What turns CREB on?

doi:10.1016/j.cellsig.2004.05.001

Cellular Signalling

Volume 16, Issue 11, November 2004, Pages 1211-1227

https://doi.org/10.1016/j.cellsig.2004.05.001 Get rights and content

Abstract

The transactivation domain of the cAMP response element-binding protein (CREB) consists of two major domains. The glutamine-rich Q2 domain, which interacts with the general transcription factor TAFII130/135, is sufficient for the recruitment of a functional RNA polymerase II complex and allows basal transcriptional activity. The kinase-inducible domain, however, mediates signal-induced activation of CREB-mediated transcription. It is generally believed that recruitment of the coactivators CREB-binding protein (CBP) and p300 after signal-induced phosphorylation of this domain at serine-133 strongly enhances CREB-dependent transcription. Transcriptional activity of CREB can also be potentiated by phosphoserine-133-independent mechanisms, and not all stimuli that provoke phosphorylation of serine-133 stimulate CREB-dependent transcription. This review presents an overview of the diversity of stimuli that induce CREB phosphorylation at Ser-133, focuses on phosphoserine-133-dependent and -independent mechanisms that affect CREB-mediated transcription, and discusses different models that may explain the discrepancy between CREB Ser-133 phosphorylation and activation of CREB-mediated transcription.

Introduction

Induction of gene expression by the second messenger cyclic adenosine 3′,5′-monophosphate (cAMP) is generally believed to be mediated by binding of the cAMP response element-binding protein (CREB) to a conserved TGACGTCA sequence present in the promoter of many cAMP-responsive genes. CREB was originally shown to become phosphorylated at serine residue 133 (Ser-133) by an activated cAMP-dependent protein kinase (PKA) and phosphorylation of CREB at this residue allows recruitment of the CREB-binding protein CBP or its paralogue p300. The intrinsic histone acetyltransferase activities and the bridging properties with RNA polymerase II via RNA helicase A of the coactivators CBP/p300 contribute to the augmented CREB-mediated transcription. The functions of CREB and the molecular mechanisms governing cAMP-induced activation of CREB-mediated gene expression have been excellently reviewed elsewhere [1], [2], [3], [4], [5].

Section snippets

Stimuli that induce phosphorylation of CREB at Ser-133

A stringent genome-wide analysis for CREB binding motifs resulted in 1349 sites in the mouse genome and 1663 hits in the human genome [6]. This vast amount of putative CREB-regulated genes and the enormous functional diversity of the proteins encoded by these genes indicate the important biological role of CREB in many cellular processes. One mode to investigate the involvement of CREB in the regulation of a specific target gene is by examining whether a stimulus, known to activate the

CREB-interacting proteins

The CREB protein has a modular structure with distinct domains exerting different functions. The basic leucine zipper motif mediates dimerization and DNA binding, while the glutamine-rich domains Q1 and Q2, and the kinase-inducible domain (KID) constitute the transcription activation domains of CREB. These different domains can recruit distinct proteins that can modify the transcriptional activity of CREB. CREB-interacting proteins and their effect on CREB-dependent transcription are summarised

Ser-133 phosphorylation: foreplay or main act?

It is generally accepted that phosphorylation of Ser-133 is necessary, but not always sufficient for stimulus-induced activation of CREB. Stimuli like serum, dibutyryl cAMP, TPA, hypoxia, glutamate, TGF-β, and ionophore A23187 induce phosphorylation, but not activation of CREB in some cell types, while they provoke both phosphorylation and activation in other cell types (Table 1 and references in table of supplementary data). Other stimuli can provoke CREB phosphorylation with comparable

Conclusions and further challenges

Almost 20 years have elapsed since CREB was isolated, the major molecular mechanisms of CREB-mediated transcription were solved, and many of the biological functions of CREB were identified. Despite intensive research, reflected in the more than 4000 articles on CREB published in PubMed, researches are left with a crucial unanswered question: how to explain the discrepancy between CREB phosphorylation at Ser-133 and activation of CREB-mediated transcription? Solving this enigma forms a true

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^☆: Supplementary data associated with this article can be found in the on line version, at doi:10.1016/j.cellsig.2004.05.001.

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ReviewWhat turns CREB on?☆

Abstract

Introduction

Section snippets

Stimuli that induce phosphorylation of CREB at Ser-133

Other post-translational modifications of CREB

CREB-interacting proteins

Ser-133 phosphorylation: foreplay or main act?

Conclusions and further challenges

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Review
What turns CREB on?☆