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At least 649 records · Page 36Linked to original sources
PubMed1999

Factor-specific modulation of CREB-binding protein acetyltransferase activity.

CREB-binding proteins (CBP) and p300 are essential transcriptional coactivators for a large number of regulated DNA-binding transcription factors, including CREB, nuclear receptors, and STATs. CBP and p300 function in part by mediating the assembly of multiprotein complexes that contain additional cofactors such as p300/CBP interacting protein (p/CIP), a member of the p160/SRC family of coactivators, and the p300/CBP associated factor p/CAF. In addition to serving as molecular scaffolds, CBP and p300 each possess intrinsic acetyltransferase activities that are required for their function as coactivators. Here we report that the adenovirus E1A protein inhibits the acetyltransferase activity of CBP on binding to the C/H3 domain, whereas binding of CREB, or a CREB/E1A fusion protein to the KIX domain, fails to inhibit CBP acetyltransferase activity. Surprisingly, p/CIP can either inhibit or stimulate CBP acetyltransferase activity depending on the specific substrate evaluated and the functional domains present in the p/CIP protein. While the CBP interaction domain of p/CIP inhibits acetylation of histones H3, H4, or high mobility group by CBP, it enhances acetylation of other substrates, such as Pit-1. These observations suggest that the acetyltransferase activities of CBP/p300 and p/CAF can be differentially modulated by factors binding to distinct regions of CBP/p300. Because these interactions are likely to result in differential effects on the coactivator functions of CBP/p300 for different classes of transcription factors, regulation of CBP/p300 acetyltransferase activity may represent a mechanism for integration of diverse signaling pathways.

Acetylation↗
PubMed2001

Retroviral transduction model of mixed lineage leukemia fused to CREB binding protein.

The in-frame fusion of mixed lineage leukemia to CREB binding protein has been cloned from several patients with t-acute myeloid leukemia and a t(11;16)(q23;p13). A murine retroviral transduction model of mixed lineage leukemia fused to CREB binding protein successfully recapitulates the disease. Interestingly, the mice also develop a preleukemic phase reminiscent of what is often seen in patients with t(11;16). From this work, it was determined that minimally, the amino terminus of mixed lineage leukemia fused to the bromodomain and histone acetyltransferase domain of CREB binding protein are necessary for developing acute myeloid leukemia. This model provides a useful tool for understanding the biologic basis of mixed lineage leukemia leukemogenesis and for developing and testing potential therapeutic agents.

Animals↗
PubMed2005

Inhibition of MuSK expression by CREB interacting with a CRE-like element and MyoD.

The type I receptor-like protein tyrosine kinase MuSK is essential for the neuromuscular junction formation. MuSK expression is tightly regulated during development, but the underlying mechanisms were unclear. Here we identified a novel mechanism by which MuSK expression may be regulated. A cyclic AMP response element (CRE)-like element in the 5'-flanking region of the MuSK gene binds to CREB1 (CRE-binding protein 1). Mutation of this element increases the MuSK promoter activity, suggesting a role for CREB1 in attenuation of MuSK expression. Interestingly, CREB mutants unable to bind to DNA also inhibit MuSK promoter activity, suggesting a CRE-independent inhibitory mechanism. In agreement, CREB1 could inhibit a mutant MuSK transgene reporter whose CRE site was mutated. We provide evidence that CREB interacts directly with MyoD, a myogenic factor essential for MuSK expression in muscle cells. Suppression of CREB expression by small interfering RNA increases MuSK promoter activity. These results demonstrate an important role for CREB1 in the regulation of MuSK expression.

5' Flanking Region↗
PubMed2005

A genetic screen identifies putative targets and binding partners of CREB-binding protein in the developing Drosophila eye.

Drosophila CREB-binding protein (dCBP) is a very large multidomain protein, which belongs to the CBP/p300 family of proteins that were first identified by their ability to bind the CREB transcription factor and the adenoviral protein E1. Since then CBP has been shown to bind to >100 additional proteins and functions in a multitude of different developmental contexts. Among other activities, CBP is known to influence development by remodeling chromatin, by serving as a transcriptional coactivator, and by interacting with terminal members of several signaling transduction cascades. Reductions in CBP activity are the underlying cause of Rubinstein-Taybi syndrome, which is, in part, characterized by several eye defects, including strabismus, cataracts, juvenile glaucoma, and coloboma of the eyelid, iris, and lens. Development of the Drosophila melanogaster compound eye is also inhibited in flies that are mutant for CBP. However, the vast array of putative protein interactions and the wide-ranging roles played by CBP within a single tissue such as the retina can often complicate the analysis of CBP loss-of-function mutants. Through a series of genetic screens we have identified several genes that could either serve as downstream transcriptional targets or encode for potential CBP-binding partners and whose association with eye development has hitherto been unknown. The identification of these new components may provide new insight into the roles that CBP plays in retinal development. Of particular interest is the identification that the CREB transcription factor appears to function with CBP at multiple stages of retinal development.

Animals↗
PubMed2001

Vagal-enteric interface: vagal activation-induced expression of c-Fos and p-CREB in neurons of the upper gastrointestinal tract and pancreas.

Many gastrointestinal and pancreatic functions are under strong modulatory control by the brain via the vagus nerve. To start identifying location and neurochemical phenotype of the enteric neurons receiving functional vagal efferent input, we activated vagal preganglionic neurons either by electrical or chemical stimulation and examined the expression of phosphorylated CREB (c-AMP response element binding protein) and the immediate early gene c-Fos. There was no spontaneous expression of both markers in the pancreas and considerable spontaneous expression of p-CREB but not Fos in the upper GI-tract. Unilateral electrical vagal stimulation-induced p-CREB was found in 40% of neurons in the head of the pancreas. Fos expression was found in 70-90% of neurons in the esophagus and stomach, in 20-30% of myenteric plexus neurons and 5-15% in submucosal neurons of the proximal duodenum. Double-labeling experiments showed that a majority of pancreatic neurons and about 25-35% of neurons in the stomach and duodenum contain NADPH-diaphorase and that many of these receive functional vagal input. Other neurons that can be vagally activated contain gastrin-releasing peptide or calretinin. Chemical stimulation of the dorsal surface of the caudal brainstem with the stable TRH analog RX77368 resulted in selective activation of vagal efferents with expression of Fos in a small number of gastric myenteric plexus neurons. The results demonstrate the suitability of this method to investigate magnitude and local distribution of vagal input to the enteric nervous system as well as specificity of its neurochemically coded pathways. They represent the first step in the identification of function-specific units of parasympathetic vagal outflow.

Activating Transcription Factor 1↗
PubMed2005

Pigment epithelium-derived factor induces pro-inflammatory genes in neonatal astrocytes through activation of NF-kappa B and CREB.

Pigment epithelium-derived factor (PEDF) is a potent and broadly acting neurotrophic factor that protects neurons in various types of cultured neurons against glutamate excitotoxicity and induced-apoptosis. Some of the effects of PEDF reflect specific changes in gene expression, mediated via activation of the transcription factor NF-kappa B in neurons. To investigate whether PEDF also modulates gene expression in astrocytes, we employed the use of RT-PCR to analyze the gene expression of certain pro-inflammatory genes and found that genes such as IL-1 beta, IL-6, TNF-alpha, MIP1 alpha, and MIP3 alpha were induced in PEDF-treated cultured neonatal astrocytes, but not in adult astrocytes. Electrophoresis mobility shift assay (EMSA) revealed that a time- and dose-dependent increase of NF-kappa B- and AP-1-DNA binding activity was observed in PEDF-treated neonatal astrocytes. Furthermore, rapid phosphorylation of CREB protein had occurred in PEDF-treated neonatal astrocytes. Upregulation of pro-inflammatory and AP-1-related genes by PEDF was blocked by overexpression of dominant negative CREB or a mutated form of I kappa B alpha. These results suggest that the induction of pro-inflammatory genes is mediated via activation of NF-kappa B, AP-1, and CREB in neonatal astrocytes. Taken together, these results demonstrate that PEDF is a multipotent factor, capable of affecting not only neurons, but also neonatal astrocytes, and suggests that it may act as a neuroimmune modulator in the developmental brain.

Animals↗
PubMed1990

Cyclic-AMP-responsive transcriptional activation of CREB-327 involves interdependent phosphorylated subdomains.

Cyclic AMP-regulated gene expression is mediated by specific phosphoproteins (CREBs) which bind to cAMP-responsive elements of gene promoters. By analyzing the transactivation activities and phosphorylations in vivo of deletion and point mutated chimeric fusion proteins of the placental CREB-327, in which the DNA-binding domain is replaced by the heterologous binding-domain of the yeast transcription factor GAL4, we localized the cAMP-responsive and phosphorylated domain to a minimal-essential sequence module of 46 amino acids (residues 92-137). This serine-rich, multiply-phosphorylated sequence consists of at least three interdependent subdomains required for transcriptional activation. Although phosphorylation of serine-119 by cyclic AMP-dependent protein kinase A is necessary for transcriptional activation, such activation requires both a phosphorylated heptadecapeptide domain located ten residues amino terminal to the serine-119 and an eleven-residue domain carboxyl terminal to the serine-119. Deletion of these two domains does not impair phosphorylation of serine-119. Further, deletion of the carboxyl-terminal domain does not alter phosphorylation of the heptadecapeptide domain. We propose that akin to the phosphorylation-dependent activation of enzymes, the transcriptional transactivation functions of CREB-327 involve a phosphorylation-dependent allosteric conformational mechanism.

Amino Acid Sequence↗
PubMed2007

Phosphorylation of CREB and DARPP-32 during late LTP at hippocampal to prefrontal cortex synapses in vivo.

Specific patterns of stimulation applied in the ventral hippocampus produce long-term potentiation (LTP) of postsynaptic synapses in the prefrontal cortex in vivo. The induction of LTP is dependent on NMDA receptors and cAMP-dependant kinase (PKA) activation. Yet little is known concerning the cellular mechanisms underlying the expression of this neocortical form of LTP. In the present study, we tested whether LTP at hippocampal to prefrontal cortex synapses leads to activation of DARPP-32 and CREB as well as defined the temporal regulation of the phosphorylation states of both proteins. Our data indicate a peak in CREB and DARPP-32 phosphorylation during the late phase of prefrontal LTP (2 h posttetanus). These findings support the hypothesis that prolonged expression of hippocampal-prefrontal cortex LTP depends on a synergistic mechanism involving phosphorylation of both CREB and DARPP-32 via activation of the cAMP/PKA-dependent pathway.

Animals↗
PubMed2005

Diurnal variation in CREB phosphorylation and PER1 protein levels in lactotroph cells of melatonin-proficient C3H and melatonin-deficient C57BL mice: similarities and differences.

The pineal hormone melatonin plays an important role in the maintenance of rhythmic functions of the hypophyseal pars tuberalis, which controls the lactotroph cells of the pars distalis. To analyze the effects of melatonin deficiency on the activity state of these cells, we have investigated the levels of Ser133-phosphorylated (p)CREB and PER1 protein in immunocytochemically identified lactotroph cells of melatonin-proficient C3H and melatonin-deficient C57BL mice at four different time points of a 12/12 LD cycle. At night, the percentage of lactotroph cells showing a positive nuclear pCREB and PER1 immunoreaction is significantly smaller in C57BL than in C3H mice. In both mouse strains, the percentage of pCREB-immunoreactive cells is minimal in the early morning and gradually increases to reach a maximum in the late night. PER1 levels show a parallel temporal variation in C3H, but in C57BL, they are drastically reduced in the early afternoon. The observation that, during darkness, the percentage of lactotroph cells with nuclear pCREB immunoreaction is significantly higher in C3H than in C57BL mice suggests the existence of a distinct cell population that is under the control of melatonin-dependent intrapituitary signaling. Interestingly, the percentage of pCREB- and PER1-immunoreactive lactotroph cells reaches minimal and maximal values at the same time points. This suggests that the correlation between CREB phosphorylation and PER1 induction differs between these cells and other neuroendocrine centers, e.g., the pineal organ and suprachiasmatic nucleus, displaying a temporal gap between CREB phosphorylation and PER1 induction.

Animals↗
PubMed2002

Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?

Chronic administration of noradrenergic antidepressants causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system. In the present studies, we attempted to answer the question of whether or not this deamplification is reflected beyond the second messenger system. Nuclear CREB-P was determined in frontal cortex of rats following acute and chronic administration of desipramine (DMI) or reboxetine and in human fibroblasts following incubation for 48 hours with DMI, reboxetine or venlafaxine. Nuclear CREB-P in the frontal cortex was significantly decreased following chronic administration of DMI or reboxetine. Moreover, incubation of human fibroblasts with DMI or reboxetine, but not with venlafaxine, caused a highly significant reduction in nuclear CREB-P suggesting that the noradrenergic antidepressants exert direct effects beyond beta adrenoceptors. The results are consistent with the view that chronic treatment with antidepressants causes a net deamplification of the norepinephrine mediated signal transduction cascade which might "normalize" the increased noradrenergic activity evident in major depression.

Animals↗
PubMed1996

Levodopoa but not bromocriptine induces AP-1 and creb DNA-binding activity in the dopamine-depleted striatum of the rat.

To elucidate the neurochemical mechanism that underlies the effect of anti-parkinsonian agents on motor activities in the dopamine-depleted striatum, we evaluated AP-I and CREB DNA-binding activity in the striatum of 6-hydroxydopamine-lesioned rats by use of a gel mobility-shift assay. Rats with a unilateral lesion of the nigrostriatal dopamine pathway were injected i.p. with either SKF38393 (a DI receptor agonist), bromocriptine (a D2 receptor agonist), or levodopa (a Dl/D2 receptor agonist). Each treatment increased the number of rotational responses of rats contralateral to the lesioned side. However, only SKF38393 and levodopa increased AP-I and CREB DNA-binding activity in the dopamine-depleted striatum. As with the expression of c-fos, supersensitive DI receptors may play a key role in the enhanced induction of AP-I and CREB DNA-binding activity in the dopamine-depleted striatum. Supershift analysis revealed that c-Fos; and Jun family proteins are the main components for AP-1 induced in the dopamine-depleted striaturn by SKF38393 or levodopa.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Nerve growth factor activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB.

A mechanism by which the nerve growth factor (NGF) signal is transduced to the nucleus to induce gene expression has been characterized. An NGF-inducible, Ras-dependent protein kinase has been identified that catalyzes the phosphorylation of the cyclic AMP response element-binding protein (CREB) at Ser-133. Phosphorylation of Ser-133 stimulates the ability of CREB to activate transcription in NGF-treated cells. These findings suggest that CREB has a more widespread function than previously believed and functions in the nucleus as a general mediator of growth factor responses.

Animals↗
PubMed2005

TSSK5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates CREB at Ser-133, and stimulates the CRE/CREB responsive pathway.

Several protein kinases have been shown to be involved in spermatogenesis. Recently, a novel subfamily of serine/threonine kinases has been isolated whose expression is limited to testis. Here, we report the fifth family member, named TSSK5, which encodes a 328 amino acid protein. RT-PCR analysis showed that TSSK5 is exclusively expressed in human testis. We isolated cAMP responsive element binding protein (CREB), a TSSK5 interacting protein via yeast two-hybrid system. The in vitro kinase assay showed that TSSK5 phosphorylated CREB at Ser-133. Using a CRE reporter system, we found that TSSK5 could stimulate the CREB/CRE responsive pathway in Hek293 cells. These results suggest that this kinase may be involved in spermatogenesis through phosphorylating CREB and then stimulating the CREB/CRE responsive pathway.

Amino Acid Sequence↗
PubMed2006

Chronic exposure to estrogen and tamoxifen regulates synaptophysin and phosphorylated cAMP response element-binding (CREB) protein expression in CA1 of ovariectomized rat hippocampus.

We report here the in vivo effects of estrogen (E2) on modulation of synaptic plasticity and the agonistic (estrogen-like) role of selective estrogen receptor modulator (SERM), tamoxifen (TAM) in the CA1 of the rat hippocampus. Effects on synaptophysin (SYP), a presynaptic vesicular protein, and phosphorylated cyclic AMP responsive element-binding (p-CREB) protein, a signal transduction pathway molecule, were studied using the ovariectomized (OVX) experimental rat model. Bilateral ovariectomy was performed on 40 rats and these were divided into 4 groups based on the treatment they received (at 2 weeks post-ovariectomy, a subcutaneous injection daily for 4 weeks) viz., OVX+E2 (0.1 mg/kg body weight), OVX+TAM (0.05 mg/kg body weight), OVX+vehicle and one group served as OVX control. An additional 10 animals served as the ovary intact control group. At the end of the treatment schedule, five animals/group were used for immunohistochemical staining of SYP and p-CREB using specific antibodies with peroxidase anti-peroxidase technique on paraformaldehyde-fixed cryostat sections. Protein estimation and Western blot analysis coupled with densitometric analysis (using gel-documentation system and image analysis software) were performed on unfixed hippocampus collected from rest of the five animals/group. Serum estradiol levels were estimated with radioimmunoassay prior to sacrifice. The results revealed that ovariectomy reduced SYP and p-CREB expression whereas E2 or TAM administration resulted in their upregulation. Serum estradiol levels of E2 administered animals were comparable with the ovary intact group whereas those of TAM administered group persisted in the range of OVX controls. To conclude, long-term estrogen therapy modulates the synaptic plasticity of hippocampal neurons and presumably, the agonist biocharacter of TAM as observed in the present investigations, may in the long run have a potential in the treatment and prevention of various estrogen-related disorders.

Animals↗
PubMed2003

Long-term effects of early-life malnutrition and status epilepticus: assessment by spatial navigation and CREB(Serine-133) phosphorylation.

Malnutrition and/or seizure in the developing brain cause hippocampal damages. However, underlying mechanisms remain unclear. The malnutrition group (MN) subjected with malnutrition alone was culled to 20-22 rats per dam on postnatal day 1 (P1). The rats subjected to lithium-pilocarpine (Li/PC)-induced status epilepticus at P21 were grouped as the SE group. The rats subjected to malnutrition and subsequent status epilepticus were grouped as the MS group. Visual-spatial memory test using the Morris water maze task was performed at P80. Following behavioral tests, the hippocampus was evaluated for histological lesions and phosphorylated cAMP-responsive, element-binding protein at serine-133 (pCREB(Ser-133)), an important transcription factor underlying learning and memory in the mammalian brain. Here, the MN group exhibited decreased body weight at P21. There was no significant difference in the seizure duration and mortality between the SE and MS groups. In adulthood (P80), both the SE and MS groups showed the spatial learning deficit, hippocampal cell loss and decreased pCREB(Ser133) level within hippocampal CA1 region. Although the MN group demonstrated a decreased level of pCREB(Ser133), no distinguishable changes in the cognitive deficit and hippocampal neuronal loss were detected. Collectively, the present results suggest that early-life malnutrition led to a reduced phosphorylation of CREB(Ser133) in hippocampal CA1 in the absence of the long-term spatial learning deficit. This decreased phosphorylation of CREB(Ser133) could suggest that cascades of signal transduction responsible for the phosphorylation of CREB(Ser133) might be disturbed by early-life malnutrition. In addition, malnutrition caused no discernible synergistic effects on Li/PC-induced status epilepticus.

Animals↗
PubMed2005

Phospho-CREB and other phospho-proteins: improved recovery from brain tissue.

During attempts to quantify levels of phosphorylated cAMP response element binding protein (CREB-P) in guinea pig brain stem auditory nuclei by Western blotting, we compared the decay of CREB-P levels when tissues were homogenized in traditional Lysis buffer containing detergents or in 50 mM Tris-HCl buffer containing 0.32 M sucrose. The decay of CREB-P levels was retarded considerably in the Tris-Sucrose medium as compared to the Lysis buffer. Similarly, the levels of two other phospho-proteins, extracellular regulated kinases (ERK1/2-P) and stress activated protein/Jun-N-terminal kinase (SAP/JNK-P), were better preserved by the Tris-Sucrose medium. These findings imply that the detergents typically present in the Lysis buffer may disrupt organelles and increase the exposure of soluble phospho-proteins to hydrolyzing enzymes. In contrast, such exposure was probably minimized in the Tris-Sucrose medium, which is thought to preserve organelle integrity.

Animals↗
PubMed2007

Activation of MAPKs by 1alpha,25(OH)2-Vitamin D3 and 17beta-estradiol in skeletal muscle cells leads to phosphorylation of Elk-1 and CREB transcription factors.

The mitogen activated protein kinases (MAPKs) have been classified into at least six subfamilies, among which ERK1/2, JNK1/2 and p38 MAPK are the most extensively studied. The steroid hormones 1alpha,25-dihydroxy-Vitamin D(3) and 17beta-estradiol promote biological responses through activation of MAPK cascades in various cell types. We previously reported that 1alpha,25(OH)(2)D(3) rapidly (within 1 min) activates p38 MAPK in C2C12 skeletal muscle cells. In this work, using the same muscle cell line, we demonstrate that 1alpha,25(OH)(2)D(3) or 17beta-estradiol phosphorylate and activate ERK1/2 and p38 MAPK after longer treatment intervals, maximal effects seen at 90 and 30 min (ERK1/2) and at 60 and 15 min (p38 MAPK) for these hormones, respectively. Hormone-dependent ERK and p38 activation was abolished by MAPK specific inhibitors U0126 and SB203580. 1alpha,25(OH)(2)D(3) and 17beta-estradiol also induced the phosphorylation of CREB and Elk-1 transcription factors in an ERK1/2-dependent manner. Simultaneous addition of both hormones potentiated CREB phosphorylation. 1alpha,25(OH)(2)D(3)- and 17beta-estradiol-induced c-fos expression, which was mediated by p38 phosphorylation. The action of 17beta-estradiol on c-fos levels was also dependent on ERK1/2. These results suggest that MAPK signalling pathways play an important role in regulating early gene expression through CREB and Elk-1 activation in skeletal muscle cells.

Animals↗
PubMed2003

CREB isoform represses yolk protein gene expression in the mosquito fat body.

In mosquitoes, the steroid 20-hydroxyecdysone (20E) is the main regulator of yolk protein precursor (YPP) gene expression. However, peptide hormones have also been implicated. To investigate involvement of the cAMP-mediated signal-transduction cascade in regulation of mosquito vitellogenic events, we cloned an Aedes aegypti cAMP response element binding protein (AaCREB). The AaCREB contained the domains characteristic to members of the cAMP response element binding protein (CREB) family of transcription factors: a kinase inducible domain region and a bZIP domain responsible for DNA binding and protein dimerization. In the mosquito fat body (site of YPP gene expression), the AaCREB gene was constitutively expressed and produced a transcript of 3.5-4 kb. In vitro fat body organ culture experiments demonstrated that elicitors of the cAMP signal-transduction pathway attenuated 20E-stimulated YPP gene expression. Cell transfection analysis indicated that AaCREB served as a potent repressor of transcription (designated AaCREBr). The role of AaCREBr as a transcriptional repressor supported the electrophoretic mobility shift assay (EMSA) with nuclear extracts from vitellogenic fat bodies. This analysis detected CREB-specific band-shift complexes in nuclear extracts at 24 and 36 h post-blood meal (PBM), when YPP gene expression reaches its peak then terminates. Examination of the regulatory regions of two major YPP genes, vitellogenin (Vg) and vitellogenic carboxypeptidase (VCP), revealed the presence of putative CREB response elements (CREs). These elements competed with the CRE consensus sequence for binding of in vitro-expressed AaCREBr. We propose that AaCREBr functions as a repressor of YPP gene expression at the time of vitellogenesis termination in the fat body.

Amino Acid Sequence↗