Activation of cAMP and mitogen responsive genes relies on a common nuclear factor.
A number of signalling pathways stimulate transcription of target genes through nuclear factors whose activities are primarily regulated by phosphorylation. Cyclic AMP regulates the expression of numerous genes, for example, through the protein kinase-A (PKA)-mediated phosphorylation of transcription factor CREB at Ser 133. Although phosphorylation may stimulate transcriptional activators by modulating their nuclear transport or DNA-binding affinity, CREB belongs to a class of proteins whose phosphorylation appears specifically to enhance their trans-activation potential. Recent work describing a phospho-CREB binding protein (CBP) which interacts specifically with the CREB trans-activation domain prompted us to examine whether CBP is necessary for cAMP regulated transcription. We report here that microinjection of an anti-CBP antiserum into fibroblasts can inhibit transcription from a cAMP responsive promoter. Surprisingly, CBP also cooperates with upstream activators such as c-Jun, which are involved in mitogen responsive transcription. We propose that CBP is recruited to the promoter through interaction with certain phosphorylated factors, and that CBP may thus play a critical role in the transmission of inductive signals from cell surface receptor to the transcriptional apparatus.
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037.
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D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D050882:CREB-Binding Protein; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008934:Mitogens / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D011817:Rabbits; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D008934:Mitogens; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D014157:Transcription Factors; D012694:Serine; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse