Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic adenosine monophosphate (cAMP) stimulates transcription of somatostatin and other target genes with burst-attenuation kinetics. The kinetics of protein kinase (PK-A)-dependent cAMP response element binding protein (CREB) phosphorylation closely parallel the changes in transcription of cAMP-responsive genes by run-on assay. Nuclear translocation of PK-A, visualized by microinjection of fluorescently labeled PK-A holoenzyme, appears to represent the rate-limiting step in CREB phosphorylation and transcriptional activation. We and others have recently characterized a CREB-binding protein (CBP), which specifically recognizes sequences within the Ser133 phosphorylated form of CREB. CBP does not regulate the DNA binding, dimerization, or nuclear targeting properties of CREB, but binds selectively to the kinase-inducible 60 amino acid trans-activation domain (KID) of CREB, critical for PK-A-inducible transcription. We developed an antiserum directed against amino acid 634-648 within the CREB-binding domain of CBP. We detected a 265-kd polypeptide by Western blot as predicted from the cDNA, which coincided with the predominant phospho-CREB-binding activity in Hela nuclear extracts by "Far Western" blot assay. An identical phospho-CREB-binding activity was also found in NIH-3T3 cells. This phospho-CREB-binding protein appeared to be specific for Ser133-phosphorylated CREB, because no such band was detected with CREB labeled to the same specific activity at a nonregulatory phosphoacceptor site (Ser156) by casein kinase II (CKII). Following microinjection into nuclei of NIH-3T3 cells, a cAMP response element (CRE)-lacZ reporter was markedly induced by treatment with 8-Br cAMP plus isobutyl methyl xanthine (IBMX). Coinjection of CBP antiserum with the CRE-lacZ plasmid inhibited cAMP-dependent activity in a dose-dependent manner, but control immunoglobulin G (lgG) had no effect on this response. We can now begin reconstituting PK-A-dependent transcription in vitro, using well-characterized proteins such as CREB, TAF 110, and CBP. The assembly of such factors on cAMP-regulated promoters like somatostain may enable responsiveness to a variety of hormonal stimuli that employ cAMP as their second messenger.
 ...
PMID:Regulation of somatostatin gene transcription by cyclic adenosine monophosphate. 876 68

The human cytomegalovirus (HCMV) immediate-early region 2 86-kDa protein (IE2 86) is the major transactivator of the promoter for the 2.2-kb class of early RNAs (open reading frame UL 112-113). Previously, we reported that a DNA segment on this promoter between nucleotides (nt) -113 and -59 was critical for activation by IE2 86 in vivo and could be bound by IE2 86 in vitro (R. Schwartz, M. H. Sommer, A. Scully, and D. H. Spector, J. Virol. 68:5613-5622, 1994). With a set of site-specific mutations within nt -84 to -61, we have localized the essential cis-acting sequences to nt -72 to -61, which contain an ATF/CREB-binding site. The IE2 86-binding site between nt -113 and -85 is not essential for activation of the promoter by IE2 86 in transient-expression assays, but its presence can enhance the level of activation mediated through the sequences located between nt -84 and -59. Electrophoretic mobility shift assays with a segment containing nt -84 to -59 and nuclear extracts from human cells permissive for the HCMV infection revealed a complex band pattern. However, by supershift analysis with specific antibodies, we were able to identify CREB as the major ATF/CREB family member in the protein-DNA complexes. Further evidence that CREB is a target for IE2 86-mediated induction, is provided by the finding that IE2 86 activates the somatostatin promoter to high levels. Although the binding of IE2 86 to nonphosphorylated full-length CREB or deltaCREB is minimal, IE2 86 does form complexes with p300 and the CREB-binding protein (CBP), which in turn bind to CREB and can serve as adaptor proteins for CREB function. In addition, the in vivo functional relevance of the interaction between IE2 86 and CBP is indicated by the ability of IE2 86 to enhance transcriptional activation mediated by a GAL4-CBP fusion protein brought to a promoter by GAL4-binding sites.
 ...
PMID:CREB and CREB-binding proteins play an important role in the IE2 86-kilodalton protein-mediated transactivation of the human cytomegalovirus 2.2-kilobase RNA promoter. 879 39

The human T-cell leukemia virus type 1 (HTLV-1) Tax protein activates viral transcription through three 21-bp repeats located in the U3 region of the HTLV-1 long terminal repeat and called Tax-responsive elements (TxREs). Each TxRE contains nucleotide sequences corresponding to imperfect cyclic AMP response elements (CRE). In this study, we demonstrate that the bZIP transcriptional factor CREB-2 is able to bind in vitro to the TxREs and that CREB-2 binding to each of the 21-bp motifs is enhanced by Tax. We also demonstrate that Tax can weakly interact with CREB-2 bound to a cellular palindromic CRE motif such as that found in the somatostatin promoter. Mutagenesis of Tax and CREB-2 demonstrates that both N- and C-terminal domains of Tax and the C-terminal region of CREB-2 are required for direct interaction between the two proteins. In addition, the Tax mutant M47, defective for HTLV-1 activation, is unable to form in vitro a ternary complex with CREB-2 and TxRE. In agreement with recent results suggesting that Tax can recruit the coactivator CREB-binding protein (CBP) on the HTLV-1 promoter, we provide evidence that Tax, CREB-2, and CBP are capable of cooperating to stimulate viral transcription. Taken together, our data highlight the major role played by CREB-2 in Tax-mediated transactivation.
 ...
PMID:Molecular interactions involved in the transactivation of the human T-cell leukemia virus type 1 promoter mediated by Tax and CREB-2 (ATF-4). 1077 37

The cAMP-response element-binding protein (CREB) transcription factor was initially identified as a mediator of cAMP-induced gene expression. CREB binds to a target sequence termed the cAMP-response element (CRE) found in many cellular and viral gene promoters. One of the best-characterized CREs resides in the promoter of the gene encoding the neuropeptide somatostatin, and this element has served as a model for studies of CREB function. Phosphorylation of CREB by protein kinase A allows recruitment of the coactivator CREB-binding protein (CBP). A central tenet of the CREB-CBP model is that CREB binds constitutively to the CRE and that regulation occurs through the phosphorylation-dependent recruitment of CBP. In this report, we use chromatin immunoprecipitation assays to show that CREB does not interact in vivo with the somatostatin CRE, or similar elements in several other genes, in PC12 cells, a standard model for studies of CREB function. Rather, CREB binding in vivo is regulated in a cell-specific manner, a finding that was confirmed by using in vivo genomic footprinting assays. The CREs in other genes were also found to interact differentially with CREB in PC12 cells, hepatoma cells, and cortical neurons. We conclude that the family of CREB target genes differs from one cell type to another and that the ability of CREB to bind to a particular CRE represents an important component of gene regulation.
 ...
PMID:Cell-type-specific binding of the transcription factor CREB to the cAMP-response element. 1534 15

Recent evidence has shown that the activity of cAMP responsive element-binding protein (CREB) and of CREB-binding protein (CBP) is decreased in Huntington's disease (HD) [Steffan et al. (2000)Proc. Natl Acad. Sci. USA, 97, 6763-6768; Gines et al. (2003)Hum. Mol. Genet., 12, 497-508; Rouaux et al. (2004) Biochem. Pharmacol., 68, 1157-1164; Sugars et al. (2004)J. Biol. Chem., 279, 4988-4999]. Such decrease is thought to reflect the impaired energy metabolism observed in a HD mouse model, where a decline in striatum cAMP levels has been observed [Gines et al. (2003)Hum. Mol. Genet., 12, 497-508]. Increased levels of CREB have also been demonstrated to exert neuroprotective functions [Lonze & Ginty (2002)Neuron, 35, 605-623; Lonze et al. (2002)Neuron, 34, 371-385]. Our study aimed to investigate the distribution of CREB in the neuronal subpopulations of the striatum in normal rats compared to the HD model of quinolinic acid lesion. Twenty-five Wistar rats were administered quinolinic acid 100 mm into the right striatum, and killed after 24 h, 48 h, 1 week, 2 weeks, and six weeks, respectively. The contralateral striata were used as controls. Dual-label immunofluorescence was employed using antibodies against phosphorylated CREB and each of the different neuronal subpopulations markers. Our results show that activated CREB levels decrease progressively in projection neurons and parvalbumin (PARV) and calretinin (CALR) interneurons, whereas such levels remain stable in cholinergic and somatostatin interneurons. Thus, we speculate that the ability of cholinergic interneurons to maintain their levels of CREB after excitotoxic lesions is one of the factors determining their protection in Huntington's disease.
 ...
PMID:Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions: implications with neuronal vulnerability in Huntington's disease. 1642 Apr 11