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Bcl‐2 overexpression in human melanoma cells increases angiogenesis through VEGF mRNA stabilization and HIF‐1mediated transcriptional activity
Author(s) -
Iervolino Angela,
Trisciuoglio Daniela,
Ribatti Domenico,
Candiloro Antonio,
Biroccio Annamaria,
Zupi Gabriella,
Del Bufalo Donatella
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0122fje
Subject(s) - angiogenesis , vascular endothelial growth factor , messenger rna , hypoxia (environmental) , transcription factor , cancer research , cell culture , melanoma , microbiology and biotechnology , hif1a , transcription (linguistics) , in vivo , hypoxia inducible factors , chemistry , biology , vascular endothelial growth factor a , vegf receptors , gene , biochemistry , genetics , organic chemistry , oxygen , linguistics , philosophy
The aim of this paper was to study the molecular mechanisms by which bcl‐2 increases hypoxiainduced vascular endothelial growth factor (VEGF) expression. We demonstrated that bcl‐2 overexpression in M14 human melanoma cell line enhances hypoxia‐induced VEGF mRNA stability and promoter activation. In particular, the half‐life of the message was longer in bcl‐2 transfectants (approximately 330 min) than in control cells (approximately 180 min). In addition, bcl‐2 overexpression increased VEGF promoter activity through the hypoxia‐inducible factor‐1 (HIF‐1) transcription factor. Increased HIF‐1α protein expression and DNA binding activity were detected in bcl‐2 overexpressing cells compared with control cells. An enhanced functional activity of secreted VEGF was found both in in vitro and in vivo angiogenic assays, and the use of VEGF specific antibodies validated the role of VEGF on bcl‐2‐induced angiogenesis. Taken together our results indicate that bcl‐2 plays an important role in melanoma angiogenesis, and that VEGF mRNA stabilization and HIF‐1‐mediated transcriptional activity are two important control points in bcl‐2/hypoxia‐induced VEGF expression.