherapy. Exp Cell Res 256: 42

    Article  CAS  PubMed  Google Scholar 

  25. Vander Heiden MG, Thompson CB (1999) Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis? Nat Cell Biol 1: E209

    Article  Google Scholar 

  26. Sakahira H, Enari M, Nagata S (1998) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391: 96

    Article  CAS  PubMed  Google Scholar 

  27. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, its inhibitor ICAD. Nature 391: 43

    Article  CAS  PubMed  Google Scholar 

  28. Shimizu S, Narita M, Tsujimoto Y (1999) Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399: 483

    Article  CAS  PubMed  Google Scholar 

  29. Shimizu S, Konishi A, Kodama T, Tsujimoto Y (2000) BH4 domain of antiapoptotic Bcl-2 family members closes voltage- dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Proc Natl Acad Sci U S A 97: 3100

    Article  Google Scholar 

  30. Kauselmann G, Weiler M, Wulff P, Jessberger S, Konietzko U, Scafidi J, Staubli U, Bereiter-Hahn J, Strebhardt K, Kuhl D (1999) The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity. Embo J 18: 5528

    Article  Google Scholar 

  31. Foyouzi-Youssefi R, Arnaudeau S, Borner C, Kelley WL, Tschopp J, Lew DP, Demaurex N, Krause KH (2000) Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. Proc Natl Acad Sci U S A 97: 5723

    Article  Google Scholar 

  32. Zhu L, Ling S, Yu XD, Venkatesh LK, Subramanian T, Chinnadurai G, Kuo TH (1999) Modulation of mitochondrial Ca(2+) homeostasis by Bcl-2. J Biol Chem 274: 33267

    Article  CAS  PubMed  Google Scholar 

  33. Pack-Chung E, Meyers MB, Pettingell WP, Moir RD, Brownawell AM, Cheng I, Tanzi RE, Kim TW (2000) Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor. J Biol Chem 275: 14440

    Article  Google Scholar 

  34. Gething MJ (2000) Presenilin mutants subvert chaperone function. Nat Cell Biol 2: E21

    Article  Google Scholar 

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Acknowledgements

Yeast L-40 strain and pBTM116/HA for yeast two-hybrid screening were kindly supplied by Dr Y Takai (Osaka University, Japan). Anti-GST rabbit pAb was kindly provided by Dr. M. Nakata (Sumitomo Electric Industries, Japan). Anti-human CIB/KIP/calmyrin antibody was kindly provided by Leslie V. Parise (North Carolina University, USA). A mammalian expression plasmid, pCXN was kindly provided by Dr J. Miyazaki (Osaka University, Japan). This work was supported by Grant-in Aid from the Ministry of Education, Science, Sports and Culture of Japan.

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Authors and Affiliations

  1. Department of Cellular and Molecular Biology, Division of Integerated Medical Science, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minamiku-ku, Hiroshima, 734-8551, Japan

    Eiji Tahara Jr, Hidetoshi Tahara, Yayoi Takeda & Toshinori Ide

  2. Department of Immunology and Parasitology, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minamiku-ku, Hiroshima, 734-8551, Japan

    Eiji Tahara Jr, Masamoto Kanno & Hiroto Ishihara

  3. Department of Molecular Pathology, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi, Minamiku-ku, Hiroshima, 734-8551, Japan

    Kazuhito Naka & Wataru Yasui

  4. Yakult Central Institute for Microbiological Research, 1796 Yaho, Kunitachi, 186-8650, Japan

    Takeshi Matsuzaki, Ryuta Yamazaki & J Carl Barrett

  5. Center for Cancer Research, National Cancer Institute, Bldg. 31, Room 3A11, 31 Center Drive, MSC-2440, Bethesda, MD, 20892-2440, USA

    Eiichi Tahara

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  1. Eiji Tahara Jr
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  2. Hidetoshi Tahara
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Correspondence to Hidetoshi Tahara.

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Tahara, E., Tahara, H., Kanno, M. et al. G1P3, an interferon inducible gene 6-16, is expressed in gastric cancers and inhibits mitochondrial-mediated apoptosis in gastric cancer cell line TMK-1 cell. Cancer Immunol Immunother 54, 729–740 (2005). https://doi.org/10.1007/s00262-004-0645-2

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