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CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals
1Department of Neurology, Children's Hospital, Boston, Massachusetts, USA.
Abstract:
Extracellular stimuli elicit changes in gene expression in target cells by activating intracellular protein kinase cascades that phosphorylate transcription factors within the nucleus. One of the best characterized stimulus-induced transcription factors, cyclic AMP response element (CRE)-binding protein (CREB), activates transcription of target genes in response to a diverse array of stimuli, including peptide hormones, growth factors, and neuronal activity, that activate a variety of protein kinases including protein kinase A (PKA), pp90 ribosomal S6 kinase (pp90RSK), and Ca2+/calmodulin-dependent protein kinases (CaMKs)[corrected]. These kinases all phosphorylate CREB at a particular residue, serine 133 (Ser133), and phosphorylation of Ser133 is required for CREB-mediated transcription. Despite this common feature, the mechanism by which CREB activates transcription varies depending on the stimulus. In some cases, signaling pathways target additional sites on CREB or proteins associated with CREB, permitting CREB to regulate distinct programs of gene expression under different conditions of stimulation. This review discusses the molecular mechanisms by which Ser133-phosphorylated CREB activates transcription, intracellular signaling pathways that lead to phosphorylation of CREB at Ser133, and features of each signaling pathway that impart specificity at the level of CREB activation.
Insights
Cyclic AMP response element (CRE)-binding protein (CREB) activates gene transcription via phosphorylation at serine 133. Different stimuli use distinct signaling pathways to regulate CREB, enabling specific gene expression programs.
Area of Science:
- Molecular Biology
- Cell Signaling
- Gene Regulation
Background:
- Extracellular signals modulate gene expression through protein kinase cascades.
- Cyclic AMP response element (CRE)-binding protein (CREB) is a key transcription factor activated by diverse stimuli.
- Phosphorylation of CREB at serine 133 (Ser133) is crucial for its transcriptional activity.
Purpose of the Study:
- To review the molecular mechanisms of Ser133-phosphorylated CREB transcriptional activation.
- To explore intracellular signaling pathways leading to CREB phosphorylation at Ser133.
- To understand how signaling pathways confer specificity to CREB activation.
Main Methods:
- Literature review of molecular mechanisms.
- Analysis of intracellular signaling pathways.
- Examination of CREB phosphorylation and transcriptional regulation.
Main Results:
- Multiple protein kinases (PKA, pp90RSK, CaMKs) phosphorylate CREB at Ser133.
- Phosphorylation at Ser133 is essential for CREB-mediated transcription.
- Stimulus-specific mechanisms, including additional phosphorylation sites or protein interactions, allow CREB to regulate distinct gene expression programs.
Conclusions:
- CREB activation is a central node for integrating diverse extracellular signals.
- Specificity in CREB-mediated gene regulation arises from stimulus-dependent signaling pathways.
- Understanding CREB regulation provides insights into cellular responses to various stimuli.