title: Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells.
abstract: In addition to act as an antiapoptotic protein, B-cell lymphoma (bcl)-2 can also promote tumor angiogenesis. In this context, we have previously demonstrated that under hypoxia bcl-2 promotes hypoxia-inducible factor-1 (HIF-1)-mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. Here, we report on the role of the BH4 domain in bcl-2 functions, by showing that removal of or mutations at the BH4 domain abrogate the ability of bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells. We have also extended this observation to other human tumor histotypes, such as colon, ovarian and lung carcinomas. The involvement of BH4 on HIF-1α protein expression, stability, ubiquitination and HIF-1 transcriptional activity was also demonstrated in melanoma experimental model. Moreover, we validated the role of the BH4 domain of bcl-2 in the regulation of HIF-1/VEGF axis, demonstrating that BH4 peptide is sufficient to increase HIF-1α protein half-life impairing HIF-1α protein ubiquitination, and to enhance VEGF secretion in melanoma cells exposed to hypoxia. Finally, we found that the mechanism by which bcl-2 regulates HIF-1-mediated VEGF expression does not require BH1 and BH2 domains, and it is independent of antiapoptotic and prosurvival function of bcl-2.
authors.affiliation: Experimental Chemotherapy Laboratory, Experimental Oncology Department, Regina Elena Cancer Institute, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Trisciuoglio
authors.forename: C
authors.initials: C
authors.lastname: Gabellini
authors.forename: M
authors.initials: M
authors.lastname: Desideri
authors.forename: Y
authors.initials: Y
authors.lastname: Ragazzoni
authors.forename: T
authors.initials: T
authors.lastname: De Luca
authors.forename: E
authors.initials: E
authors.lastname: Ziparo
authors.forename: D
authors.initials: D
authors.lastname: Del Bufalo
mesh_terms: D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D054875:Ubiquitination / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A