Transcriptional regulation of gene expression by hypoxia is an important, but yet only marginally characterized mechanism by which organisms adapt to low oxygen concentrations. The human hepatoma cell line HepG2 is a widely used model for studying hypoxic induction of the hematopoietic growth factor erythropoietin. In an attempt to identify additional genes expressed in HepG2 cells during hypoxia, we differentially screened a cDNA library derived from hypoxic (1% O) HepG2 cells using probes isolated from either normoxic (21% O) or hypoxic cells. Two genes were identified, one encoding aldolase, a member of the glycolytic enzymes, and the other encoding -antitrypsin which belongs to the family of the acute phase (AP) responsive proteins. Whereas hypoxic induction of glycolytic enzymes is well established, oxygen-dependent regulation of AP genes has not been reported so far. AP proteins are liver-derived plasma proteins whose production during inflammation is either up-regulated (positive AP reactants) or down-regulated (negative AP reactants). In the present study, we demonstrate that on the mRNA level hypoxic stimulation of HepG2 cells led to (i) an induction of the positive AP reactants -antitrypsin, -antichymotrypsin, complement C3, haptoglobin, and -acid glycoprotein; (ii) a down-regulation of the negative AP reactant albumin; (iii) an up-regulation of the negative AP reactant transferrin; and (iv) unchanged levels of the positive AP reactants - and -fibrinogen as well as hemopexin. Cycloheximide inhibited hypoxic up-regulation of AP mRNAs demonstrating that de novo protein synthesis is required for hypoxic induction. Nuclear run-on assays indicate that the hypoxic increase in AP mRNAs is mainly due to transcriptional regulation. The hypoxic response was compared to AP stimulation by interleukin 6. The results suggest that the adaptive response to hypoxia overlaps with, but is not identical with, the AP response mediated by interleukin 6.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				P. K. Wright and C. Raine Molecular Heterogeneity in Acute Renal Allograft Rejection and DNA Microarrays N. Engl. J. Med., December 4, 2003; 349(23): 2269 - 2269. [Full Text] [PDF]

				M. Kunz, S. Moeller, D. Koczan, P. Lorenz, R. H. Wenger, M. O. Glocker, H.-J. Thiesen, G. Gross, and S. M. Ibrahim Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells J. Biol. Chem., November 14, 2003; 278(46): 45651 - 45660. [Abstract] [Full Text] [PDF]

				A. Svatikova, R. Wolk, A. S. Shamsuzzaman, T. Kara, E. J. Olson, and V. K. Somers Serum Amyloid A in Obstructive Sleep Apnea Circulation, September 23, 2003; 108(12): 1451 - 1454. [Abstract] [Full Text] [PDF]

				H. J. Schoch, S. Fischer, and H. H. Marti Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain Brain, November 1, 2002; 125(11): 2549 - 2557. [Abstract] [Full Text] [PDF]

				M. Ellis, N. Davis, A. Coop, M. Liu, L. Schumaker, R. Y. Lee, R. Srikanchana, C. G. Russell, B. Singh, W. R. Miller, et al. Development and Validation of a Method for Using Breast Core Needle Biopsies for Gene Expression Microarray Analyses Clin. Cancer Res., May 1, 2002; 8(5): 1155 - 1166. [Abstract] [Full Text] [PDF]

				R. S. Thomas, D. R. Rank, S. G. Penn, G. M. Zastrow, K. R. Hayes, K. Pande, E. Glover, T. Silander, M. W. Craven, J. K. Reddy, et al. Identification of toxicologically predictive gene sets using cDNA microarrays Mol. Pharmacol., December 1, 2001; 60(6): 1189 - 1194. [Abstract] [Full Text] [PDF]

				D. M. STROKA, T. BURKHARDT, I. DESBAILLETS, R. H. WENGER, D. A. H. NEIL, C. BAUER, M. GASSMANN, and D. CANDINAS HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia FASEB J, November 1, 2001; 15(13): 2445 - 2453. [Abstract] [Full Text] [PDF]

				M. Piva, G. M. Horowitz, and K. L. Sharpe-Timms Interleukin-6 Differentially Stimulates Haptoglobin Production by Peritoneal and Endometriotic Cells in Vitro: A Model for Endometrial-Peritoneal Interaction in Endometriosis J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2553 - 2561. [Abstract] [Full Text] [PDF]

				J. J. E. Haddad, B. Safieh-Garabedian, N. E. Saadé, and S. C. Land Thiol Regulation of Pro-Inflammatory Cytokines Reveals a Novel Immunopharmacological Potential of Glutathione in the Alveolar Epithelium J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 996 - 1005. [Abstract] [Full Text]

				M. H. Ali, S. A. Schlidt, N. S. Chandel, K. L. Hynes, P. T. Schumacker, and B. L. Gewertz Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction Am J Physiol Lung Cell Mol Physiol, November 1, 1999; 277(5): L1057 - L1065. [Abstract] [Full Text] [PDF]

				T. Hellwig-Burgel, K. Rutkowski, E. Metzen, J. Fandrey, and W. Jelkmann Interleukin-1beta and Tumor Necrosis Factor-alpha Stimulate DNA Binding of Hypoxia-Inducible Factor-1 Blood, September 1, 1999; 94(5): 1561 - 1567. [Abstract] [Full Text] [PDF]

				S. BICHET, R. H. WENGER, G. CAMENISCH, A. ROLFS, W. EHLEBEN, T. PORWOL, H. ACKER, J. FANDREY, C. BAUER, and M. GASSMANN Oxygen tension modulates ß-globin switching in embryoid bodies FASEB J, February 1, 1999; 13(2): 285 - 295. [Abstract] [Full Text]

				U. E. Knies, H. A. Behrensdorf, C. A. Mitchell, U. Deutsch, W. Risau, H. C. A. Drexler, and M. Clauss Regulation of endothelial monocyte-activating polypeptide II release by apoptosis PNAS, October 13, 1998; 95(21): 12322 - 12327. [Abstract] [Full Text] [PDF]

				A. Rolfs, I. Kvietikova, M. Gassmann, and R. H. Wenger Oxygen-regulated Transferrin Expression Is Mediated by Hypoxia-inducible Factor-1 J. Biol. Chem., August 8, 1997; 272(32): 20055 - 20062. [Abstract] [Full Text] [PDF]

				E. C. McGary, I. J. Rondon, and B. S. Beckman Post-transcriptional Regulation of Erythropoietin mRNA Stability by Erythropoietin mRNA-binding Protein J. Biol. Chem., March 28, 1997; 272(13): 8628 - 8634. [Abstract] [Full Text] [PDF]

				A. Behrooz and F. Ismail-Beigi Dual Control of glut1 Glucose Transporter Gene Expression by Hypoxia and by Inhibition of Oxidative Phosphorylation J. Biol. Chem., February 28, 1997; 272(9): 5555 - 5562. [Abstract] [Full Text] [PDF]

				H. Li, H. P. Ko, and J. P. Whitlock Jr. Induction of Phosphoglycerate Kinase 1Gene Expression by Hypoxia. ROLES OF ARNT AND HIF1alpha J. Biol. Chem., August 30, 1996; 271(35): 21262 - 21267. [Abstract] [Full Text] [PDF]

				C. K. Mukhopadhyay, B. Mazumder, and P. L. Fox Role of Hypoxia-inducible Factor-1 in Transcriptional Activation of Ceruloplasmin by Iron Deficiency J. Biol. Chem., July 7, 2000; 275(28): 21048 - 21054. [Abstract] [Full Text] [PDF]