Coupling gene expression to cAMP signalling: role of CREB and CREM.
Several endocrine and neuronal functions are governed by the cAMP-dependent pathway. Transcriptional regulation upon stimulation of this pathway is mediated by a family of cAMP-responsive nuclear factors. This family consists of a large number of members, which may act as activators or repressors. These factors contain the basic domain/leucine zipper motifs and bind as dimers to cAMP-response elements (CRE). CRE-binding protein (CREBs) function is modulated by phosphorylation by several kinases. Direct activation of gene expression by CREB requires phosphorylation by the cAMP-dependent PKA to serine 133. Among the repressors, ICER (Inducible cAMP Early Repressor) deserves special mention. ICER is generated from an alternative CREM promoter and is the only inducible CRE-binding protein. ICER negatively autoregulates the alternative promoter, generating a feedback loop. ICER expression is tissue specific and developmentally regulated. The kinetics of ICER expression are characteristic of an early response gene. CREM plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. The transcriptional activator CREM is highly expressed in postmeiotic cells. The role of CREM in spermiogenesis was addressed using CREM knock-out mice. Spermatogenesis stops at the first step of spermiogenesis in the mutants and there is a significant increase in apoptotic germ cells. This phenotype is reminiscent of cases of human infertility. ICER is regulated in a circadian manner in the pineal gland, the site of the hormone melatonin production. This night-day oscillation is driven by the endogenous clock (located in the suprachiasmatic nucleus). The synthesis of melatonin is regulated by a rate-limiting enzyme, serotonin N-acetyltransferase (NAT). Analysis of the CREM-null mice and of the promoter of the NAT gene revealed that ICER controls the amplitude and rhythmicity of NAT, and thus the oscillation in the hormonal synthesis of melatonin.
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Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, C.U. de Strasbourg, France.
D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism; D050882:CREB-Binding Protein; D002940:Circadian Rhythm / Q000502:physiology; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D051786:Cyclic AMP Response Element Modulator; D004268:DNA-Binding Proteins / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D017781:Genes, Immediate-Early / Q000235:genetics; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013091:Spermatogenesis / Q000502:physiology; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; D001191:Arylamine N-Acetyltransferase