Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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

Various endocrine and neuronal functions are governed by the cAMP-dependent signaling pathway. In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signaling 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). The function of CRE-binding proteins (CREBs) is modulated by phosphorylation by several kinases. Direct activation of gene expression by CREBs requires phosphorylation by the cAMP-dependent protein kinase A to the serine-133 residue. The gene CREM encodes various transcription factors which play key physiological and developmental roles within the hypothalamic-pituitary-gonadal axis. We have previously shown that the transcriptional activator CREMtau 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 which 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.
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PMID:Regulating the balance between differentiation and apoptosis: role of CREM in the male germ cells. 984 51

The mechanism by which nerve growth factor (NGF) regulates adrenergic expression was examined in PC-12 cells transfected with a rat phenylethanolamine N-methyl-transferase (PNMT) promoter-luciferase reporter gene construct pGL3RP893. NGF treatment increased PNMT promoter-driven luciferase activity in a dose- and time-dependent manner. Induction was attenuated by inhibition of the extracellular signal-regulated kinase mitogen-activated protein kinase (MAPK) pathway ( approximately 60%) but not by inhibition of the protein kinase A (PKA), protein kinase C, phosphoinositol kinase, or p38 MAPK pathways. Deletion PNMT promoter-luciferase reporter gene constructs showed that the NGF-responsive sequences lay within the proximal -392 base pairs (bp) of PNMT promoter, wherein binding elements for Egr-1 (-165 bp) and Sp1 (-48 bp) reside. Western analysis further showed that NGF increased nuclear levels of Egr-1, but not Sp1 or the catalytic subunit of PKA. Gel mobility shift assays showed increased potential for Egr-1, but not Sp1, protein-DNA binding complex formation. Mutation of either the Egr-1 or Sp1 binding sites in the PNMT promoter attenuated NGF activation. NGF, combined with pituitary adenylyl cyclase-activating protein (PACAP), another PNMT transcriptional activator, cooperatively stimulated PNMT promoter driven-luciferase activity beyond levels observed with either neurotrophin alone. Finally, post-transcriptional control seems to be another important mechanism by which neurotrophins regulate the adrenergic phenotype. NGF, PACAP, and a combination of the two stimulated both intron-retaining and intronless PNMT mRNA and PNMT protein, but to different extents.
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PMID:Nerve growth factor regulates adrenergic expression. 1692 81

Yersinia pestis is one of the most dangerous bacterial pathogens. PhoP and cyclic AMP receptor protein (CRP) are global regulators of Y. pestis, and they control two distinct regulons that contain multiple virulence-related genes. The PhoP regulator and its cognate sensor PhoQ constitute a two-component regulatory system. The regulatory activity of CRP is triggered only by binding to its cofactor cAMP, which is synthesized from ATP by adenylyl cyclase (encoded by cyaA). However, the association between the two regulatory systems PhoP/PhoQ and CRP-cAMP is still not understood for Y. pestis. In the present work, the four consecutive genes YPO1635, phoP, phoQ, and YPO1632 were found to constitute an operon, YPO1635-phoPQ-YPO1632, transcribed as a single primary RNA, whereas the last three genes comprised another operon, phoPQ-YPO1632, transcribed with two adjacent transcriptional starts. Through direct PhoP-target promoter association, the transcription of these two operons was stimulated and repressed by PhoP, respectively; thus, both positive autoregulation and negative autoregulation of PhoP/PhoQ were detected. In addition, PhoP acted as a direct transcriptional activator of crp and cyaA. The translational/transcriptional start sites, promoter -10 and -35 elements, PhoP sites, and PhoP box-like sequences were determined for these PhoP-dependent genes, providing a map of the PhoP-target promoter interaction. The CRP and PhoP regulons have evolved to merge into a single regulatory cascade in Y. pestis because of the direct regulatory association between PhoP/PhoQ and CRP-cAMP.
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PMID:Autoregulation of PhoP/PhoQ and positive regulation of the cyclic AMP receptor protein-cyclic AMP complex by PhoP in Yersinia pestis. 2326 79

Identification of new therapeutic targets may improve the survival rate of patients with colorectal cancer (CRC). Recent studies have suggested that the level of phosphodiesterase 4B (PDE4B) is elevated in fatal/refractory diffuse large B-cell lymphoma (DLBCL), and therapeutic efficacy of a PDE4 inhibitor in B-cell lymphoma has been successfully tested in clinical settings. Here, we show that PDE4B is a potential therapeutic target in CRC. Treatment with forskolin, an activator of adenylyl cyclase (AC), increased intracellular cyclic AMP (cAMP) levels in PDE4B-low, but not PDE4B-high cells, indicating that PDE4B was a major regulator of cAMP levels in CRC cells. Furthermore, cAMP modulated the activities of AKT and AMPK in a PDE4B-dependent manner, which was associated with a marked decrease in mTOR-Myc signals and oncogenic properties of CRC cells such as anchorage-independent growth and colony formation. We found that the Myc proto-oncogene was a crucial downstream target of the AKT/mTOR and AMPK/mTOR signals that mediated cAMP-induced anti-tumor effect. A natural polyphenol resveratrol that was reported to have PDE4 inhibitory effects also showed tumor suppressive effects by inhibiting the mTOR-Myc axis. Intriguingly, we identified Myc as a transcriptional activator of PDE4B in CRC cells, which maintains the intracellular cAMP levels low and promotes cell survival. These data suggest that cAMP/PDE4B signals play a significant role in regulating the malignant phenotype of CRC cells and targeting of PDE4B should be actively pursued.
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PMID:Phosphodiesterase 4B is an effective therapeutic target in colorectal cancer. 3052 30