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)

Members of the C/EBP family of basic-leucine zipper (bZip) transcription factors form heterodimers and bind to the CAAT box and other sequence-related enhancer motifs. Using a 32P-labeled protein probe consisting of the bZip domain of C/EBP beta, we isolated a clone encoding C/EBP-related ATF (C/ATF), a bZip protein that heterodimerizes with C/EBP-like proteins but belongs to the CREB/ATF family. C/ATF homodimers do not bind to typical C/EBP DNA sites. Instead they bind to palindromic cAMP response elements such as that of the somatostatin gene. In addition, C/ATF-C/EBP beta heterodimers bind to a subclass of asymmetric cAMP response elements exemplified by those in the phosphoenolpyruvate carboxykinase and proenkephalin genes. Transient transfection studies indicate that interactions between C/ATF and C/EBP beta are the basis for a functional cross talk between these two families of transcription factors that may be important for the integration of hormonal and developmental stimuli that determine the expression of subsets of genes in specific cellular phenotypes.
 ...
PMID:C/ATF, a member of the activating transcription factor family of DNA-binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs their binding to cAMP response elements. 850 17

Gene expression from the human T-cell leukemia virus type I (HTLV-I) long terminal repeat (LTR) is mediated by three cis-acting regulatory elements known as 21-base pair (bp) repeats in addition to the transactivator protein Tax. Each of the 21-bp repeats contain nucleotide sequences which are homologous to a cAMP response element (CRE) which bind members of the ATF/CREB family of transcription factors. In this study, we investigated whether CREB alone or in the presence of Tax was able to induce DNA structural changes when bound to CRE sites in the HTLV-I 21 bp, the cellular somatostatin promoter, or a hybrid CRE construct comprised of both the somatostatin and 21-bp repeat sequences. Circular permutation analysis indicated that CREB was able to induce DNA flexure upon binding to each of these elements. However, phasing analysis, which is a more sensitive method to determine the degree and orientation of directed DNA bending, demonstrated that CREB induced DNA bending of the HTLV-I 21-bp repeat and the hybrid CRE but not the somatostatin CRE. The addition of Tax did not change CREB-mediated bending of the 21-bp repeat or the hybrid CRE although it markedly increased the amount of CREB bound to each of these DNA elements. These results indicate that sequence motifs flanking the CRE in the 21-bp repeat are critical for inducing DNA structural changes and that these changes are likely important in mediating Tax activation of the HTLV-I LTR.
 ...
PMID:cAMP-response element-binding protein induces directed DNA bending of the HTLV-I 21-base pair repeat. 861 46

The regulation of human T-cell leukemia virus type 1 (HTLV-1) gene expression is dependent on three cis-acting elements, known as the 21-bp repeats, in the long terminal repeat. Each of the 21-bp repeats contains a nonpalindromic cyclic AMP response element (CRE) sequence which is capable of binding members of the ATF/CREB family of transcription factors. The HTLV-1 transactivator protein Tax is able to markedly stimulate the in vitro binding of CREB to the CRE sites present in each of the 21-bp repeats but not to CRE sites present in cellular promoters. The ability to Tax to stimulate CREB binding to different CRE sites correlates with the ability of Tax to activate gene expression from these sites. We wished to determine how sequence differences between the somatostatin CRE and the 21-bp repeat were involved in this different response to Tax. Scatchard analysis indicated that CREB bound to the somatostatin CRE with a single class of high-affinity binding while CREB bound to the 21-bp repeats with a biphasic binding pattern, indicating the presence of both low- and high-affinity binding. Tax increased the affinity of CREB binding but not that of another ATF/CREB protein, CREB2, to the 21-bp repeat. However, Tax did not increase affinity of binding of CREB to the somatostatin CRE. To determine the mechanism by which Tax increased dCREB binding affinity, immobilized oligonucleotides corresponding to either the 21-bp repeat or the somatostatin CRE were used to demonstrate that Tax formed a highly specific complex with CREB on the 21-bp repeat but not on the somatostatin CRE. These results indicate that formation of a complex between Tax and CREB results in specific high-affinity binding of this ternary complex to the HTLV-1 21 bp repeats.
 ...
PMID:Complex formation between CREB and Tax enhances the binding affinity of CREB for the human T-cell leukemia virus type 1 21-base-pair repeats. 864 26

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 I (HTLV-I) transactivator protein Tax is critical for the activation of viral gene expression and the transformation of T-lymphocytes. Tax activation of HTLV-I gene expression is mediated by three highly homologous regulatory elements known as 21 bp repeats which bind the transcription factor CREB. Questions remain about the mechanism by which Tax can stimulate CREB binding, whether Tax alters CREB binding affinity, what specific sequences in the HTLV-I 21 bp repeat mediate ternary complex formation, and if the ternary complex comprised of Tax and CREB can recruit coactivators such as CBP. To address these points, we used immobilized templates containing either the HTLV-I 21 bp repeats or the somatostatin CRE to assay Tax association with ATF/CREB family members. Tax formed a stable ternary complex on each of the 21 bp repeats with the transcription factor CREB but not related ATF/CREB proteins. In contrast, Tax did not form a similar complex on the CREB binding site in the somatostatin promoter. The formation of this complex was dependent on 3' sequences flanking the CREB binding site within each of the 21 bp repeats and resulted in marked increases in CREB association and binding affinity. Tax increased the binding of phosphorylated CREB to the 21 bp repeat resulting in increased association of the coactivator CBP. However, Tax did not form a complex on the somatostatin CRE in the presence of either phosphorylated or non-phosphorylated CREB and it did not stimulate CBP association to this element. These studies extend previous work and demonstrate how specific DNA sequences flanking the CREB binding site regulate the formation of a stable ternary complex that is able to more efficiently recruit the coactivator CBP.
 ...
PMID:HTLV-1 21 bp repeat sequences facilitate stable association between Tax and CREB to increase CREB binding affinity. 895 Feb 64

The cellular oncoprotein Ewing's sarcoma oncogene (EWS)/activating transcription factor 1 (ATF1) is a highly specific marker for malignant melanoma of soft parts (MMSP) and is a potent activator of several cAMP-inducible promoters, including the somatostatin promoter. Here we explored the potential for using the somatostatin promoter to direct toxic gene expression in MMSP cells. When introduced into MMSP cells, a somatostatin-herpes simplex virus thymidine kinase fusion gene confers strong and cell-specific sensitivity to the cytotoxic prodrug ganciclovir. Ganciclovir sensitivity requires the ATF-binding site present in the somatostatin promoter, indicating that toxic gene expression is caused by EWS/ATF1. We also tested the efficacy of recombinant adenoviruses adenoviruses for gene delivery and expression in two MMSP cell lines (DTC1 and Su-ccs-1). Surprisingly, several promoters (including somatostatin) that are strongly activated by EWS/ATF1 in transient assays are not activated in DTC1 and Su-ccs-1 cells when present in an adenovirus vector. In summary, our findings demonstrate the potential for using the somatostatin promoter for cytotoxic prodrug therapy for MMSP. However, first-generation adenovirus vectors cannot be used as promoter delivery vehicles for toxic gene expression in MMSP cells.
 ...
PMID:The cellular oncogene EWS/activating transcription factor 1 is unable to activate adenovirus-borne promoters: implications for cytotoxic prodrug therapy of malignant melanoma of soft parts. 1076 45

The opposing effects on proliferation mediated by G-protein-coupled receptor isoforms differing in their COOH termini could be correlated with the abilities of the receptors to differentially activate p38, implicated in apoptotic events, or phosphatidylinositol 3-kinase (PI 3-K), which provides a source of survival signals. These contrasting growth responses of the somatostatin sst(2) receptor isoforms, which couple to identical Galpha subunit pools (Galpha(i3) > Galpha(i2) >> Galpha(0)), were both inhibited following betagamma sequestration. The sst(2(a)) receptor-mediated ATF-2 activation and inhibition of proliferation induced by basic fibroblast growth factor (bFGF) were dependent on prolonged phosphorylation of p38. In contrast, cell proliferation and the associated transient phosphorylation of Akt and p70(rsk) induced by sst(2(b)) receptors were blocked by the PI 3-K inhibitor LY 294002. Stimulation with bFGF alone had no effect on the activity of either p38 or Akt but markedly enhanced p38 phosphorylation mediated by sst(2(a)) receptors, suggesting that a complex interplay exists between the transduction cascades activated by these distinct receptor types. In addition, although all receptors mediated a sustained activation of extracellular signal-regulated kinases (ERK1 and ERK2), induction of the tumor suppressor p21(cip1) was detected only following amplification of ERK and p38 phosphorylation by concomitant bFGF and sst(2(a)) receptor activation. Expression of constitutively active Akt in the presence of a p38 inhibitor enabled a proliferative response to be detected in sst(2(a)) receptor-expressing cells. These findings demonstrate that the duration of activation and a critical balance between the mitogen-activated protein kinase and PI 3-K pathways are important for controlling cell proliferation and that the COOH termini of the sst(2) receptor isoforms may determine the selection of appropriate betagamma-pairings necessary for interaction with distinct kinase cascades.
 ...
PMID:Receptor isoforms mediate opposing proliferative effects through gbetagamma-activated p38 or Akt pathways. 1091 80


<< Previous 1 2