Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals.
A mechanism has been characterized by which the transcription factor CREB regulates neurotrophin-induced gene expression. Whereas CREB can mediate calcium- or cyclic AMP-induced c-fos transcription independently of other promoter-bound transcription factors, CREB mediates NGF induction of c-fos transcription via a novel mechanism that appears to require a cooperative interaction with another transcription factor, the serum response factor. A similar transcriptional mechanism may explain how neurotrophins and growth factors induce distinct subsets of delayed response genes. Neurotrophins induce the phosphorylation of CREB at a key regulatory site, Serine 133, with prolonged kinetics that are distinct from the transient kinetics of CREB phosphorylation elicited by growth factors. These results indicate that CREB is a versatile transcription factor that activates transcription via distinct mechanisms in a stimulus-specific manner. In addition, by selectively activating delayed response genes, CREB may confer specificity to neurotrophin signals that promote the survival and differentiation of neurons.
Bonni
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A
Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ginty
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DD
Dudek
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Greenberg
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ME
D000818:Animals; D001483:Base Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D016762:Genes, fos / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism*; D026362:Serum Response Factor; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D009414:Nerve Growth Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger; D026362:Serum Response Factor; D014157:Transcription Factors; D012694:Serine