The cyclic AMP response element in the Bcl-2 promoter confers inducibility by hypoxia in neuronal cells.
In neuronal cells, expression of the anti-apoptotic Bcl-2 gene is induced by hypoxia and produces a protective effect. We show here that this effect is dependent upon the cyclic AMP response element (CRE) in the Bcl-2 promoter since mutation of this element abolishes the response and the isolated CRE can confer the response on a heterologous promoter. Interestingly however, the CRE in the Bcl-2 promoter does not render the promoter responsive to cyclic AMP and is not essential for its response to nerve growth factor. Despite the lack of cyclic AMP responsiveness, activation of the Bcl-2 promoter via the CRE in response to hypoxia requires the CREB transcription factor and is associated with the enhanced phosphorylation of CREB on serine 133 and enhanced transcriptional activation by the CREB-binding protein, CBP, in response to hypoxia. This finding establishes the importance of the CRE in the induction of Bcl-2 gene expression by hypoxia, allowing the Bcl-2 protein to protect neuronal cells against this damaging stimulus.
Freeland
K
K
Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Boxer
L M
LM
Latchman
D S
DS
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001665:Binding Sites; D003994:Bucladesine / Q000494:pharmacology; D050882:CREB-Binding Protein; D015687:Cell Hypoxia / Q000235:genetics*; D000242:Cyclic AMP / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D004268:DNA-Binding Proteins; D005656:Fungal Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D017930:Genes, Reporter; D019254:Genes, bcl-2; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020932:Nerve Growth Factor / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D018384:Oxidative Stress; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D029701:Saccharomyces cerevisiae Proteins; D015290:Second Messenger Systems / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D003994:Bucladesine; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D008156:Luciferases; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D011493:Protein Kinase C