Multi-faceted regulation of CREB family transcription factors

Abstract

cAMP response element-binding protein (CREB) is a ubiquitously expressed nuclear transcription factor, which can be constitutively activated regardless of external stimuli or be inducibly activated by external factors such as stressors, hormones, neurotransmitters, and growth factors. However, CREB controls diverse biological processes including cell growth, differentiation, proliferation, survival, apoptosis in a cell-type-specific manner. The diverse functions of CREB appear to be due to CREB-mediated differential gene expression that depends on cAMP response elements and multi-faceted regulation of CREB activity. Indeed, the transcriptional activity of CREB is controlled at several levels including alternative splicing, post-translational modification, dimerization, specific transcriptional co-activators, non-coding small RNAs, and epigenetic regulation. In this review, we present versatile regulatory modes of CREB family transcription factors and discuss their functional consequences.

Keywords: CREB; alternative splicing; cAMP responsive element; epigenetic modification; post-transcriptional modification; post-translational modification; transcriptional co-activator.

FIGURE 1

Evolutionarily conserved domains of CREB family transcription factors. The glutamine-rich domains (Q1 and Q2), the kinase-inducible domain (KID), and the basic region/leucine zipper domain (bZIP) are conserved from hydra to human. The KID domain contains several functional phosphorylation sites which are shown in closed diamond shape. The basic region mediates the binding to CRE sequences, whereas the leucine zipper domain induces dimerization. The Q1-KID-Q2 domains together provide transcriptional activation function.

FIGURE 2

Alternative splicing of the dCREBB gene. Alternative splicing produces at least 7 different protein isoforms from a single dCREBB gene in Drosophila. The protein dCREBB-a contains Q1, Q2, KID, and bZIP domains, whereas the isoform dCREBB-b lacks Q2 domain. Each arrow indicates the start codon (ATG). Stop codon (TAA) is marked by “Stop.”

FIGURE 3

Several phosphorylation sites (in yellow) observed in the human kinase-inducible domain (KID) appear to be conserved in the Drosophila KID. Multiple protein kinases that can phosphorylate specific serine residue(s) are shown in the bottom. Homologous protein kinases to some of human protein kinases are also found in Drosophila (see Table 2).