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)

The human immunodeficiency virus type I (HIV-1) transactivator protein Tat is an unusual transcriptional activator that is thought to act solely by promoting RNA polymerase II processivity. Here we study the mechanism of Tat action by analyzing transcription complex (TC) assembly in vivo using chromatin immunoprecipitation assays. We find, unexpectedly, that like typical activators Tat dramatically stimulates TC assembly. Surprisingly, however, the TC formed on the HIV-1 long terminal repeat is atypical and contains TATA-box-binding protein (TBP) but not TBP-associated factors (TAFs). Tat function involves direct interaction with the cellular cofactor positive transcription elongation factor b (P-TEFb). Artificial tethering of P-TEFb subunits to HIV-1 promoter DNA or nascent RNA indicates that P-TEFb is responsible for directing assembly of a TC containing TBP but not TAFs. On the basis of this finding, we identify P-TEFb-dependent cellular promoters that also recruit TBP in the absence of TAFs. Thus, in mammalian cells transcription of protein-coding genes involves alternative TCs that differ by the presence or absence of TAFs.
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PMID:HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs. 1571 58

We recently described a pair of ligands, PPKID4(P) (4(P)) and PPKID6(U) (6(U)), which present the alpha-helical functional epitope found on helix B of the CREB KID activation domain (KID(P)) on a pancreatic fold protein scaffold. 4(P) and 6(U) bind the natural target of KID(P), the KIX domain of the coactivator CBP, with equilibrium dissociation constants between 515 nM and 1.5 microM and compete effectively with KID(P) for binding to CBP KIX (KIX). Here we present a detailed investigation of the binding mode, orientation, and transcriptional activation potential of 4(P) and 6(U). Equilibrium binding experiments using a panel of well-characterized KIX variants support a model in which 4(P) binds KIX in a manner that closely resembles that of KID(P) but 6(U) binds an overlapping, yet distinct region of the protein. Equilibrium binding experiments using a judiciously chosen panel of 4(P) variants containing alanine or sarcosine substitutions along the putative alpha- or PPII helix of 4(P) support a model in which 4(P) folds into a pancreatic fold structure upon binding to KIX. Transcriptional activation assays performed in HEK293 cells using GAL4 DNA-binding domain fusion proteins indicate that 4(P) functions as a potent activator of p300/CBP-dependent transcription. Notably, 6(U) is a less potent transcriptional activator in this context than 4(P)despite the similarity of their affinities for CBP KIX. This final result suggests that thermodynamic affinity is an important, although not exclusive, criterion controlling the level of KIX-dependent transcriptional activation.
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PMID:Binding mode and transcriptional activation potential of high affinity ligands for the CBP KIX domain. 1579 30

TonEBP [TonE (tonicity-responsive enhancer)-binding protein] is a transcriptional activator of the Rel family like NF-kappaB (nuclear factor kappaB) and NFAT (nuclear factor of activated T-cells). TonEBP plays a key role in the protection of cells in the kidney medulla from the deleterious effects of hyperosmolality. This is achieved by enhancing expression of HSP70 (heat-shock protein 70) and other genes whose products drive cellular accumulation of organic osmolytes. TonEBP is stimulated by ambient hypertonicity via multiple pathways that regulate nuclear translocation and transactivation. In the present paper, we report that TonEBP is associated in vivo with RHA (RNA helicase A). The N- and C-termini of RHA bound the E'F loop of the DNA-binding domain of TonEBP. The interaction was not affected by DNA binding or dimerization of TonEBP. Overexpression of RHA inhibited the activity of TonEBP; however, catalytic activity of RHA was dispensable for the inhibition. When the ambient tonicity was raised, the TonEBP-RHA interaction decreased, suggesting that dissociation of RHA is a pathway to stimulate TonEBP. We conclude that the E'F loop of TonEBP interacts with RHA like NFAT and NF-kappaB interact with AP1 (activator protein 1) and the high-mobility group protein HMG-I(Y) respectively. While RHA interacts with and stimulates other transcription factors such as CREB (cAMP-response-element-binding protein), NF-kappaB and mineralocorticoid receptor, it inhibits TonEBP.
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PMID:TonEBP is inhibited by RNA helicase A via interaction involving the E'F loop. 1617 19

Human T-lymphotropic virus type 1 (HTLV-1) encodes a transcriptional activator, Tax, whose function is essential for viral transcription and replication. Tax transactivates the viral long-terminal repeat through a series of protein-protein interactions which facilitate CREB and CBP/p300 binding. In addition, Tax dissociates transcription repressor histone deacetylase 1 interaction with the CREB response element. The subsequent events through which Tax interacts and communicates with RNA polymerase II and cyclin-dependent kinases (CDKs) are not clearly understood. Here we present evidence that Tax recruits positive transcription elongation factor b (P-TEFb) (CDK9/cyclin T1) to the viral promoter. This recruitment likely involves protein-protein interactions since Tax associates with P-TEFb in vitro as demonstrated by glutathione S-transferase fusion protein pull-down assays and in vivo as shown by co-immunoprecipitation assays. Functionally, small interfering RNA directed toward CDK9 inhibited Tax transactivation in transient assays. Consistent with these findings, the depletion of CDK9 from nuclear extracts inhibited Tax transactivation in vitro. Reconstitution of the reaction with wild-type P-TEFb, but not a kinase-dead mutant, recovered HTLV-1 transcription. Moreover, the addition of the CDK9 inhibitor flavopiridol blocked Tax transactivation in vitro and in vivo. Interestingly, we found that Tax regulates CDK9 kinase activity through a novel autophosphorylation pathway.
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PMID:Tax interacts with P-TEFb in a novel manner to stimulate human T-lymphotropic virus type 1 transcription. 1664 Dec 71

The transcriptional activator retinoic acid (RA) is a regulator of neural development and regeneration. Synergistic effects with brain-derived neurotrophic factor suggested that RA influences neurotrophin signaling. To test this hypothesis RA was administered systemically to E17 chick embryos, and retinas were prepared 12h and 24h later to measure mRNA or protein expression. While there was no significant influence on activation of Akt, CREB and STAT-3, RA-treatment caused elevated levels of Erk-phosphorylation, a kinase involved in Trk signaling. A small but significant increase in the expression of TrkB mRNA and protein was observed but no significant change in TrkA, TrkC and p75 expression.
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PMID:Retinoic acid enhances Erk phosphorylation in the chick retina. 1788 Nov 22

Aberrant expression of the steroidogenic acute regulatory (StAR) protein in human endometriotic stromal cells plays an important role in the development of endometriosis. Prostaglandin E(2) (PGE(2)) is a potent inducer of StAR expression in these cells; however, the mechanisms responsible for the transcriptional regulation of StAR remain to be elucidated. Herein we report that PGE(2)-induced StAR expression is independent of the transcriptional suppressor DAX-1 but is regulated by the transcriptional activator cyclic adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB). A promoter activity assay revealed that the cis-element needed for the binding of the CCAAT/enhancer-binding protein (C/EBP) was critical for PGE(2)-induced StAR expression. Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells. Results from a chromatin immunoprecipitation assay demonstrated that the binding of C/EBPbeta to the StAR promoter was increased whereas CREB binding was unchanged after PGE(2) treatment. Taken together, PGE(2)-induced StAR promoter activity appears to be regulated by CREB and C/EBPbeta in a cooperative manner in ectopic human endometriotic stromal cells, providing a molecular framework for the etiology of endometriosis.
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PMID:Cyclic adenosine 3',5'-monophosphate response element-binding protein and CCAAT/enhancer-binding protein mediate prostaglandin E2-induced steroidogenic acute regulatory protein expression in endometriotic stromal cells. 1858 20

CREB is a cAMP- and calcium-responsive transcriptional activator that is required for islet beta cell proliferation and survival. Glucose and incretin hormones elicit beta cell insulin secretion and promote synergistic CREB activity by inducing the nuclear relocalization of TORC2 (also known as Crtc2), a coactivator for CREB. In islet cells under basal conditions when CREB activity is low, TORC2 is phosphorylated and sequestered in the cytoplasm by 14-3-3 proteins. In response to feeding stimuli, TORC2 is dephosphorylated, enters the nucleus, and binds to CREB located at target gene promoters. The dephosphorylation of TORC2 at Ser-171 in response to cAMP is insufficient to account for the dynamics of TORC2 localization and CREB activity in islet cells. Here, we identify Ser-275 of TORC2 as a 14-3-3 binding site that is phosphorylated under low glucose conditions and which becomes dephosphorylated by calcineurin in response to glucose influx. Dephosphorylation of Ser-275 is essential for both glucose and cAMP-mediated activation of CREB in beta cells and islets. Using a cell-based screen of 180 human protein kinases, we identified MARK2, a member of the AMPK family of Ser/Thr kinases, as a Ser-275 kinase that blocks TORC2:CREB activity. Taken together, these data provide the mechanistic underpinning for how cAMP and glucose cooperatively promote a transcriptional program critical for islet cell survival, and identifies MARK2 as a potential target for diabetes treatment.
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PMID:Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. 1862 18

During fasting periods, hepatic glucose production is enhanced by glucagon to provide fuels for other organs. This process is mediated via cAMP-dependent induction of the CREB regulated transcriptional coactivator (CRTC) 2, a critical transcriptional activator for hepatic gluconeogenesis. We have previously shown that CRTC2 activity is regulated by AMP activated protein kinase (AMPK) family members. Here we show that adiponectin and thiazolidinedione directly regulate AMPK to modulate CRTC2 activity in hepatocytes. Adiponectin or thiazolidinedione lowered glucose production from primary hepatocytes. Treatment of both reagents reduced gluconeogenic gene expression as well as cAMP-mediated induction of CRE reporter, suggesting that these reagents directly affect CREB/CRTC2- dependent transcription. Furthermore, adiponectin or thiazolidinedione mediated repression of CRE activity is largely blunted by co-expression of phosphorylation defective mutant CRTC2, underscoring the importance of serine 171 residue of this factor. Taken together, we propose that adiponectin and thiazolidinedione promote the modulation of AMPK-dependent CRTC2 activity to influence hepatic gluconeogenesis.
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PMID:Adiponectin and thiazolidinedione targets CRTC2 to regulate hepatic gluconeogenesis. 1938 Oct 67

The complete cDNA sequence of a novel gene, SCIRR69 (spinal cord injury and regeneration related no. 69 gene), was obtained by RACE technique. It codes for a protein of 521 amino acid residues homologous to human CREB3l2 (also known as BBF2H7) and mouse CREB3l2. The protein contains a basic DNA binding and leucine zipper dimerization (B-ZIP) motif and a hydrophobic region representing a putative transmembrane domain, similar to the structure of other CREB/ATF transcription factors. Monoclonal antibody against SCIRR69 was developed and could recognize the SCIRR69 protein in both native and denatured forms. Constructing of SCIRR69 fusion proteins with the GAL4 DNA-binding domain disclosed that SCIRR69 functioned as a transcriptional activator and its N-terminal 60 amino acids accounted for the activation ability. SCIRR69 resides in the cytoplasm of primary neurons, whereas neuron damage by incision led to the cleavage and translocation from the cytoplasm to the nucleus. These results suggest that SCIRR69 is activated by proteolytic cleavage at the transmembrane domain in response to neuron damage and its amino-terminal cytoplasmic domain translocates into the nucleus to activate the transcription of target genes.
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PMID:Cloning and characterization of SCIRR69: a novel transcriptional factor belonging to the CREB/ATF family. 2253 19

CREB-responsive transcription has an important role in adaptive responses in all cells and tissue. In the nervous system, it has an essential and well established role in long-term memory formation throughout a diverse set of organisms. Activation of this transcription factor correlates with long-term memory formation and disruption of its activity interferes with this process. Most convincingly, augmenting CREB activity in a number of different systems enhances memory formation. In Drosophila, a sequence rearrangement in the original transgene used to enhance memory formation has been a source of confusion. This rearrangement prematurely terminates translation of the full-length protein, leaving the identity of the "enhancing molecule" unclear. In this report, we show that a naturally occurring, downstream, in-frame initiation codon is used to make a dCREB2 protein off of both transgenic and chromosomal substrates. This protein is a transcriptional activator and is responsible for memory enhancement. A number of parameters can affect enhancement, including the short-lived activity of the activator protein, and the time-of-day when induction and behavioral training occur. Our results reaffirm that overexpression of a dCREB2 activator can enhance memory formation and illustrate the complexity of this behavioral enhancement.
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PMID:dCREB2-mediated enhancement of memory formation. 2361 53


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