A monomeric derivative of the cellular transcription factor CREB functions as a constitutive activator.
The mammalian transcriptional activator CREB binds as a dimer to a broad spectrum of inducible promoters. CREB activity is modulated by several signalling agents (protein kinase A [PKA], Ca2+, and transforming growth factor beta) and via functional interactions with cell-specific transcription factors. In addition, CREB can activate transcription constitutively and repress the activity of several other transcriptional activators. The mechanisms that allow CREB to act in such a malleable manner and the role that CREB dimerization might play in this are poorly understood. To probe the latter issue, we have created monomeric forms of CREB by fusing CREB to the DNA-binding domain of a protein (B-cell specific activator protein [BSAP]) that binds to DNA as a monomer. Remarkably, monomeric CREB acts as a potent, constitutive activator under conditions in which native CREB is inducible by PKA. Thus, CREB contains constitutive activation regions that are unable to function in native CREB. Two glutamine-rich domains that are important for native, PKA-inducible CREB activity are required for the constitutive activity of monomeric CREB. In contrast, two elements within the kinase-inducible domain of CREB are dispensable for constitutive activity. We discuss our results in relation to inducible and constitutive CREB activity and the potential modes of action of other activators that directly interact with CREB.
Krajewski
W
W
Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire, United Kingdom.
Lee
K A
KA
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D051757:PAX5 Transcription Factor; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D004247:DNA