The Sequential Activation and Repression of the Human PDGF-B Gene During Chronic Hypoxia Reveals Antagonistic Roles for the Depletion of Oxygen and Glucose

Abstract Hypoxia and glucose deprivation, are important during many physiological and pathological processes. Cells respond to these stimuli by activating genes involved in the regulation of metabolism and angiogenesis. Platelet derived growth factor-B (PDGF-B) is involved in the regulation of angiogenesis and tumour progression and is induced by hypoxia. Most known hypoxia-induced genes are activated by the hypoxia inducible factor (HIF-1), via its binding to specific response elements. The mechanism of hypoxic induction and the effect of low glucose on PDGF-B expression have not been characterised. We show that PDGF-B exhibits a novel, biphasic regulation (induction, followed by repression below basal levels) in bladder carcinoma cells cultured under chronic hypoxia. We show that the repression observed after long-term hypoxia is due to glucose-depletion and that this can also abrogate short-term hypoxic induction. This is in contrast to the previous results showing that hypoxiahypogly-caemia elicit the same response. We also show that a putative hypoxia response element in the PDGF-B promoter is not sufficient for hypoxic induction, although it does function as a hypoxia independent enhancer element in hepatocellular carcinoma cells.

[1]  H. Esumi,et al.  Identification of Hypoxia-inducible Factor 1 Ancillary Sequence and Its Function in Vascular Endothelial Growth Factor Gene Induction by Hypoxia and Nitric Oxide* , 2001, The Journal of Biological Chemistry.

[2]  M. Vasseur-Cognet,et al.  Glucose Regulation of Gene Transcription* , 2000, The Journal of Biological Chemistry.

[3]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[4]  J. M. Arbeit,et al.  Hypoxia-inducible Factor-1α Is a Positive Factor in Solid Tumor Growth , 2000 .

[5]  Y. Fujii‐Kuriyama,et al.  Repression of heme oxygenase-1 by hypoxia in vascular endothelial cells. , 2000, Biochemical and biophysical research communications.

[6]  L. Khachigian,et al.  Novel Negative Regulatory Element in the Platelet-derived Growth Factor B Chain Promoter That Mediates ERK-dependent Transcriptional Repression* , 2000, The Journal of Biological Chemistry.

[7]  E. Rofstad.  Microenvironment-induced cancer metastasis , 2000, International journal of radiation biology.

[8]  Y. M. Lee,et al.  Egr-1 mediates transcriptional activation of IGF-II gene in response to hypoxia. , 1999, Cancer research.

[9]  W. Qi,et al.  Intermittent high glucose enhances cell growth and collagen synthesis in cultured human tubulointerstitial cells , 1999, Diabetologia.

[10]  G. Semenza,et al.  Oncogenic alterations of metabolism. , 1999, Trends in biochemical sciences.

[11]  C. Heldin,et al.  Mechanism of action and in vivo role of platelet-derived growth factor. , 1999, Physiological reviews.

[12]  P. Carmeliet,et al.  Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis , 1998, Nature.

[13]  P. Ratcliffe,et al.  Selection and analysis of a mutant cell line defective in the hypoxia-inducible factor-1 alpha-subunit (HIF-1alpha). Characterization of hif-1alpha-dependent and -independent hypoxia-inducible gene expression. , 1998, The Journal of biological chemistry.

[14]  M. Muraguchi,et al.  Up‐regulation of vascular endothelial growth factor in response to glucose deprivation , 1998, Biology of the cell.

[15]  M. Gassmann,et al.  Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. , 1998, Genes & development.

[16]  K. Nakanishi,et al.  Expression of platelet-derived growth-factor B-chain mRNA and tumor angiogenesis in invasive transitional cell carcinoma of the upper urinary tract. , 1997, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[17]  David Baunoch,et al.  Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT , 1997, Nature.

[18]  G. Semenza,et al.  Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia* , 1997, The Journal of Biological Chemistry.

[19]  G. Semenza,et al.  Hypoxia Response Elements in the Aldolase A, Enolase 1, and Lactate Dehydrogenase A Gene Promoters Contain Essential Binding Sites for Hypoxia-inducible Factor 1* , 1996, The Journal of Biological Chemistry.

[20]  L. Gesualdo,et al.  High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a platelet-derived growth factor loop in human mesangial cells. , 1996, The American journal of pathology.

[21]  Y. Okuda,et al.  Increased production of PDGF by angiotensin and high glucose in human vascular endothelium. , 1996, Life sciences.

[22]  G. Semenza,et al.  Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1 , 1996, Molecular and cellular biology.

[23]  O. Hankinson,et al.  The Role of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in Hypoxic Induction of Gene Expression , 1996, The Journal of Biological Chemistry.

[24]  Amyj . Williams,et al.  Egr-1-Induced Endothelial Gene Expression: A Common Theme in Vascular Injury , 1996, Science.

[25]  M. Goldberg,et al.  Post-transcriptional Regulation of Vascular Endothelial Growth Factor by Hypoxia (*) , 1996, The Journal of Biological Chemistry.

[26]  S. Kourembanas,et al.  Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide. , 1995, The Journal of clinical investigation.

[27]  C. Heldin,et al.  Platelet‐derived growth factor in human glioma , 1995, Glia.

[28]  D. Faller,et al.  Hypoxia induces AP-1-regulated genes and AP-1 transcription factor binding in human endothelial and other cell types. , 1995, Biochimica et biophysica acta.

[29]  M. Neeman,et al.  Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes , 1995, Molecular and cellular biology.

[30]  M. Matsumoto,et al.  Hypoxia-mediated induction of acidic/basic fibroblast growth factor and platelet-derived growth factor in mononuclear phagocytes stimulates growth of hypoxic endothelial cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Neeman,et al.  Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Bonthron,et al.  Novel cis-acting elements in the human platelet-derived growth factor B-chain core promoter that mediate gene expression in cultured vascular endothelial cells. , 1994, The Journal of biological chemistry.

[33]  C. Heldin,et al.  Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[34]  G. Semenza,et al.  A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation , 1992, Molecular and cellular biology.

[35]  R. Ohlsson,et al.  Expression of the human PDGF‐B gene is regulated by both positively and negatively acting cell type‐specific regulatory elements located in the first intron. , 1991, The EMBO journal.

[36]  D. Faller,et al.  Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. , 1990, The Journal of clinical investigation.

[37]  L. Ratner.  Regulation of expression of the c-sis proto-oncogene. , 1989, Nucleic acids research.

[38]  R. Press,et al.  Expression and stability of c-sis mRNA in human glioblastoma cells. , 1988, Biochemistry.

[39]  C. Chang,et al.  Evidence of autocrine regulation in human hepatoma cell lines. , 1988, Biochemical and biophysical research communications.

[40]  K. Jungermann,et al.  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Induction of the Plasminogen Activator Inhibitor-1 Gene Expression by Mild Hypoxia Via a Hypoxia Response Element Binding the Hypoxia-Inducible Factor-1 in Rat Hepatocytes , 2016 .

[41]  J. M. Arbeit,et al.  Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. , 2000, Cancer research.

[42]  G. Semenza,et al.  Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. , 1999, Annual review of cell and developmental biology.

[43]  B. Ebert,et al.  Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. , 1995, The American journal of physiology.