Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic AMP (cAMP) response element binding protein (CREB) is a transcription factor that has been implicated in neuronal responses to ischemia. We examined the effect of global cerebral ischemia in the rat on the expression of CREB, its transcriptionally active phosphorylated form (pCREB), and the nuclear adaptor protein, CREB binding protein (CBP). Global ischemia induced the expression of pCREB and CBP in vulnerable neurons of the hippocampal CA1 sector. In primary cultures of murine cortical neurons subjected to hypoxia, CBP was selectively expressed in cells with morphologically intact cell nuclei, and not in cells with condensed or fragmented nuclei indicative of irreversibly damaged neurons. These results support a role for transcriptional activation by CREB and CBP in neuronal cell-survival programs following cerebral ischemia.
J Mol Neurosci 2001 Feb
PMID:Cyclic AMP response element binding protein (CREB) and CREB binding protein (CBP) in global cerebral ischemia. 1134 20

Estrogens are essential regulators in the development and control of reproductive functions. The estrogenic signal is now known to be transduced by two estrogen receptors, ERalpha and ERbeta. Hormone-dependent transcriptional activation of ER and other nuclear receptors involves assembly of a coactivation complex which includes various cofactors such as the steroid receptor-coactivators (SRC) and CREB binding protein (CBP). Our findings on ERbeta have revealed a ligand-independent activation pathway which involves growth factor-mediated phosphorylation of ERbeta activation function-1 (AF-1) and subsequent recruitment of SRC-1 independently of the presence of estrogens. The presence of the cointegrator CBP is also shown to potentiate the SRC-1-mediated ERbeta ligand-independent activation, suggesting that CBP may participate in unliganded ERbeta coactivation. These findings demonstrate the ability of alternate signaling pathways to mediate coregulator assembly, hence resulting in ligand-independent activation of ERbeta.
J Steroid Biochem Mol Biol 2001 Apr
PMID:Contribution of steroid receptor coactivator-1 and CREB binding protein in ligand-independent activity of estrogen receptor beta. 1135 71

Ying Yang transcription factor (YY1) can repress or activate transcription. 25-Hydroxyvitamin D(3)-24-hydroxylase [24(OH)ase], an enzyme involved in the catabolism of 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], is up-regulated at the transcriptional level by 1,25-(OH)(2)D(3) to self-induce its deactivation. Here we report that YY1 can repress 1,25-(OH)(2)D(3)-induced 24(OH)ase transcription in CV1 cells transfected with vitamin D receptor (VDR) expression vector or in LLCPK(1) cells that contain VDR endogenously. With increasing amounts of YY1 DNA transfected (500 ng to 2 microg), ligand-dependent VDR activation of 24(OH)ase transcription was steadily repressed (maximum repression was 10-fold). Thus, YY1 may be a key modulator preventing activation at times that do not require the enzyme to be expressed. Relief of YY1 repression was observed in the presence of TFIIB or CBP (CREB binding protein) suggesting that YY1 may exert repression, in part, by sequestering TFIIB/CBP. Glutathione-S-transferase (GST) pull-down assays identified regions in the N and C termini of CBP that can bind YY1. In addition, the N-terminal region of CBP that interacts with YY1 can inhibit YY1 from binding to TFIIB. Thus, CBP may alleviate YY1-mediated repression, in part, by preventing YY1 from binding to TFIIB, which is required for VDR-mediated transcription. In summary, our results suggest that YY1 represses 24(OH)ase transcription, at least in part, by sequestering activator proteins involved in VDR-mediated transcription. In addition, our findings demonstrate a role for CBP in relief of repression of VDR-mediated transcription.
Mol Endocrinol 2001 Jun
PMID:YY1 represses vitamin D receptor-mediated 25-hydroxyvitamin D(3)24-hydroxylase transcription: relief of repression by CREB-binding protein. 1137 20

Studies with live cells demonstrate that agonist and antagonist rapidly (within minutes) modulate the subnuclear dynamics of estrogen receptor alpha (ER) and steroid receptor coactivator 1 (SRC-1). A functional cyan fluorescent protein (CFP)-tagged lac repressor-ER chimera (CFP-LacER) was used in live cells to discretely immobilize ER on stably integrated lac operator arrays to study recruitment of yellow fluorescent protein (YFP)-steroid receptor coactivators (YFP-SRC-1 and YFP-CREB binding protein [CBP]). In the absence of ligand, YFP-SRC-1 is found dispersed throughout the nucleoplasm, with a surprisingly high accumulation on the CFP-LacER arrays. Agonist addition results in the rapid (within minutes) recruitment of nucleoplasmic YFP-SRC-1, while antagonist additions diminish YFP-SRC-1-CFP-LacER associations. Less ligand-independent colocalization is observed with CFP-LacER and YFP-CBP, but agonist-induced recruitment occurs within minutes. The agonist-induced recruitment of coactivators requires helix 12 and critical residues in the ER-SRC-1 interaction surface, but not the F, AF-1, or DNA binding domains. Fluorescence recovery after photobleaching indicates that YFP-SRC-1, YFP-CBP, and CFP-LacER complexes undergo rapid (within seconds) molecular exchange even in the presence of an agonist. Taken together, these data suggest a dynamic view of receptor-coregulator interactions that is now amenable to real-time study in living cells.
Mol Cell Biol 2001 Jul
PMID:Ligand-mediated assembly and real-time cellular dynamics of estrogen receptor alpha-coactivator complexes in living cells. 1139 Jun 68

RNA helicase A (RHA) is a member of an ATPase/DNA and RNA helicase family and is a homologue of Drosophila maleless protein (MLE), which regulates X-linked gene expression. RHA is also a component of holo-RNA polymerase II (Pol II) complexes and recruits Pol II to the CREB binding protein (CBP). The ATPase and/or helicase activity of RHA is required for CREB-dependent transcription. To further understand the role of RHA on gene expression, we have identified a 50-amino-acid transactivation domain that interacts with Pol II and termed it the minimal transactivation domain (MTAD). The protein sequence of this region contains six hydrophobic residues and is unique to RHA homologues and well conserved. A mutant with this region deleted from full-length RHA decreased transcriptional activity in CREB-dependent transcription. In addition, mutational analyses revealed that several tryptophan residues in MTAD are important for the interaction with Pol II and transactivation. These mutants had ATP binding and ATPase activities comparable to those of wild-type RHA. A mutant lacking ATP binding activity was still able to interact with Pol II. In CREB-dependent transcription, the transcriptional activity of each of these mutants was less than that of wild-type RHA. The activity of the double mutant lacking both functions was significantly lower than that of each mutant alone, and the double mutant had a dominant negative effect. These results suggest that RHA could independently regulate CREB-dependent transcription either through recruitment of Pol II or by ATP-dependent mechanisms.
Mol Cell Biol 2001 Jul
PMID:Dual roles of RNA helicase A in CREB-dependent transcription. 1141 26

Estrogen receptor (ER) and cAMP signaling pathways interact in a number of estrogen target tissues including mammary and uterine tissues. One aspect of this interaction is that estradiol and protein kinase A (PKA) activators can cooperate synergistically to activate ER-mediated transcription of both endogenous genes and reporter genes containing only estrogen response elements. The purpose of this study was to investigate the molecular mechanism of this interaction between signaling pathways. Site-directed mutagenesis of the potential PKA phosphorylation sites in the ER indicated that phosphorylation of these sites was not necessary for the observed transcriptional synergy. In transient transfection assays in two different cell lines using reporter constructs containing either cAMP response elements, estrogen response elements or both types of elements, with the addition or absence of cAMP response element binding protein (CREB) expression plasmid, we observed that only one of these cell lines exhibited estrogen/PKA transcriptional synergy. Experiments demonstrated that CREB itself was involved in the transcriptional synergy, and that transfection of CREB restored transcriptional synergy in the cell line in which it was lacking. A functional interaction between ER and CREB was also demonstrated using a mammalian cell protein interaction assay; a dominant negative mutant of CREB did not exhibit this interaction. Therefore, these data indicate that CREB protein is required for the transcriptional synergy between cAMP and estrogen signaling pathways. Furthermore, CREB cooperated with the ER on genes that did not contain cAMP response elements, but contained only estrogen response elements. We propose that activated CREB is recruited to estrogen responsive genes by an ER--coactivator complex containing proteins such as CREB binding protein (CBP) and that the interaction of CREB with ER may assist in stabilizing its interaction with CBP and in promoting estrogen-ER and PKA transcriptional synergy.
J Steroid Biochem Mol Biol 2001 Jun
PMID:Involvement of cyclic AMP response element binding protein (CREB) and estrogen receptor phosphorylation in the synergistic activation of the estrogen receptor by estradiol and protein kinase activators. 1145 57

Growth factors such as epidermal growth factor (EGF) and insulin regulate development and metabolism via genes containing both POU homeodomain (Pit-1) and phorbol ester (AP-1) response elements. Although CREB binding protein (CBP) functions as a coactivator on these elements, the mechanism of transactivation was previously unclear. We now demonstrate that CBP is recruited to these elements only after it is phosphorylated at serine 436 by growth factor-dependent signaling pathways. In contrast, p300, a protein closely related to CBP that lacks this phosphorylation site, binds only weakly to the transcription complex and in a growth factor-independent manner. A small region of CBP (amino acids 312-440), which we term GF box, contains a potent transactivation domain and mediates this effect. Direct phosphorylation represents a novel mechanism controlling coactivator recruitment to the transcription complex.
Mol Cell 2001 Mar
PMID:CREB binding protein recruitment to the transcription complex requires growth factor-dependent phosphorylation of its GF box. 1146 80

Huntington's disease (HD) is a hereditary neurodegenerative condition caused by a characteristic mutation in the huntingtin (htt) gene. This gene was identified in 1993. Both the mitochondria and the nucleus play an important role in HD pathology. However, the precise molecular mechanisms remain unclear. A key strategy for understanding HD pathology is to identify signaling cascades initiated by mutant Htt that lead to neuronal cell death and dysfunction. Apoptotic stress induces greater mitochondrial depolarization in HD lymphoblasts than in control subjects. This leads to overactivation of caspase-3, which is capable of cleaving htt. Truncated forms of Htt, which are similar to the caspase-cleaved products in size, exist in the nucleus of HD patient and animal model brains. We hypothesize that caspases, which are activated by mitochondrial depolarization, play a role in producing truncated forms of Htt, which accumulate in the nucleus. Truncated forms of mutant Htt that accumulate in the nucleus are toxic to cells. There is growing evidence that truncated forms of mutant Htt in the nucleus influence gene transcription by binding to proteins such as CREB binding protein (CBP) response element binding protein binding protein, N-COR, glyceraldehyde-3-phosphate dehydrogenase, and p53. p53 regulates the transcription of various mitochondrial proteins which may underlie the mitochondrial abnormalities, especially the vulnerability to mitochondrial depolarization, seen in HD tissues. Taken together, we hypothesize a noxious signaling cascade between the mitochondria and the nucleus, initiated by mutant Htt, which may underlie HD pathology.
J Mol Med (Berl) 2001 Jul
PMID:Mechanisms for neuronal cell death and dysfunction in Huntington's disease: pathological cross-talk between the nucleus and the mitochondria? 1146 59

The cyclic AMP (cAMP)-responsive factor CREB induces target gene expression via constitutive (Q2) and inducible (KID, for kinase-inducible domain) activation domains that function synergistically in response to cellular signals. KID stimulates transcription via a phospho (Ser133)-dependent interaction with the coactivator paralogs CREB binding protein and p300, whereas Q2 recruits the TFIID complex via a direct association with hTAF(II)130. Here we investigate the mechanism underlying cooperativity between the Q2 domain and KID in CREB by in vitro transcription assay with naked DNA and chromatin templates containing the cAMP-responsive somatostatin promoter. The Q2 domain was highly active on a naked DNA template, and Ser133 phosphorylation had no additional effect on transcriptional initiation in crude extracts. Q2 activity was repressed on a chromatin template, however, and this repression was relieved by the phospho (Ser133) KID-dependent recruitment of p300 histone acetyltransferase activity to the promoter. In chromatin immunoprecipitation assays of NIH 3T3 cells, cAMP-dependent recruitment of p300 to the somatostatin promoter stimulated acetylation of histone H4. Correspondingly, overexpression of hTAFII130 potentiated CREB activity in cells exposed to cAMP, but had no effect on reporter gene expression in unstimulated cells. We propose that cooperativity between the KID and Q2 domains proceeds via a chromatin-dependent mechanism in which recruitment of p300 facilitates subsequent interaction of CREB with TFIID.
Mol Cell Biol 2001 Dec
PMID:Chromatin-dependent cooperativity between constitutive and inducible activation domains in CREB. 1168 82

We have previously demonstrated that overexpression of Cdc25B in transgenic mice resulted in mammary gland hyperplasia and increased steroid hormone responsiveness. To address how Cdc25B enhances the hormone responsiveness in mammary glands, we showed that Cdc25B stimulates steroid receptor-dependent transcription in transient transfection assays and in a cell-free assay with chromatin templates. Surprisingly, the effect of Cdc25B on steroid receptors is independent of its protein phosphatase activity in vitro. The direct interactions of Cdc25B with steroid receptors, on the other hand, were evidenced in in vivo and in vitro assays, suggesting the potential direct contribution of Cdc25B on the steroid receptor-mediated transcription. In addition, p300/CBP-associated factor and CREB binding protein were shown to interact and synergize with Cdc25B and further enhance its coactivation activity. Thus, we have uncovered a novel function of Cdc25B that serves as a steroid receptor coactivator in addition to its role as a regulator for cell cycle progression. This dual function might likely contribute to its oncogenic action in breast cancer.
Mol Cell Biol 2001 Dec
PMID:Cdc25B functions as a novel coactivator for the steroid receptors. 1168 96


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