Elsevier

Cellular Signalling

Volume 20, Issue 3, March 2008, Pages 460-466
Cellular Signalling

Review
Regulating gene transcription in response to cyclic AMP elevation

https://doi.org/10.1016/j.cellsig.2007.10.005Get rights and content

Abstract

Many of the effects of prototypical second messenger cyclic adenosine 3′,5′-monophosphate (cAMP) on complex processes such as the regulation of fuel metabolism, spermatogenesis and steroidogenesis are mediated via changes in target gene transcription. A large body of research has defined members of the cAMP-response element binding (CREB) protein family as the principal mediators of positive changes in gene expression in response to cAMP following phosphorylation by cAMP-dependent protein kinase (PKA). However, persistent observations of cAMP-mediated induction of specific genes occurring via PKA-independent mechanisms have challenged the generality of the PKA–CREB pathway. In this review, we will discuss in detail both PKA-dependent and -independent mechanisms that have been proposed to explain how cAMP influences the activation status of multiple transcription factors, and how these influence critical biological processes whose defective regulation may lead to disease.

Introduction

Changes in cAMP levels are translated into pleiotropic intracellular effects by a panel of cAMP-binding effector proteins, which include cyclic nucleotide-gated ion channels, cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs) [1]. Signal termination is achieved by hydrolysis of cAMP to 5′AMP catalysed by the large superfamily of cyclic nucleotide phosphodiesterases (PDEs). A key aspect of cAMP's effects is the generation of intracellular cAMP gradients arising from the opposing effects of adenylyl cyclases and phosphodiesterases [2]. The ability of distinct regions within the cell to sample these gradients is dictated in part by specific A-kinase anchoring protein (AKAP) scaffolds that localise PDEs, RI and RII regulatory cAMP-binding subunits of PKA and Epacs to defined intracellular compartments. In the case of PKA, binding of cAMP to R subunits releases catalytic C subunits from the PKA holoenzyme, and allows phosphorylation of adjacent substrates [3].

The ability of cAMP to positively control transcription of the somatostatin gene was pivotal to the original identification of the transcription factor “cAMP-response element binding protein” (CREB) [4]. In this review, we will outline our current understanding of how cAMP controls gene transcription though CREB and CREB-related proteins. In addition, we will also describe the growing body of evidence for separate PKA-independent mechanisms by which cAMP can positively regulate transcription.

Section snippets

CREB and related bZIP transcription factors

Following the isolation of CREB cDNAs, several CREB-related genes termed were subsequently identified, termed “cAMP response element modulator” (CREM) and ATF-1. Collectively, CREB, CREM and ATF-1 form a subgroup of a larger family of transcription factors that contain basic region leucine zippers (bZIPs), which refers to a cluster of basic residues required for DNA binding followed by heptad leucine repeats which form a zipper region responsible for homo- and heterodimerisation with similar

The regulation of CREB by cyclic AMP

Following activation of PKA, a subset of catalytic C subunits is able to enter the nucleus from the cytoplasm after dissociation from cAMP-bound regulatory R subunits [2], [3], [4]. While CREB is now known to be phosphorylated in response to various stimuli, including Ca2+/calmodulin-dependent kinase IV [13], [14] and the mitogen/stress-activated kinase Msk1 [15], [16], an overwhelming body of evidence has demonstrated that PKA-mediated phosphorylation of CREB on Ser133 (numbering in

Activation of CREB-mediated transcription upon Ser133 phosphorylation

CREB appears to be constitutively bound to conserved cAMP-responsive elements that occur either as a full site palindrome (TGACGTCA) or a half site (CGTCA/TGACG), although the identities of the genes occupied appear to vary in a cell type-dependent fashion [6], [23]. Thus, CREB binding to chromatin does not appear to be significantly modulated by either cAMP elevation or Ser133 phosphorylation [24] even though DNA and/or chromatin binding can induce distinct conformations of the KID [25]. Thus,

PKA-independent transcription in response to cyclic AMP

Although it has been known for some time that cAMP can either activate or repress transcription, it has only been appreciated recently that not all of its effects are mediated via PKA. This became apparent when several groups independently demonstrated that certain cAMP-dependent phenomena were not inhibited by PKA-selective inhibitors such as H89 or PKI. Other groups have also demonstrated that some of the effects of intracellular cAMP elevation are only partially mimicked by the

Epac-mediated gene transcription

In terms of transcription, the most widely studied of the alternative cAMP sensors are the Epacs, particularly Epac1. These proteins were originally identified as guanine nucleotide exchange factors (GEFs) for the Rap 1 and Rap2 small GTPases. Epac1 and Epac2 each has several important structural features, including a cyclic nucleotide-binding domain (Epac2 has two such domains), a DEP (Dishevelled, Egl, Pleckstrin) domain, a REM (Ras exchanger motif) domain and a GEF catalytic domain [48], [49]

Other possible cyclic AMP-dependent mechanisms for regulating gene transcription

Other cAMP sensors which may participate in gene transcription events include the PDZ-GEFs. These have an E. coli CAP-like cAMP-binding domain that contains -GE-VI-G-V- and -G-FG motifs required for cAMP binding in other proteins [52]. PDZ-GEF1/CNrasGEF has also been shown to interact via its cyclic nucleotide-binding domain with cAMP immobilised on agarose beads in a cGMP-inhibitable manner [50]. However, it has been shown to activate Rap1 in a cAMP-independent manner when overexpressed in

Conclusions and future directions

As outlined in this review, the study of PKA-independent regulation of transcription by cAMP is an area still in its infancy, but given the diverse biological effects controlled by such pathways, it should prove to be a fruitful area for not only understanding how changes in cAMP accumulation are translated into specific gene expression patterns, but also identifying new targets for exploiting the beneficial effects of cAMP elevation. Clearly, identification of the transcription factors

Acknowledgements

Work in TMP's laboratory is supported by the British Heart Foundation and the UK Biotechnology and Biological Sciences Research Council.

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