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 bro ad spectrum of inducible promoters. CREB activity is modulated by seve ral 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 c onstitutively and repress the activity of several other transcriptiona l activators. The mechanisms that allow CREB to act in such a malleabl e manner and the role that CREB dimerization might play in this are po orly 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 monome r. 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 nati ve, PKA-inducible CREB activity are required for the constitutive acti vity of monomeric CREB. In contrast, two elements within the kinase-in ducible domain of CREB are dispensable for constitutive activity. We d iscuss our results in relation to inducible and constitutive CREB acti vity and the potential modes of action of other activators that direct ly interact with CREB.