Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1)

A E Greijer, P van der Groep, D Kemming, A Shvarts, G L Semenza, G A Meijer, M A van de Wiel, J A M Belien, P J van Diest, E van der Wall

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The hypoxia-inducible factor 1 (HIF-1) plays a critical role in cellular responses to hypoxia. The aim of the present study was to evaluate which genes are induced by hypoxia, and whether this induction is mediated by HIF-1, by expression microarray analysis of wt and HIF-1alpha null mouse fibroblasts. Forty-five genes were up-regulated by hypoxia and 40 (89%) of these were regulated by HIF-1. Of the 114 genes down-regulated by hypoxia, 19 (17%) were HIF-1-dependent. All glycolytic enzymes were strongly up-regulated by hypoxia in a HIF-1-dependent manner. Genes already known to be related to hypoxia, such as glucose transporter 1, BNIP3, and hypoxia-induced gene 1, were induced. In addition, multiple new HIF-1-regulated genes were identified, including genes involved in metabolism (adenylate kinase 4, galactokinase), apoptosis (galectin-3 and gelsolin), and invasion (RhoA). Genes down-regulated by hypoxia were involved in cytoskeleton maintenance (Rho kinase), mRNA processing (heterogeneous nuclear ribonucleoprotein H1 and splicing factor), and DNA repair (REV3). Furthermore, seven cDNAs from genes with unknown function or expressed sequence tags (ESTs) were up-regulated and 27 such cDNAs were down-regulated. In conclusion, hypoxia causes down- rather than up-regulation of gene expression and HIF-1 seems to play a major role in the regulation of hypoxia-induced genes.

Original languageEnglish
Pages (from-to)291-304
Number of pages14
JournalJournal of Pathology
Volume206
Issue number3
DOIs
Publication statusPublished - Jul 2005

Cite this

Greijer, A. E., van der Groep, P., Kemming, D., Shvarts, A., Semenza, G. L., Meijer, G. A., ... van der Wall, E. (2005). Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). Journal of Pathology, 206(3), 291-304. https://doi.org/10.1002/path.1778
Greijer, A E ; van der Groep, P ; Kemming, D ; Shvarts, A ; Semenza, G L ; Meijer, G A ; van de Wiel, M A ; Belien, J A M ; van Diest, P J ; van der Wall, E. / Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). In: Journal of Pathology. 2005 ; Vol. 206, No. 3. pp. 291-304.
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abstract = "The hypoxia-inducible factor 1 (HIF-1) plays a critical role in cellular responses to hypoxia. The aim of the present study was to evaluate which genes are induced by hypoxia, and whether this induction is mediated by HIF-1, by expression microarray analysis of wt and HIF-1alpha null mouse fibroblasts. Forty-five genes were up-regulated by hypoxia and 40 (89{\%}) of these were regulated by HIF-1. Of the 114 genes down-regulated by hypoxia, 19 (17{\%}) were HIF-1-dependent. All glycolytic enzymes were strongly up-regulated by hypoxia in a HIF-1-dependent manner. Genes already known to be related to hypoxia, such as glucose transporter 1, BNIP3, and hypoxia-induced gene 1, were induced. In addition, multiple new HIF-1-regulated genes were identified, including genes involved in metabolism (adenylate kinase 4, galactokinase), apoptosis (galectin-3 and gelsolin), and invasion (RhoA). Genes down-regulated by hypoxia were involved in cytoskeleton maintenance (Rho kinase), mRNA processing (heterogeneous nuclear ribonucleoprotein H1 and splicing factor), and DNA repair (REV3). Furthermore, seven cDNAs from genes with unknown function or expressed sequence tags (ESTs) were up-regulated and 27 such cDNAs were down-regulated. In conclusion, hypoxia causes down- rather than up-regulation of gene expression and HIF-1 seems to play a major role in the regulation of hypoxia-induced genes.",
keywords = "Animals, Apoptosis, Cell Movement, Cytoskeleton, DNA Repair, DNA-Binding Proteins, DNA-Directed DNA Polymerase, Down-Regulation, Fibroblasts, Galactokinase, Galectin 3, Gelsolin, Gene Expression Profiling, Glucose Transporter Type 1, Glycolysis, Hypoxia, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Membrane Proteins, Mice, Monosaccharide Transport Proteins, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins, RNA, Messenger, Transcription Factors, Up-Regulation, rhoA GTP-Binding Protein, Journal Article, Research Support, Non-U.S. Gov't",
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Greijer, AE, van der Groep, P, Kemming, D, Shvarts, A, Semenza, GL, Meijer, GA, van de Wiel, MA, Belien, JAM, van Diest, PJ & van der Wall, E 2005, 'Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1)' Journal of Pathology, vol. 206, no. 3, pp. 291-304. https://doi.org/10.1002/path.1778

Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). / Greijer, A E; van der Groep, P; Kemming, D; Shvarts, A; Semenza, G L; Meijer, G A; van de Wiel, M A; Belien, J A M; van Diest, P J; van der Wall, E.

In: Journal of Pathology, Vol. 206, No. 3, 07.2005, p. 291-304.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1)

AU - Greijer, A E

AU - van der Groep, P

AU - Kemming, D

AU - Shvarts, A

AU - Semenza, G L

AU - Meijer, G A

AU - van de Wiel, M A

AU - Belien, J A M

AU - van Diest, P J

AU - van der Wall, E

N1 - Copyright 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PY - 2005/7

Y1 - 2005/7

N2 - The hypoxia-inducible factor 1 (HIF-1) plays a critical role in cellular responses to hypoxia. The aim of the present study was to evaluate which genes are induced by hypoxia, and whether this induction is mediated by HIF-1, by expression microarray analysis of wt and HIF-1alpha null mouse fibroblasts. Forty-five genes were up-regulated by hypoxia and 40 (89%) of these were regulated by HIF-1. Of the 114 genes down-regulated by hypoxia, 19 (17%) were HIF-1-dependent. All glycolytic enzymes were strongly up-regulated by hypoxia in a HIF-1-dependent manner. Genes already known to be related to hypoxia, such as glucose transporter 1, BNIP3, and hypoxia-induced gene 1, were induced. In addition, multiple new HIF-1-regulated genes were identified, including genes involved in metabolism (adenylate kinase 4, galactokinase), apoptosis (galectin-3 and gelsolin), and invasion (RhoA). Genes down-regulated by hypoxia were involved in cytoskeleton maintenance (Rho kinase), mRNA processing (heterogeneous nuclear ribonucleoprotein H1 and splicing factor), and DNA repair (REV3). Furthermore, seven cDNAs from genes with unknown function or expressed sequence tags (ESTs) were up-regulated and 27 such cDNAs were down-regulated. In conclusion, hypoxia causes down- rather than up-regulation of gene expression and HIF-1 seems to play a major role in the regulation of hypoxia-induced genes.

AB - The hypoxia-inducible factor 1 (HIF-1) plays a critical role in cellular responses to hypoxia. The aim of the present study was to evaluate which genes are induced by hypoxia, and whether this induction is mediated by HIF-1, by expression microarray analysis of wt and HIF-1alpha null mouse fibroblasts. Forty-five genes were up-regulated by hypoxia and 40 (89%) of these were regulated by HIF-1. Of the 114 genes down-regulated by hypoxia, 19 (17%) were HIF-1-dependent. All glycolytic enzymes were strongly up-regulated by hypoxia in a HIF-1-dependent manner. Genes already known to be related to hypoxia, such as glucose transporter 1, BNIP3, and hypoxia-induced gene 1, were induced. In addition, multiple new HIF-1-regulated genes were identified, including genes involved in metabolism (adenylate kinase 4, galactokinase), apoptosis (galectin-3 and gelsolin), and invasion (RhoA). Genes down-regulated by hypoxia were involved in cytoskeleton maintenance (Rho kinase), mRNA processing (heterogeneous nuclear ribonucleoprotein H1 and splicing factor), and DNA repair (REV3). Furthermore, seven cDNAs from genes with unknown function or expressed sequence tags (ESTs) were up-regulated and 27 such cDNAs were down-regulated. In conclusion, hypoxia causes down- rather than up-regulation of gene expression and HIF-1 seems to play a major role in the regulation of hypoxia-induced genes.

KW - Animals

KW - Apoptosis

KW - Cell Movement

KW - Cytoskeleton

KW - DNA Repair

KW - DNA-Binding Proteins

KW - DNA-Directed DNA Polymerase

KW - Down-Regulation

KW - Fibroblasts

KW - Galactokinase

KW - Galectin 3

KW - Gelsolin

KW - Gene Expression Profiling

KW - Glucose Transporter Type 1

KW - Glycolysis

KW - Hypoxia

KW - Hypoxia-Inducible Factor 1

KW - Hypoxia-Inducible Factor 1, alpha Subunit

KW - Membrane Proteins

KW - Mice

KW - Monosaccharide Transport Proteins

KW - Nuclear Proteins

KW - Oligonucleotide Array Sequence Analysis

KW - Proto-Oncogene Proteins

KW - RNA, Messenger

KW - Transcription Factors

KW - Up-Regulation

KW - rhoA GTP-Binding Protein

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/path.1778

DO - 10.1002/path.1778

M3 - Article

VL - 206

SP - 291

EP - 304

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 3

ER -

Greijer AE, van der Groep P, Kemming D, Shvarts A, Semenza GL, Meijer GA et al. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). Journal of Pathology. 2005 Jul;206(3):291-304. https://doi.org/10.1002/path.1778