PMID- 21233846
OWN - NLM
STAT- MEDLINE
DCOM- 20110822
LR  - 20211020
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 18
IP  - 6
DP  - 2011 Jun
TI  - Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF 
      expression in hypoxic tumor cells.
PG  - 1024-35
LID - 10.1038/cdd.2010.175 [doi]
AB  - 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-1alpha 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-1alpha protein 
      half-life impairing HIF-1alpha 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.
FAU - Trisciuoglio, D
AU  - Trisciuoglio D
AD  - Experimental Chemotherapy Laboratory, Experimental Oncology Department, Regina 
      Elena Cancer Institute, Rome, Italy.
FAU - Gabellini, C
AU  - Gabellini C
FAU - Desideri, M
AU  - Desideri M
FAU - Ragazzoni, Y
AU  - Ragazzoni Y
FAU - De Luca, T
AU  - De Luca T
FAU - Ziparo, E
AU  - Ziparo E
FAU - Del Bufalo, D
AU  - Del Bufalo D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110114
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - Cell Hypoxia/genetics
MH  - Cell Line, Tumor
MH  - Female
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Male
MH  - *Mutation
MH  - Neoplasms/genetics/*metabolism
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism
MH  - Transcription, Genetic/genetics
MH  - Ubiquitination/genetics
MH  - Vascular Endothelial Growth Factor A/*biosynthesis/genetics
PMC - PMC3131942
EDAT- 2011/01/15 06:00
MHDA- 2011/08/23 06:00
PMCR- 2012/06/01
CRDT- 2011/01/15 06:00
PHST- 2011/01/15 06:00 [entrez]
PHST- 2011/01/15 06:00 [pubmed]
PHST- 2011/08/23 06:00 [medline]
PHST- 2012/06/01 00:00 [pmc-release]
AID - cdd2010175 [pii]
AID - 10.1038/cdd.2010.175 [doi]
PST - ppublish
SO  - Cell Death Differ. 2011 Jun;18(6):1024-35. doi: 10.1038/cdd.2010.175. Epub 2011 
      Jan 14.