Coupling cAMP Signaling to Transcription in the Liver: Pivotal Role of CREB and CREM

doi:10.1006/excr.2002.5491

Experimental Cell Research

Volume 275, Issue 2, 1 May 2002, Pages 143-154

https://doi.org/10.1006/excr.2002.5491 Get rights and content

Abstract

Transcriptional factors binding to cAMP-responsive elements (CREs) in the promoters of various genes belong to the basic domain-leucine zipper superfamily and are composed of three genes in mammals, CREB, CREM, and ATF-1. A large number of CREB, CREM, and ATF-1 proteins are generated by posttranscriptional events, mostly alternative splicing, and regulate gene expression by acting as activators or repressors. Activation is classically brought about by signaling-dependent phosphorylation of a key acceptor site (Ser133 in CREB) by a number of possible kinases, including PKA, CamKIV, and Rsk-2. Phosphorylation is the prerequisite for the interaction of CBP (CREB-binding protein), a co-activator that has also histone acetyltransferase activity. Repression may involve dynamic dephosphorylation of the activators and thus decreased association with CBP. Another pathway of transcriptional repression on CRE sites implicates the inducible repressor ICER (inducible cAMP early repressor), a product of the CREM gene. Being an inducible repressor, ICER is involved in autoregulatory feedback loops of transcription that govern the down-regulation of early response genes, such as the proto-oncogene c-fos. The liver represents a remarkable physiological setting where cAMP-responsive signaling plays a major role. Indeed, a finely tuned program of gene expression is triggered by partial hepatectomy, so that through specific checkpoints a coordinated regeneration of the tissue is obtained. Temporal kinetics of transcriptional activation after hepatectomy reveals a pattern of early induction for several genes, some of them controlled by the CREB/CREM transcription factors. An important role of CREM in liver physiology was suggested by the robust induction of ICER after partial hepatectomy. The delay in tissue regeneration in CREM-deficient mice confirmed the important function of this factor in regulating hepatocyte proliferation. As gene induction is accompanied by critical changes in chromatin organization, the deciphering of the specific modification codes that histones display during liver regeneration and physiology will provide exciting new insights into the dynamics of chromatin architecture.

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MinireviewCoupling cAMP Signaling to Transcription in the Liver: Pivotal Role of CREB and CREM

Abstract

Cell

Cell

Trends Biochem. Sci.

Trends Biochem. Sci.

Curr. Opin. Cell Biol.

Recent Prog. Horm. Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

Trends Genet.

Cell

J. Biol. Chem.

Mol. Cell Endocrinol.

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

Cell

J. Biol. Chem.

Cell

Neuron

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

Cell

Cell

Cell

The language of covalent histone modifications

Nature

Structure and function in the nucleus

Science

RNA polymerase II and the integration of nuclear events

Genes Dev.

Differential regulation and expression of jun, c-fos and c-myc proto-oncogenes during mouse liver regeneration and after inhibition of protein synthesis

Oncogene

Regeneration of Mammalian Liver

Regulation of signal transduction during liver regeneration

FASEB J.

Liver regeneration

Science

Role of growth factors and cytokines in hepatic regeneration

FASEB J.

Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice

Science

Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

Proc. Natl. Acad. Sci. USA

Transcriptional control of liver regeneration

FASEB J.

The mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade activation is a key signalling pathway involved in the regulation of G(1) phase progression in proliferating hepatocytes

Cell Biol.

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J. Clin. Invest.

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J. Cell Physiol.

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J. Cell Physiol.

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J. Cell Physiol.

On the mechanisms of the growth-promoting effect of prostaglandins in hepatocytes: The relationship between stimulation of DNA synthesis and signaling mediated by adenylyl cyclase and phosphoinositide-specific phospholipase C

J. Cell Physiol.

Synergistic antiproliferative actions of cyclic adenosine 3′,5′-monophosphate, interleukin-1 beta, and activators of Ca2+/calmodulin-dependent protein kinase in primary hepatocytes

Endocrinology

Minireview
Coupling cAMP Signaling to Transcription in the Liver: Pivotal Role of CREB and CREM

Synergistic antiproliferative actions of cyclic adenosine 3′,5′-monophosphate, interleukin-1 beta, and activators of Ca²⁺/calmodulin-dependent protein kinase in primary hepatocytes