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2013 | 60 | 4 | 595-602
Article title

Limited GADD45α expression and function in IL-1β toxicity towards insulin-producing cells

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Growth arrest and DNA damage-inducible (GADD) 45 proteins are regulators of cell death and survival. The proinflammatory cytokine IL-1β strongly increases the level of the transcript encoding GADD45α in rat insulin-producing INS-1E cells. The activation of Gadd45α gene is clearly dependent on JNK and NF-κB activation and the synthesis of the secondary mediator nitric oxide (NO). Interestingly, the observed twelve-fold increase in the GADD45α-coding transcript level is not followed by increased expression of GADD45α at the protein level. An analysis of IL-1β toxicity in INS-1E cells overexpressing GADD45α revealed no correlation between the GADD45α protein level and the sensitivity to IL-1β toxicity. These findings suggest that the potential engagement of GADD45α in IL-1β toxicity towards beta cells is limited to the effects induced by the basal expression level of this protein.
Physical description
  • Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
  • Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany
  • Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
  • Laboratory of Molecular Genetics and Virology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
  • Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
  • Abdelli S, Abderrahmani A, Hering B. J, Beckmann JS, Bonny C (2007) The c-Jun N-terminal kinase JNK participates in cytokine- and isolation stress-induced rat pancreatic islet apoptosis. Diabetologia 50: 1660-1669.
  • Al-Romaih K, Sadikovic B, Yoshimoto M, Wang Y, Zielenska M, Squire JA (2008) Decitabine-induced demethylation of 5' CpG island in GADD45A leads to apoptosis in osteosarcoma cells. Neoplasia 10: 471-480.
  • Cardozo AK, Heimberg H, Heremans Y, Leeman R, Kutlu B, Kruhoffer M, Orntoft T, Eizirik DL (2001) A comprehensive analysis of cytokine-induced and nuclear factor-kappa B-dependent genes in primary rat pancreatic beta-cells. J Biol Chem 276: 48879-48886.
  • Cnop M, Welsh N, Jonas J. C, Jorns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences few similarities. Diabetes 54 (Suppl 2): S97-S107.
  • Darville MI, Eizirik DL (1998) Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. Diabetologia 41: 1101-1108.
  • Eckhoff DE, Smyth CA, Eckstein C, Bilbao G, Young CJ, Thompson JA, Contreras JL (2003) Suppression of the c-Jun N-terminal kinase pathway by 17beta-estradiol can preserve human islet functional mass from proinflammatory cytokine-induced destruction. Surgery 134: 169-179.
  • Eldor R, Yeffet A, Baum K, Doviner V, Amar D, Ben-Neriah Y, Christofori G, Peled A, Carel JC, Boitard C, Klein T, Serup P, Eizirik DL, Melloul D (2006) Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents. Proc Natl Acad Sci USA 103: 5072-5077.
  • Fan Y, Dutta J, Gupta N, Fan G, Gelinas C (2008) Regulation of programmed cell death by NF-kappaB and its role in tumorigenesis and therapy. Adv Exp Med Biol 615: 223-250.
  • Gilmore TD, Kalaitzidis D, Liang MC, Starczynowski DT (2004) The c-Rel transcription factor and B-cell proliferation: a deal with the devil. Oncogene 23: 2275-2286.
  • Guevara I, Iwanejko J, Dembinska-Kiec A, Pankiewicz J, Wanat A, Anna P, Golabek I, Bartus S, Malczewska-Malec M, Szczudlik A (1998) Determination of nitrite/nitrate in human biological material by the simple Griess reaction. Clin Chim Acta 274: 177-188.
  • Heimberg H, Heremans Y, Jobin C, Leemans R, Cardozo AK, Darville M, Eizirik DL (2001) Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. Diabetes 50: 2219-2224.
  • Hildesheim J, Bulavin DV, Anver MR, Alvord WG, Hollander MC, Vardanian L, Fornace AJ, Jr (2002) Gadd45a protects against UV irradiation-induced skin tumors and promotes apoptosis and stress signaling via MAPK and p53. Cancer Res 62: 7305-7315.
  • Hoffman B, Liebermann D. A (2009) Gadd45 modulation of intrinsic and extrinsic stress responses in myeloid cells. J Cell Physiol 218: 26-31.
  • Hughes KJ, Meares GP, Chambers KT, Corbett JA (2009) Repair of nitric oxide-damaged DNA in beta-cells requires JNK-dependent GADD45alpha expression. J Biol Chem 284: 27402-27408.
  • Kearsey JM, Coates PJ, Prescott AR, Warbrick E, Hall PA (1995) Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene 11: 1675-1683.
  • Kleinert H, Schwarz PM, Forstermann U (2003) Regulation of the expression of inducible nitric oxide synthase. Biol Chem 384: 1343-1364.
  • Kovalsky O, Lung FD, Roller PP, Fornace AJ, Jr (2001) Oligomerization of human Gadd45a protein. J Biol Chem 276: 39330-39339.
  • Lal A, Abdelmohsen K, Pullmann R, Kawai T, Galban S, Yang X, Brewer G, Gorospe M (2006) Posttranscriptional derepression of GADD45alpha by genotoxic stress. Mol Cell 22: 117-128.
  • Larsen CM, Dossing MG, Papa S, Franzoso G, Billestrup N, Mandrup-Poulsen T (2006) Growth arrest- and DNA-damage-inducible 45beta gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1beta-induced apoptosis in insulin-producing INS-1E cells. Diabetologia 49: 980-989.
  • Lenzen S (2008) Oxidative stress: the vulnerable beta-cell. Biochem Soc Trans 36: 343-347.
  • Li Y, Qian H, Li X, Wang H, Yu J, Liu Y, Zhang X, Liang X, Fu M, Zhan Q, Lin C (2009) Adenoviral-mediated gene transfer of Gadd45a results in suppression by inducing apoptosis and cell cycle arrest in pancreatic cancer cell. J Gene Med 11: 3-13.
  • Liebermann DA, Hoffman B (2007) Gadd45 in the response of hematopoietic cells to genotoxic stress. Blood Cells Mol Dis 39: 329-335.
  • Liebermann DA, Hoffman B (2008) Gadd45 in stress signaling. J Mol Signal 3: 15.
  • Mandrup-Poulsen T, Zumsteg U, Reimers J, Pociot F, Morch L, Helqvist S, Dinarello CA, Nerup J (1993) Involvement of interleukin 1 and interleukin 1 antagonist in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus. Cytokine 5: 185-191.
  • Okura T, Nakamura M, Takata Y, Watanabe S, Kitami Y, Hiwada K (2000) Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells. Eur J Pharmacol 407: 227-235.
  • Orlowski RZ, Baldwin AS, Jr (2002) NF-kappaB as a therapeutic target in cancer. Trends Mol Med 8: 385-389.
  • Ortis F, Pirot P, Naamane N, Kreins AY, Rasschaert J, Moore F, Theatre E, Verhaeghe C, Magnusson NE, Chariot A, Orntoft TF, Eizirik DL (2008) Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells. Diabetologia 51: 1213-1225.
  • Papa S, Bubici C, Zazzeroni F, Franzoso G (2009) Mechanisms of liver disease: cross-talk between the NF-kappaB and JNK pathways. Biol Chem 390: 965-976.
  • Papa S, Monti SM, Vitale RM, Bubici C, Jayawardena S, Alvarez K, De Smaele E, Dathan N, Pedone C, Ruvo M, Franzoso G (2007) Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase MKK7/JNKK2. J Biol Chem 282: 19029-19041.
  • Pavlovic D, Andersen NA, Mandrup-Poulsen T, Eizirik DL (2000) Activation of extracellular signal-regulated kinase (ERK)1/2 contributes to cytokine-induced apoptosis in purified rat pancreatic beta-cells. Eur Cytokine Netw 11: 267-274.
  • Saldeen J, Lee JC, Welsh N (2001) Role of p38 mitogen-activated protein kinase (p38 MAPK) in cytokine-induced rat islet cell apoptosis. Biochem Pharmacol 61: 1561-1569.
  • Satomi Y, Nishino H (2009) Implication of mitogen-activated protein kinase in the induction of G1 cell cycle arrest and gadd45 expression by the carotenoid fucoxanthin in human cancer cells. Biochim Biophys Acta 1790: 260-266.
  • Skalniak L, Mizgalska D, Zarebski A, Wyrzykowska P, Koj A, Jura J (2009) Regulatory feedback loop between NF-kappaB and MCP-1-induced protein 1 RNase. Febs J 276: 5892-5905.
  • Song L, Li J, Zhang D, Liu ZG, Ye J, Zhan Q, Shen HM, Whiteman M, Huang C (2006) IKKbeta programs to turn on the GADD45alpha-MKK4-JNK apoptotic cascade specifically via p50 NF-kappaB in arsenite response. J Cell Biol 175: 607-617.
  • Souza KL, Gurgul-Convey E, Elsner M, Lenzen S (2008) Interaction between pro-inflammatory and anti-inflammatory cytokines in insulin-producing cells. J Endocrinol 197: 139-150.
  • Takekawa M, Saito H (1998) A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95: 521-530.
  • Tornatore L, Marasco D, Dathan N, Vitale RM, Benedetti E, Papa S, Franzoso G, Ruvo M, Monti SM (2008) Gadd45 beta forms a homodimeric complex that binds tightly to MKK7. J Mol Biol 378: 97-111.
  • Vairapandi M, Balliet AG, Fornace AJ Jr, Hoffman B, Liebermann DA (1996) The differentiation primary response gene MyD118 related to GADD45 encodes for a nuclear protein which interacts with PCNA and p21WAF1/CIP1. Oncogene 12: 2579-2594.
  • Vairapandi M, Balliet AG, Hoffman B, Liebermann DA (2002) GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J Cell Physiol 192: 327-338.
  • Ximenes HM, Lortz S, Jorns A, Lenzen S (2007) Triiodothyronine (T3)-mediated toxicity and induction of apoptosis in insulin-producing INS-1 cells. Life Sci 80: 2045-2050.
  • Yang Z, Song L, Huang C (2009) Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Curr Cancer Drug Targets 9: 915-930.
  • Zerbini LF, Libermann TA (2005) Life and death in cancer. GADD45 alpha and gamma are critical regulators of NF-kappaB mediated escape from programmed cell death. Cell Cycle 4: 18-20.
  • Zerbini LF, Wang Y, Czibere A, Correa R G, Cho JY, Ijiri K, Wei W, Joseph M, Gu X, Grall F, Goldring MB, Zhou JR, Libermann TA (2004) NF-kappa B-mediated repression of growth arrest- and DNA-damage-inducible proteins 45alpha and gamma is essential for cancer cell survival. Proc Natl Acad Sci USA 101: 13618-13623.
  • Zhang Y, Bhatia D, Xia H, Castranova V, Shi X, Chen F (2006) Nucleolin links to arsenic-induced stabilization of GADD45alpha mRNA. Nucleic Acids Res 34: 485-495.
  • Zheng X, Zhang Y, Chen YQ, Castranova V, Shi X, Chen F (2005) Inhibition of NF-kappaB stabilizes gadd45alpha mRNA. Biochem Biophys Res Commun 329: 95-99.
  • Zheng Y, Vig M, Lyons J, Van Parijs L, Beg AA (2003) Combined deficiency of p50 and cRel in CD4+T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function. J Exp Med 197: 861-874.
  • Zhu N, Shao Y, Xu L, Yu L, Sun L (2009) Gadd45-alpha and Gadd45-gamma utilize p38 and JNK signaling pathways to induce cell cycle G2/M arrest in Hep-G2 hepatoma cells. Mol Biol Rep 36: 2075-2085.
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