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

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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, Ibrahim, Saleh M.·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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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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