The Role of CREB and CBP in Brain Function

Abstract

In this chapter, the various functions in the nervous system of the CRE-binding protein (CREB), its paralogues CREM and ATF1, and its co-activator the CREB-binding protein (CBP), are reviewed. A wide array of techniques, including mouse transgenesis, gene targeting, genome-wide analyses and behavioral and electrophysiological studies, have revealed an important role for the CREB activation pathway in different brain functions. These studies have clarified our understanding of the mechanisms whereby CREB activity is regulated and have provided essential clues about how the same family of transcription factors can mediate such apparently distinct biological functions as memory storage, neuroprotection, and drug addiction. 11.1208 11 The Role of CREB and CBP in Brain Function demonstrated that CBP also interacts with other transcription factors, and thereby participates in other essential biological processes, including the control of a variety of neuronal responses.In this chapter, we describe selected aspects of our understanding of the functions of the CREB activation pathway in the nervous system, focusing in particular on the roles of CREB and CBP proteins. A number of excellent articles have reviewed this area [3][4][5][6][7][8][9]. Here, we will focus on the central nervous system, where CREB has been implicated, in the mechanisms of activity-dependent synaptic plasticity [10,11], neurogenesis [12], neuronal survival [13, 14], synaptic refinement during development [15], drug addiction [16, 17], circadian rhythm [18], and depression [19]. The CREB Family of Transcription Factors CREB Family Members and Close FriendsThe genes Creb, Crem, and Atf-1 encode for a group of highly homologous proteins that is frequently referred as the CREB family of transcription factors. This family is characterized by a conserved basic region/leucine zipper (bZIP) domain that bind to CRE sites found in one or several copies in the promoters of many genes (Figs. 11.1 and 11.2). CREB and ATF1 are the two most abundant CRE-binding proteins expressed in neurons, and are expressed ubiquitously throughout the nervous system and elsewhere. In contrast, CREM is expressed primarily in the neuroendocrine system [3]. However, these three proteins are not the only transcription factors known to bind to CRE sites. Other factors also bind to these sites and contribute to regulate cAMP-mediated gene expression. These other factors share many structural features with the CREB family, and the larger group is frequently referred to as the ATF/CREB family of transcription factors. This larger family includes not only the CREB family, as a subgroup, but also other bZIP proteins such as ATF2, ATF3, and ATF4. Different ATF/CREB proteins can form selective heterodimers with each other, and also with other transcription factors such as AP-1 and C/EBP that do not belong to this family but share a bZIP DNA-binding domain. Members of different families may compete for the same DNA sites and form heterodimers with members of other families. As has occurr...

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

“…Many promoters of cAMP-responsive genes only contain a half-site TGACG sequence (Barco and Kandel, 2006), which is essential for biological activity (Fink et al, 1988). This same sequence found here in reverse orientation was shown to be a functional element.…”

Transcription Factors in Long-Term Memory and Synaptic Plasticity

“…CREB factors are critical in many important functions in the nervous system, including neurogenesis and neuronal survival, development, and differentiation, as well as neuroprotection, axonal outgrowth and regeneration, circadian rhythms, addiction, synaptic plasticity, and memory formation (24, 43, 60, 171, 177, 194, 219). …”

Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection

“…PKA directly phosphorylates and activates transcription factors such as the cAMP responsive element binding protein (CREB), which in the brain mediates neuronal plasticity, long-term memory formation, neuronal survival and neurogenesis (Figure 2) [5]. In the past decade, Epac has emerged as an alternative cAMP sensor [6].…”

“…For example, like PKA, Epac can also activate CREB directly [9]. Interestingly, PKA signaling is often related to neuronal survival [5, 12, 16], whereas Epac activation can lead to oxidative stress and neuronal injury [12, 13] (Figure 2). The differential regulation of PKA and Epac by cAMP could be related to the gradient of cytoplasmic cAMP because cAMP has a lower affinity for Epac than for PKA [17], (i.e., cAMP initially stimulates PKA signaling at the beginning of EP2 receptor activation; with sustained EP2 activation the Epac pathway dominates as the cytoplasmic cAMP level continues rising).…”

“…RNA interference for the EP2 receptor can decrease long-term potentiation (LTP) in rat visual cortex [22]. In response to theta-burst stimulation, Gs-coupled EP2 receptor translocates from cytosol to postsynaptic membrane, while Gi-coupled EP3 receptor moves oppositely, resulting in enhanced postsynaptic cAMP/PKA signaling [22], which in turn activates CREB, a well-documented transcription factor for the late stage of LTP and memory (Figure 2) [5]. Thus, EP2 receptor trafficking mimics that of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptor during LTP expression.…”