CREB-binding Protein (CREB-bind + protein)

Distribution by Scientific Domains


Selected Abstracts


Striatal modulation of cAMP-response-element-binding protein (CREB) after excitotoxic lesions: implications with neuronal vulnerability in Huntington's disease

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2006
Carmela Giampà
Abstract 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. [source]


Hypoxia-inducible factor-1, blocks differentiation of malignant gliomas

FEBS JOURNAL, Issue 24 2009
Huimin Lu
Aberrant differentiation is a characteristic feature of neoplastic transformation, while hypoxia in solid tumors is believed to be linked to aggressive behavior and poor prognosis. However, the possible relationship between hypoxia and differentiation in malignancies remains poorly defined. Here we show that rat C6 and primary human malignant glioma cells can be induced to differentiate into astrocytes by the well-known adenylate cyclase activator forskolin. However, hypoxia-inducible factor-1, expression stimulated by the hypoxia mimetics cobalt chloride or deferoxamine blocks this differentiation and this effectiveness is reversible upon withdrawal of the hypoxia mimetics. Importantly, knockdown of hypoxia inducible factor-1, by RNA interference restores the differentiation capabilities of the cells, even in the presence of cobalt chloride, whereas stabilization of hypoxia-inducible factor-1, through retarded ubiquitination by von Hippel-Lindau tumor suppressor gene silence abrogates the induced differentiation. Moreover, targeting of HIF-1 using chetomin, a disrupter of HIF-1 binding to its transcriptional co-activator CREB-binding protein (CBP)/p300, abolishes the differentiation-inhibitory effect of hypoxia-inducible factor-1,. Administration of chetomin in combination with forskolin significantly suppresses malignant glioma growth in an in vivo xenograft model. Analysis of 95 human glioma tissues revealed an increase of hypoxia-inducible factor-1, protein expression with progressing tumor grade. Taken together, these findings suggest a key signal transduction pathway involving hypoxia-inducible factor-1, that contributes to a differentiation defect in malignant gliomas and sheds new light on the differentiation therapy of solid tumors by targeting hypoxia-inducible factor-1,. Structured digital abstract ,,MINT-7292117: CBP (uniprotkb:Q6JHU9) physically interacts (MI:0915) with Hif1a (uniprotkb:O35800) by anti bait coimmunoprecipitation (MI:0006) [source]


SEI family of nuclear factors regulates p53-dependent transcriptional activation

GENES TO CELLS, Issue 8 2005
Rie Watanabe-Fukunaga
SEI family proteins, p34SEI-1 and SEI-2(TRIP-Br2), are nuclear factors that are implicated in cell cycle regulation through interaction with CDK4/CyclinD and E2F-1/DP-1 complexes. Here we report that the SEI family proteins regulate transcriptional activity of p53 tumor suppressor protein. Expression of SEI-1, SEI-2 or SEI-3 strongly stimulates p53-dependent gene activation in HeLa and U2OS cells but not in p53-deficient Saos2 or p53-knockdown HeLa cells. SEI proteins possess an intrinsic transactivation activity, interact with the coactivator CREB-binding protein, and cooperate synergistically with the ING family of chromatin-associated proteins to stimulate the transactivation function of p53. Doxycycline-induced expression of SEI proteins results in activation of the p21 gene and inhibition of cell growth, but the growth arrest was not suppressed by the siRNA-mediated knockdown of the endogenous p53 protein. These results indicate that the SEI family of nuclear proteins regulates p53 transcriptional activity and a p53-independent signaling pathway leading to growth inhibition. [source]


Specialized rules of gene transcription in male germ cells: the CREM paradigm*

INTERNATIONAL JOURNAL OF ANDROLOGY, Issue 6 2004
Lucia Monaco
Summary Specialized transcription complexes that coordinate the differentiation programme of spermatogenesis have been found in germ cells, which display specific differences in the components of the general transcription machinery. The TATA-binding protein family and its associated cofactors, for example, show upregulated expression in testis. In this physiological context, transcriptional control mediated by the activator cAMP response element modulator (CREM) represents an established paradigm. Somatic cell activation by CREM requires its phosphorylation at a unique regulatory site (Ser117) and subsequent interaction with the ubiquitous coactivator CREB-binding protein. In testis, CREM transcriptional activity is controlled through interaction with a tissue-specific partner, activator of CREM in the testis (ACT), which confers a powerful, phosphorylation-independent activation capacity. The function of ACT was found to be regulated by the testis-specific kinesin KIF17b. Here we discuss some aspects of the testis-specific transcription machinery, whose function is essential for the process of spermatogenesis. [source]


Integrative nuclear FGFR1 signaling (INFS) as a part of a universal "feed-forward-and-gate" signaling module that controls cell growth and differentiation

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2003
Michal K. Stachowiak
Abstract A novel signaling mechanism is described through which extracellular signals and intracellular signaling pathways regulate proliferation, growth, differentiation, and other functions of cells in the nervous system. Upon cell stimulation, fibroblast growth factor receptor-1 (FGFR1), a typically plasma membrane-associated protein, is released from ER membranes into the cytosol and translocates to the cell nucleus by an importin-,-mediated transport pathway along with its ligand, FGF-2. The nuclear accumulation of FGFR1 is activated by changes in cell contacts and by stimulation of cells with growth factors, neurotransmitters and hormones as well as by a variety of different second messengers and thus was named integrative nuclear FGFR1 signaling (INFS). In the nucleus, FGFR1 localizes specifically within nuclear matrix-attached speckle-domains, which are known to be sites for RNA Pol II-mediated transcription and co-transcriptional pre-mRNA processing. In these domains, nuclear FGFR1 colocalizes with RNA transcription sites, splicing factors, modified histones, phosphorylated RNA Pol II, and signaling kinases. Within the nucleus, FGFR1 serves as a general transcriptional regulator, as indicated by its association with the majority of active nuclear centers of RNA synthesis and processing, by the ability of nuclear FGFR1 to activate structurally distinct genes located on different chromosomes and by its stimulation of multi-gene programs for cell growth and differentiation. We propose that FGFR1 is part of a universal "feed-forward-and-gate" signaling module in which classical signaling cascades initiated by specific membrane receptors transmit signals to sequence specific transcription factors (ssTFs), while INFS elicited by the same stimuli feeds the signal forward to the common coactivator, CREB-binding protein (CBP). Activation of CBP by INFS, along with the activation of ssTFs by classical signaling cascades brings about coordinated responses from structurally different genes located at different genomic loci. © 2003 Wiley-Liss, Inc. [source]


Apoptosis in cerebellar granule neurons is associated with reduced interaction between CREB-binding protein and NF-,B

JOURNAL OF NEUROCHEMISTRY, Issue 2 2003
Asligul Yalcin
Abstract Cerebellar granule neurons undergo apoptosis when switched from medium containing depolarizing levels of potassium (high K+ medium, HK) to medium containing low K+ (LK). NF-,B, a ubiquitously expressed transcription factor, is involved in the survival-promoting effects of HK. However, neither the expression nor the intracellular localization of the five NF-,B proteins, or of I,B-, and I,B-,, are altered in neurons primed to undergo apoptosis by LK, suggesting that uncommon mechanisms regulate NF-,B activity in granule neurons. In this study, we show that p65 interacts with the transcriptional co-activator, CREB-binding protein (CBP), in healthy neurons. The decrease in NF-,B transcriptional activity caused by LK treatment is accompanied by a reduction in the interaction between p65 and CBP, an alteration that is accompanied by hyperphosporylation of CBP. LK-induced CBP hyperphosphorylation can be mimicked by inhibitors of protein phosphatase (PP) 2A and PP2A-like phosphatases such as okadaic acid and cantharidin, which also causes a reduction in p65,CBP association. In addition, treatment with these inhibitors induces cell death. Treatment with high concentrations of the broad-spectrum kinase inhibitor staurosporine prevents LK-mediated CBP hyperphosphorylation and inhibits cell death. In vitro kinase assays using glutathione- S -transferase (GST)-CBP fusion proteins map the LK-regulated site of phosphorylation to a region spanning residues 1662,1840 of CBP. Our results are consistent with possibility that LK-induced apoptosis is triggered by CBP hyperphosphorylation, an alteration that causes the dissociation of CBP and NF-,B. [source]


Protein aggregation in motor neurone disorders

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2003
J. D. Wood
Toxicity associated with abnormal protein folding and protein aggregation are major hypotheses for neurodegeneration. This article comparatively reviews the experimental and human tissue-based evidence for the involvement of such mechanisms in neuronal death associated with the motor system disorders of X-linked spinobulbar muscular atrophy (SBMA; Kennedy's disease) and amyotrophic lateral sclerosis (ALS), especially disease related to mutations in the superoxide dismutase (SOD1) gene. Evidence from transgenic mouse, Drosophila and cell culture models of SBMA, in common with other trinucleotide repeat expansion disorders, show protein aggregation of the mutated androgen receptor, and intraneuronal accumulation of aggregated protein, to be obligate mechanisms. Strong experimental data link these phenomena with downstream biochemical events involving gene transcription pathways (CREB-binding protein) and interactions with protein chaperone systems. Manipulations of these pathways are already established in experimental systems of trinucleotide repeat disorders as potential beneficial targets for therapeutic activity. In contrast, the evidence for the role of protein aggregation in models of SOD1-linked familial ALS is less clear-cut. Several classes of intraneuronal inclusion body have been described, some of which are invariably present. However, the lack of understanding of the biochemical basis of the most frequent inclusion in sporadic ALS, the ubiquitinated inclusion, has hampered research. The toxicity associated with expression of mutant SOD1 has been intensively studied however. Abnormal protein aggregation and folding is the only one of the four major hypotheses for the mechanism of neuronal degeneration in this disorder currently under investigation (the others comprise oxidative stress, axonal transport and cytoskeletal dysfunctions, and glutamatergic excitotoxicity). Whilst hyaline inclusions, which are strongly immunoreactive to SOD1, are linked to degeneration in SOD1 mutant mouse models, the evidence from human tissue is less consistent and convincing. A role for mutant SOD1 aggregation in the mitochondrial dysfunction associated with ALS, and in potentially toxic interactions with heat shock proteins, both leading to apoptosis, are supported by some experimental data. Direct in vitro data on mutant SOD1 show evidence for spontaneous oligomerization, but the role of such oligomers remains to be elucidated, and therapeutic strategies are less well developed for this familial variant of ALS. [source]


Wnt signaling inside the nucleus

CANCER SCIENCE, Issue 4 2008
Miki Shitashige
Accumulation of the ,-catenin protein and transactivation of a certain set of T-cell factor (TCF)-4 target genes by accumulated ,-catenin have been considered crucial in colorectal carcinogenesis. In the present review, we summarize nuclear proteins that interact with, and regulate, the ,-catenin and TCF and lymphoid enhancer factor (LEF) transcriptional complexes. Our recent series of proteomic studies has also revealed that various classes of nuclear proteins participate in the ,-catenin,TCF-4 complex and modulate its transcriptional activity. Furthermore, the protein composition of the TCF-4-containing nuclear complex is not fixed, but is regulated dynamically by endogenous programs associated with intestinal epithelial cell differentiation and exogenous stimuli. Restoration of the loss-of-function mutation of the adenomatous polyposis coli (APC) gene in colorectal cancer cells does not seem to be a realistic approach with currently available medical technologies, and only signaling molecules downstream of the APC gene product can be considered as targets of pharmacological intervention. Nuclear proteins associated with the ,-catenin,TCF-4 complex may include feasible targets for molecular therapy against colorectal cancer. Recently, an inhibitor of the interaction between CREB-binding protein and ,-catenin was shown to efficiently shut down the transcriptional activity of TCF-4 and induce apoptosis of colorectal cancer cells. We also summarize current strategies in the development of drugs against Wnt signaling. (Cancer Sci 2008; 99: 631,637) [source]