Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several endocrine and neuronal functions are governed by the cAMP-dependent signalling pathway. In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signalling pathway is mediated by a family of cAMP-responsive nuclear factors. This family consists of a large number of members that may act as activators or repressors. These factors contain the basic domain/ leucine zipper motifs and bind as dimers to cAMP-response elements (CRE). The function of CRE-binding proteins (CREBs) is modulated by phosphorylation by several kinases. Direct activation of gene expression by CREB requires phosphorylation by the cAMP-dependent protein kinase A to the serine-133 residue. Among the repressors, ICER (Inducible cAMP Early Repressor) deserves special mention. ICER is generated from an alternative CREM promoter and constitutes the only inducible cAMP-responsive element binding protein. Furthermore, ICER negatively autoregulates the alternative promoter, thus generating a feedback loop. In contrast to the other members of the CRE-binding protein family, ICER expression is tissue specific and developmentally regulated. The kinetics of ICER expression are characteristic of an early response gene. Our results indicate that CREM plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. We have previously shown that the transcriptional activator CREM is highly expressed in postmeiotic cells. Spermiogenesis is a complex process by which postmeiotic male germ cells differentiate into mature spermatozoa. This process involves remarkable structural and biochemical changes that are under the hormonal control of the hypothalamic-pituitary axis. We have addressed the specific role of CREM in spermiogenesis using CREM-mutant mice generated by homologous recombination. Analysis of the seminiferous epithelium from mutant male mice reveals that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are completely absent, while there is a significant increase in apoptotic germ cells. A series of postmeiotic germ cell-specific genes are not expressed. Mutant male mice completely lack spermatozoa. This phenotype is reminiscent of cases of human infertility. We have shown that 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, SCN). The synthesis of melatonin is regulated by a rate-limiting enzyme, the serotonin N-acetyltransferase (NAT). By using the CREM-deficient mice and by analysis of the regulatory region of the gene encoding the serotonin NAT, we have established that ICER is responsible for the amplitude and rhythmicity of NAT and thus for the oscillation in the hormonal synthesis of melatonin.
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PMID:Coupling signalling pathways to transcriptional control: nuclear factors responsive to cAMP. 923 50

The molecular basis for the circadian clock in mammals consists of a number of genes and proteins that form transcription-translation feedback loops. These loops result in a 24-h rhythm in the expression of mRNA and protein levels. Although the anatomical site of the central circadian clock is the SCN of the hypothalamus, all of the circadian clock genes are expressed in tissues other than the brain. Moreover, cyclic gene and protein expression occurs in most of these tissues. The best known exception to this rule is the testis, which shows constant rather than cyclic expression of circadian clock genes. Indeed, the testis of multiple animal species displays constant circadian clock gene expression. In recent work, the authors showed that the thymus is similar to the testis in that expression of circadian clock genes is either constant over a 24-h period or cycles with a dampened amplitude, depending on which gene is examined. In the current study, they extend and confirm their findings regarding noncyclic circadian clock gene and protein expression in the testis and the thymus. More important, they also show that expression of these genes in both testis and thymus does not depend on the transcriptional activator, CLOCK, which is necessary for cyclic gene expression in the SCN and in other tissues. These results extend the molecular similarities between the thymus and the testis and suggest that similar mechanisms are at work for regulating expression of circadian clock genes in both tissues. One commonality between these 2 organs is that they are composed primarily of differentiating cells. The authors hypothesize that the circadian clock is not operational in immature, differentiating cells. Possibly, the clock starts in mature cells upon receipt of an initiating signal.
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PMID:The thymus is similar to the testis in its pattern of circadian clock gene expression. 1583 8