Transcription factors act as the key regulators of gene expression. Sequence-specific transcription factors typically contain physically distinct functional domains (see Figure 2-2). Numerous transcription factors have been found. Some of them translocate to the nucleus to bind their cis-regulatory elements in response to activation reaction, such as nuclear factor KB (NF-1:B). However, some transcription factors are already bound to their cognate cis-regulatory elements in the nucleus under basal conditions and are converted into transcriptional activators by phosphorylation. cAMP (cyclic 3'-5'-adenosine monophosphate) response element-binding protein (CREB), for example, is bound to regions of DNA, called cAMP response elements (CREs), before cell stimulation. CREB can promote transcription when it is phosphorylated on a serine residue (ser133), because phosphorylated CREB can interact with a coactivator, CREB-binding protein, which in turn contacts and activates the basal transcription complex. Of interest, CREB-binding protein possesses intrinsic histone acetyltransferase (HAT) activity. The activity of most transcription factors is regulated through second-messenger pathways. CREB can be activated via phosphorylation at ser133 by second messengers, such as cAMP, Ca++, and growth factors (Figure 2-3).
FIGURE 2-3. Activation of cAMP response element-binding protein (CREB) via different signal transduction pathways.
Signal cascades are activated by external stimuli, such as hormones or neurotransmitters and growth factors. Arrows indicate the interaction between pathways. AC = adenylyl cyclase; C = catalytic subunits of PKA; Ca++ = calcium; CaMK IV = calmodulin-dependent kinase IV; cAMP = cyclic 3'-5'-adenosine monophosphate; CBP = CREB-binding protein; Epac = exchange protein activated by cAMP; ERK = extracellular-regulated kinase; G:is = ex subunit of the stimulatory G protein; P = phosphorylation; PKA = cAMP-dependent protein kinase; R = regulatory subunits of PKA; Rap and Ras = small GTPases (small proteins that bind to guanosine triphosphate [GTP]); RSK2 = ribosomal S6 kinase 2.
CREB is a molecule that is widely implicated in learning and memory in many species. Mice expressing mutant CREB isoforms show impaired memory, but this is dependent on the genetic background of the mice (Graves et al. 2002). CREB-binding protein (CBP) is a transcriptional coactivator with CREB. A partial-knockout mouse model, in which CBP activity is lost, exhibits learning deficiencies (Oike et al. 1999). Further, Rubinstein-Taybi syndrome (RTS) is an autosomal-dominant dysmorphic syndrome that results in severe impairment of learning and memory. The RTS gene has been mapped to chromosome 16 and identified as CBP. The loss of function of CBP is likely one important contributing factor to the learning and memory defects seen in RTS (Murata et al. 2001; Oike et al. 1999; Petrij et al. 1995).
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