Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells

Kunz, Manfred; Moeller, Steffen; Koczan, Dirk; Lorenz, Peter; Wenger, Roland H.; Glocker, Michael O.; Thiesen, Hans-Juergen; Gross, Gerd; Ibrahim, Saleh M.

doi:10.1074/jbc.m301373200

Cited by 104Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerConnective Tissue Growth Factor Research

Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells

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Kunz, Manfred, Moeller, Steffen, Koczan, Dirk, Lorenz, Peter, Wenger, Roland H., Glocker, Michael O., Thiesen, Hans-Juergen, Gross, Gerd +1 more·2003·Journal of Biological Chemistry

DOI 10.1074/jbc.m301373200

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Abstract

Hypoxia has a profound influence on progression and metastasis of malignant tumors. In the present report, we used the oligonucleotide microarray technique to identify new hypoxia-inducible genes in malignant melanoma with a special emphasis on angiogenesis factors. A commercially available Affymetrix gene chip system was used to analyze five melanoma cell lines of different aggressiveness. A total of 160 hypoxia-inducible genes were identified, clustering in four different functional clusters. In search of putative angiogenesis and tumor progression factors within these clusters, Cyr61, a recently discovered angiogenesis factor, was identified. Cyr61 was hypoxia-inducible in low aggressive melanoma cells; however, it showed constitutive high expression in highly aggressive melanoma cells. Further analyses of transcriptional mechanisms underlying Cyr61 gene expression under hypoxia demonstrated that an AP-1 binding motif within the Cyr61 promoter plays a central role in the hypoxic regulation of Cyr61. It could be shown by use of in vitro luciferase assays, electrophoretic mobility shift assays, and immunoprecipitation that hypoxia-inducible factor-1alpha interacts with c-Jun/AP-1 and may thereby contribute to Cyr61 transcriptional regulation under hypoxia. Taken together, the presented data show that Cyr61 is a hypoxia-inducible angiogenesis factor in malignant melanoma with tumor stage-dependent expression. This may argue for a hypoxia-induced selection process during tumor progression toward melanoma cells with constitutive high Cyr61 expression.

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CCN1 is highly induced under hypoxia through both HIF-1α-dependent and -independent mechanisms.
“Consistent with its angiogenic functions, CCN1 is highly induced under conditions of hypoxia, mediated through both hypoxia-inducible factor-1α (HIF-1α)-dependent and -independent mechanisms [25,43,44].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [25]

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Ultraviolet Irradiation Induces CYR61/CCN1, a Mediator of Collagen Homeostasis, through Activation of Transcription Factor AP-1 in Human Skin Fibroblasts
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Silencing cAMP-response Element-binding Protein (CREB) Identifies CYR61 as a Tumor Suppressor Gene in Melanoma
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Alternative Splicing of Cyr61 Is Regulated by Hypoxia and Significantly Changed in Breast Cancer
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Ariadne's ChemEffect and Pathway Studio knowledge base
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Oxidant Exposure Induces Cysteine-Rich Protein 61 (CCN1) via c-Jun/AP-1 to Reduce Collagen Expression in Human Dermal Fibroblasts
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CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity
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Do Genomic Factors Play a Role in Diabetic Retinopathy?
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Connective Tissue Growth Factor Regulates Retinal Neovascularization through p53 Protein-dependent Transactivation of the Matrix Metalloproteinase (MMP)-2 Gene
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Functional domains of CCN1 (Cyr61) regulate breast cancer progression
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The functional −443T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c‐Myb transcription factor
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Gene Expression Profile of B16(F10) Murine Melanoma Cells Exposed to Hypoxic Conditions In Vitro
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DNA microarray technology and its applications in dermatology
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Cyr61, a Matricellular Protein, Is Needed for Dendritic Arborization of Hippocampal Neurons
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CCN1 promotes the differentiation of endothelial progenitor cells and reendothelialization in the early phase after vascular injury
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Regulation of Cyr61/CCN1 expression by hypoxia through cooperation of c-Jun/AP-1 and HIF-1α in retinal vascular endothelial cells
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Premenstrual Regulation of the Pro-Angiogenic Factor CYR61 in Human Endometrium
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Cysteine-rich 61, a Member of the CCN Family, as a Factor Involved in the Pathogenesis of Proliferative Diabetic Retinopathy
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A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells
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Proteolysis of CCN1 by Plasmin: Functional Implications
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The matrix protein CCN1 (CYR61) promotes proliferation, migration and tube formation of endothelial progenitor cells
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Matrix reloaded: CCN, tenascin and SIBLING group of matricellular proteins in orchestrating cancer hallmark capabilities
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Loss of dual‐specificity phosphatase‐2 promotes angiogenesis and metastasis via up‐regulation of interleukin‐8 in colon cancer
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Genetic Factors Conferring Metastasis In Osteosarcoma
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Long noncoding RNA CPS1‐IT1 suppresses melanoma cell metastasis through inhibiting Cyr61 via competitively binding to BRG1
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Cancer-associated Fibroblast–specific Expression of the Matricellular Protein CCN1 Coordinates Neovascularization and Stroma Deposition in Melanoma Metastasis
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Diabetes Promotes Retinal Vascular Endothelial Cell Injury by Inducing CCN1 Expression
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Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma
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Gα 12/13 Induction of CYR61 in Association With Arteriosclerotic Intimal Hyperplasia: Effect of Sphingosine-1-Phosphate
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CCN family member 1 (CCN1) is an early marker of infarct size and left ventricular dysfunction in STEMI patients
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A multiple time-scale computational model of a tumor and its micro environment
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Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5‐fluorouracil‐based drugs
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Candidate genes responsible for early key events of phenobarbital-promoted mouse hepatocellular tumorigenesis based on differentiation of regulating genes between wild type mice and humanized chimeric mice
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Combined Treatment with Troglitazone and Lovastatin Inhibited Epidermal Growth Factor-Induced Migration through the Downregulation of Cysteine-Rich Protein 61 in Human Anaplastic Thyroid Cancer Cells
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Genetic Screening of New Genes Responsible for Cellular Adaptation to Hypoxia Using a Genome-Wide shRNA Library
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Cysteine-Rich Angiogenic Inducer 61: Pro-Survival Function and Role as a Biomarker for Disseminating Breast Cancer Cells
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CYR61 suppresses growth of human malignant melanoma
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G-quadruplexes Stabilization Upregulates CCN1 and Accelerates Aging in Cultured Cerebral Endothelial Cells
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Expression profile of malignant and non-malignant diseases of the thyroid gland reveals altered expression of a common set of genes in goiter and papillary carcinomas
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DNA Microarray Technology in Dermatology
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Analysis of Hypoxiamir-Gene Regulatory Network Identifies Critical MiRNAs Influencing Cell-Cycle Regulation Under Hypoxic Conditions
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The 5′ untranslated regions (UTRs) of CCN1, CCN2, and CCN4 exhibit cryptic promoter activity
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Mechanistic Analysis of an Extracellular Signal–Regulated Kinase 2–Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress
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Transcriptional and post-transcriptional regulation of CCN genes in failing heart
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A comprehensive assessment of networks and pathways of hypoxia-associated proteins and identification of responsive protein modules
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Expression and significance of Cyr61 in distant metastasis cells of human primary salivary adenoid cystic carcinoma
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Prognostic Value of Cysteine-Rich Protein 61 Combined with N-Terminal Pro-B-Type Natriuretic Peptide for Mortality in Acute Heart Failure Patients with and without Chronic Kidney Disease
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Comparative Gene Expression Analysis of Somatic Cell Nuclear Transfer-Derived Cloned Pigs with Normal and Abnormal Umbilical Cords1
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CCN1 : A Dermo‐Epidermal Crosstalk Mediator and Regulatory Protein in Cutaneous Homeostasis
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Forkhead box K1 facilitates growth of papillary thyroid carcinoma cells by regulating connective tissue growth factor expression
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CYR61 Is Overexpressed in Human Melanoma Tissue Ex Vivo and Promotes Melanoma Cell Survival and Proliferation Through Its Binding Ligand Integrin β3 In Vitro
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Resistance to antiangiogenic treatments: A review
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REGULATION OF CCN PROTEINS BY ALTERATIONS OF THE CYTOSKELETON
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Authors: Kunz, M., Moeller, S., Koczan, D., Lorenz, P., Wenger, R. H., Glocker, M. O., Thiesen, H.-J., Gross, G., & Ibrahim, S. M.
Affiliations: University of Rostock (DE)
Leipzig University (DE)
Corresponding author: Kunz, Manfred
ORCID: Kunz, Manfred
Koczan, Dirk
Lorenz, Peter
Wenger, Roland H.
Glocker, Michael O.
Ibrahim, Saleh M.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2003-11
Volume: 278
Issue: 46
Pages: 45651-45660
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m301373200
OpenAlex: W1988530720
Cited by: 104
References: 67
Citations by year: 2026: 2 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 6 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 4
FWCI: 3.23
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6175 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
Zurich Open Repository and Archive (University of Zurich)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
Keywords: CYR61, hypoxia, melanoma, angiogenesis, hypoxia-responsive genes, hypoxia-inducible factor-1α, AP-1, c-Jun, transcriptional regulation, tumor progression, tumor aggressiveness, tumor stage
MeSH terms: Hypoxia, Humans, Luciferases, Melanoma, Plasmids, Promoter Regions, Genetic, Protein Binding, RNA, Time Factors, Transcription Factors, Blotting, Northern, Gene Expression Regulation, Neoplastic, Mutagenesis, Protein Structure, Tertiary, Immediate-Early Proteins, DNA, Complementary, Jurkat Cells, Oligonucleotide Array Sequence Analysis, Amino Acid Motifs, Intercellular Signaling Peptides and Proteins, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit, Cysteine-Rich Protein 61

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Mechanisms of Hypoxic Gene Regulation of Angiogenesis Factor Cyr61 in Melanoma Cells

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