Preferences help
enabled [disable] Abstract
Number of results
2010 | 57 | 2 | 179-183
Article title

Induction of CMV-1 promoter by 4-hydroxy-2-nonenal in human embryonic kidney cells

Title variants
Languages of publication
Oxidative stress, i.e., excessive production of oxygen free radicals and reactive oxygen species, leads to lipid peroxidation and to formation of reactive aldehydes which act as second messengers of free radicals. It has previously been shown that oxidative stress may be involved in the transcriptional regulation of cytomegalovirus (CMV) immediate early promoter, involved in viral reactivation from latency. In the current study we used a plasmid containing the yellow fluorescent protein (YFP) gene under the control of CMV-1 promoter to monitor the influence of hydrogen peroxide and reactive aldehydes, 4-hydroxy-2-nonenal (HNE) and acrolein, on CMV-1 promoter activation in human embryonic kidney cells (HEK293). While acrolein was ineffective, hydrogen peroxide slightly (50 %) stimulated the CMV promoter. In contrast, HNE had a strong, up to 3-fold, enhancing effect on the CMV-1 promoter within four as well as after 24h of treatment. The most effective was the treatment with 24 µM HNE. This effect of HNE suggests that stressful conditions associated with lipid peroxidation could lead to CMV activation.
Physical description
  • Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
  • Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
  • Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
  • Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
  • Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
  • Biomedica Medizinprodukte GmbH & Co KG, Wien, Austria
  • Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
  • Awasthi YC, Yang Y, Tiwari NK, Patrick B, Sharma A, Li J, Awasthi S (2004) Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases. Free Radic Biol Med 37: 607-619.
  • Bartosz G (2009) Reactive oxygen species: destroyers or messengers? Biochem Pharmacol 77: 1303-1315.
  • Borovic Sunjic S, Cipak A, Rabuzin F, Wildburger R, Zarkovic N (2005) The influence of 4-hydroxy-2-nonenal on proliferation, differentiation and apoptosis of human osteosarcoma cells. Biofactors 24: 141-148.
  • Borovic S, Rabuzin F, Waeg G, Zarkovic N (2006) Enzyme-linked immunosorbent assay for 4-hydroxynonenal-histidine conjugates. Free Radic Res 40: 809-820.
  • Braughler JM, Hall ED (1989) Central nervous system trauma and stroke. I. Biochemical considerations for oxygen radical formation and lipid peroxidation. Free Radic Biol Med 6: 289-301.
  • Camandola S, Scavazza A, Leonarduzzi G, Biasi F, Chiarpotto E, Azzi A, Poli G (1997) Biogenic 4-hydroxy-2-nonenal activates transcription factor AP-1 but not NF-kappa B in cells of the macrophage lineage. Biofactors 6: 173-179.
  • Camandola S, Poli G, Mattson MP (2000) The lipid peroxidation product 4-hydroxy-2,3-nonenal inhibits constitutive and inducible activity of nuclear factor kappa B in neurons. Brain Res Mol Brain Res 85: 53-60.
  • Cheng JZ, Sharma R, Yang Y, Singhal SS, Sharma A, Saini MK, Singh SV, Zimniak P, Awasthi S, Awasthi YC (2001) Accelerated metabolism and exclusion of 4-hydroxynonenal through induction of RLIP76 and hGST5.8 is an early adaptive response of cells to heat and oxidative stress. J Biol Chem 276: 41213-41223.
  • Cheng JZ, Singhal SS, Sharma A, Saini M, Yang Y, Awasthi S, Zimniak P, Awasthi YC (2001) Transfection of mGSTA4 in HL-60 cells protects against 4-hydroxynonenal-induced apoptosis by inhibiting JNK-mediated signaling. Arch Biochem Biophys 392: 197-207.
  • Cheng JZ, Singhal SS, Saini M, Singhal J, Piper JT, Van Kuijk FJ, Zimniak P, Awasthi YC, Awasthi S (1999) Effects of mGST A4 transfection on 4-hydroxynonenal-mediated apoptosis and differentiation of K562 human erythroleukemia cells. Arch Biochem Biophys 372: 29-36.
  • Cinatl Jr J, Vogel J-U, Kotchetkov R, Scholz M, Doerr HW (2000) Proinflammatory potential of cytomegalovirus infection. Specific inhibition of cytomegalovirus immediate-early expression in combination with antioxidants as a novel treatment strategy? Intervirology 42: 419-424.
  • Dhaunsi GS, Kaur J, Turner RB (2003) Role of NADPH oxidase in cytomegalovirus-induced proliferation of human coronary artery smooth muscle cells. J Biome Sci 10: 505-509.
  • Dianzani MU, Barrera G, Parola M (1999) 4-Hydroxy-2,3-nonenal as a signal for cell function and differentiation. Acta Biochim Pol 46: 61-75.
  • Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11: 81-128.
  • Flo TH, Ryan L, Latz E, Takeuchi O, Monks BG, Lien E, Halaas Ø, Akira S, Skjåk-Braek G, Golenbock DT, Espevik T (2002) Involvement of toll-like receptor (TLR) 2 and TLR4 in cell activation by mannuronic acid polymers. J Biol Chem 277: 35489-35495.
  • Gnana-Prakasam JP, Zhang M, Martin, PM, Atherton SS, Smith SB, Ganapathy V (2009) Expression of the iron-regulatory protein haemojuvelin in retina and its regulation during cytomegalovirus infection. Biochem J 419: 533-543.
  • Hall ED, Braughler JM (1989) Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radic Biol Med 6: 303-313.
  • Hartley DP, Ruth JA, Petersen DR (1995) The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase. Arch Biochem Biophys 316: 197-205.
  • Kim YS, Park ZY, Kim SY, Jeong E, Lee JY (2009) Alteration of Toll-like receptor 4 activation by 4-hydroxy-2-nonenal mediated by the suppression of receptor homodimerization. Chem Biol Interact 182: 59-66.
  • Kreuzer T, Grube R, Wutte A, Zarkovic N, Schaur RJ (1998) 4-Hydroxynonenal modifies the effects of serum growth factors on the expression of the c-fos proto-oncogene and the proliferation of HeLa carcinoma cells. Free Radic Biol Med 25: 42-49.
  • Kruman I, Bruce-Keller AJ, Bredesen D, Waeg G, Mattson MP (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J Neurosci 17: 5089-5100.
  • Lee SJ, Seo KW, Yun MR, Bae SS, Lee WS, Hong KW, Kim CD (2008) 4-Hydroxynonenal enhances MMP-2 production in vascular smooth muscle cells via mitochondrial ROS-mediated activation of the Akt/NF-κB signaling pathways. Free Radic Biol Med 45: 1487-1492.
  • Leonarduzzi G, Robbesyn F, Poli G (2004) Signaling kinases modulated by 4-hydroxynonenal. Free Radic Biol Med 37: 1694-1702.
  • Liu R-M, Borok Z, Forman HJ (2001) 4-Hydroxy-2-nonenal increases gamma-glutamylcysteine synthetase gene expression in alveolar epithelial cells. Am J Respir Cell Mol Biol 24: 499-505.
  • Mocarski ES (1996) Cytomegaloviruses and their replication. In: Fields virology. Fields BN, Knipe DM, Howley PM, Chanock RM, Melnick JL, Monath TP, Roizman B, Straus SE, eds, pp 2447-2492, Lippincott-Raven, Philadelphia.
  • Numazaki K, Asanuma H, Chiba S (1995) Latent infection and reactivation of human cytomegalovirus. Serodiag Immun Inf D 7: 70-74.
  • Page S, Fischer C, Baumgartner B, Haas M, Kreusel U, Loidl G, Hayn M, Ziegler-Heitbrock HW, Neumeier D, Brand K (1999) 4-Hydroxynonenal prevents NF-κB activation and tumor necrosis factor expression by inhibiting IκB phosphorylation and subsequent proteolysis. J Biol Chem 274: 11611-11618.
  • Paradisi L, Panagini C, Parola M, Barrera G, Dianzani MU (1985) Effects of 4-hydroxynonenal on adenylate cyclase and 5'-nucleotidase activities in rat liver plasma membranes. Chem Biol Interact 53: 209-217.
  • Parola M, Robino G, Marra F, Pinzani M, Bellomo G, Leonarduzzi G, Chiarugi P, Camandola S, Poli G, Waeg G, Gentilini P, Dianzani MU (1998) HNE interacts directly with JNK isoforms in human hepatic stellate cells. J Clin Invest 102: 1942-1950.
  • Rinaldi M, Barrera G, Aquino A, Spinsanti P, Pizzimenti S, Farace MG, Dianzani MU, Fazio VM (2000) 4-Hydroxynonenal-induced MEL cell differentiation involves PKC activity translocation. Biochem Biophys Res Commun 272: 75-80.
  • Ruef J, Rao GN, Li F, Bode C, Patterson C, Bhatnagar A, Runge MS (1998) Induction of rat aortic smooth muscle cell growth by the lipid peroxidation product 4-hydroxy-2-nonenal. Circulation 97: 1071-1078.
  • Ruef J, Moser M, Bode C, Kübler W, Runge MS (2001) 4-hydroxynonenal induces apoptosis, NF-κB-activation and formation of 8-isoprostane in vascular smooth muscle cells. Basic Res Cardiol 96: 143-150.
  • Scholz M, Cinatl J, Gross V, Vogel JU, Blaheta RA, Freisleben HJ, Markus BH, Doerr HW (1996) Impact of oxidative stress on human cytomegalovirus replication and on cytokine-mediated stimulation of endothelial cells. Transplantation 61: 1763-1770.
  • Scholz M, Doerr HW, Cinatl J (2001) Inhibition of cytomegalovirus immediate early gene expression: a therapeutic option? Antiviral Res 49: 129-145.
  • Soh Y, Jeong KS, Lee IJ, Bae MA, Kim YC, Song BJ (2000) Selective activation of the c-Jun N-terminal protein kinase pathway during 4-hydroxynonenal-induced apoptosis of PC12 cells. Mol Pharmacol 58: 535-541.
  • Sovic A, Borovic S, Loncaric I, Kreuzer T, Zarkovic K, Vukovic T, Wäg G, Hrascan R, Wintersteiger R, Klinger R, Zurak N, Schaur RJ, Zarkovic N (2001) The carcinostatic and proapoptotic potential of 4-hydroxynonenal in HeLa cells is associated with its conjugation to cellular proteins. Anticancer Res 21: 1997-2004.
  • Speir E (2000) Cytomegalovirus gene regulation by reactive oxygen species. Agents in atherosclerosis. Ann N Y Acad Sci 899: 363-374.
  • Uchida K (2003) 4-Hydroxy-2-nonenal: a product and mediator of oxidative stress. Prog Lipid Res 42: 318-343.
  • Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y, Osawa T (1999) Activation of stress signaling pathways by the end product of lipid peroxidation. 4-Hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem 274: 2234-2242.
  • Vaillancourt F, Morquette B, Shi Q, Fahmi H, Lavigne P, Di Battista JA, Fernandes JC, Benderdour M (2007) Differential regulation of cyclooxygenase-2 and inducible nitric oxide synthase by 4-hydroxynonenal in human osteoarthritic chondrocytes through ATF-2/CREB-1 transactivation and concomitant inhibition of NF-kappaB signaling cascade. J Cell Biochem 100: 1217-1231.
  • Vereecque R, Saudemont A, Depil, S, Quesnel B (2003) Chemotherapy increases transgene expression in leukemic cells. J Gene Med 5: 852-859.
  • Zarkovic N (2003) 4-Hydroxynonenal as a bioactive marker of pathophysiological processes. Mol Aspects Med 24: 281-291.
  • Zarkovic K (2003) 4-hydroxynonenal and neurodegenerative diseases. Mol Aspects Med 24: 293-303.
  • Zarkovic N, Ilic Z, Jurin M, Schaur RJ, Puhl H, Esterbauer H (1993) Stimulation of HeLa cell growth by physiological concentrations of 4-hydroxynonenal. Cell Biochem Funct 11: 279-286.
  • Zarkovic N, Schaur RJ, Puhl H, Jurin M, Es­terbauer H (1994) Mutual dependence of growth modifying effects of 4-hydroxy-nonenal and fetal calf serum in vitro. Free Radic Biol Med 16: 877-884.
  • Zarkovic N, Tillian MH, Schaur RJ, Waeg G, Jurin M, Esterbauer H (1995) Inhibition of melanoma B16-T10 growth by lipid peroxidation product 4-hydroxynonenal, Cancer Biother 10: 153-156.
  • Zarkovic N, Zarkovic K, Schaur RJ, Stolc S, Schlag G, Redl H, Waeg G, Borovic S, Loncaric I, Juric G, Hlavka V (1999) 4-Hydroxynonenal as a second messenger of free radicals and growth modifying factor. Life Sci 65: 1901-1904.
  • Zivkovic M, Zarkovic K, Skrinjar Lj, Waeg G, Poljak-Blazi M, Borovic S, Schaur RJ, Zarkovic N (2005) A new method for detection of HNE-histidine conjugates in rat inflammatory cells. Croat Chem Acta 78: 91-98.
  • Zhang B, Liu Y, Harbrecht BG (2003) Cyclic AMP regulate adenovirus mediated inducible nitric oxide synthase expression and CMV promoter activity in cultured hepatocytes. Nitric Oxide 8: 262-265.
  • Zollner H, Schaur RJ, Esterbauer H (1991) Biological activities of 4-hydroxyalkenals In: Oxidative stress: oxidants and antioxidants, H. Sies, ed, pp 319-336, Academic Press, London.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.