Disease relevance of Crebbp

• Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice [1].
• Expression of a conditional form of adenovirus E1A in murine erythroleukemia cells blocks differentiation and expression of endogenous GATA-1 target genes, whereas mutant forms of E1A unable to bind CBP/p300 have no effect [2].
• Thus, although the CBP SID domain adopts a similar fold in complex with different p160 proteins, the topologies of the AD1 domains are strikingly different, a feature that is likely to contribute to functional specificity of these coactivator complexes [3].
• Rubinstein-Taybi syndrome (RTS), which is an autosomal dominant syndrome characterized by abnormal pattern formation, is associated with mutations in the human CBP gene [4].
• Extensive brain hemorrhage and embryonic lethality in a mouse null mutant of CREB-binding protein [4].

Psychiatry related information on Crebbp

• They are both implicated in tumorigenesis and mutations in the human CBP gene have been found in Rubinstein-Taybi syndrome (RTS), which is characterized by multiple developmental defects and mental retardation [5].
• Recently, a report has suggested a link between CREB-binding protein and presenilins, which are mutated in many cases of early onset Alzheimer's disease [6].
• Differential Role for CBP and p300 CREB-Binding Domain in Motor Skill Learning [7].

High impact information on Crebbp

• We observed increased leptin sensitivity and increased serum adiponectin levels in Crebbp+/- mice [1].
• As Crebbp null mice (Crebbp-/-) died during embryogenesis, we used Crebbp+/- mice [1].
• These increased effects of insulin-sensitizing hormones secreted from WAT may explain, at least in part, the phenotypes of Crebbp+/- mice [1].
• Unexpectedly, Crebbp+/- mice showed markedly reduced weight of white adipose tissue (WAT) but not of other tissues [1].
• Despite this lipodystrophy, Crebbp+/- mice showed increased insulin sensitivity and glucose tolerance and were completely protected from body weight gain induced by a high-fat (HF) diet [1].

Chemical compound and disease context of Crebbp

• Despite their similarities, p300 and CBP have distinct functions during retinoic acid-induced differentiation of mouse F9 embryonal carcinoma cells [8].
• Transcriptional dysregulation and cellular toxicity may be due to interaction between expanded polyglutamine and the histone acetyltransferase CREB-binding protein [9].

Biological context of Crebbp

• CBP enhances transcriptional activities via histone acetylation and the recruitment of additional co-activators such as SRC (steroid coactivator)-1 (ref. 9). To identify its physiological functions using a loss-of-function mutant, we analyzed CBP-deficient mice [1].
• Here we show that the protein-binding KIX domains of CBP and p300 have nonredundant functions in mice [10].
• Interaction mapping pinpoints contact sites to the zinc finger region of GATA-1 and to the E1A-binding region of CBP [2].
• We report here that CBP markedly stimulates GATA-1's transcriptional activity in transient transfection experiments in nonhematopoietic cells [2].
• To elucidate the importance of the cAMP-PKA-CREB-CBP pathway in pancreatic beta cells specifically at the nuclear level, we have examined mutant mice lacking the insulin-dependent phosphorylation site of CBP [11].

Anatomical context of Crebbp

• However, it remains unclear whether CBP and/or p300 is physiologically essential to the activation of PPARgamma in adipocytes and adipocyte differentiation [12].
• Later in neural development, CBP and p300 proteins could also be found in subsets of ventral neurons, including motor neurons and oligodendrocytes [5].
• Studies in tissue culture cells have implicated p300 and CBP acetyltransferases in myogenic regulatory factor (MRF) mediated transcription and terminal differentiation of skeletal muscle cells [13].
• Formation of the cardiovascular system, the lung and the small intestine are strongly impaired in p300 AT and to a much lesser extent in Cbp AT mutant embryos, a difference that is also reflected by the defects in gene expression [14].
• Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal [15].

Associations of Crebbp with chemical compounds

• In these mice, the CREB-CBP interaction is enhanced in both the absence and presence of cAMP stimulation [11].
• CBP, but not p300, is phosphorylated at serine 436 in response to insulin action [11].
• Mouse p53 is acetylated at lysine 317 by PCAF and at multiple lysine residues at the extreme carboxyl terminus by CBP/p300 in response to genotoxic and some nongenotoxic stresses [16].
• In these beta cells, however, glucose-stimulated insulin secretion was diminished, resulting from concomitant CREB-CBP-mediated pgc1a gene activation [11].
• Expression of aP2 and LPL genes, as well as glycerol-3-phosphate dehydrogenase activity and triacylglyceride accumulation after adipogenic induction, was largely suppressed in 3T3-L1 adipocytes expressing either the CBP- or p300-specific active ribozyme, but not in inactive ribozyme-expressing cells [12].

Physical interactions of Crebbp

• The coactivators CBP (Cre-element binding protein (CREB)-binding protein) and its paralogue p300 are thought to supply adaptor molecule and protein acetyltransferase functions to many transcription factors that regulate gene expression [10].
• GATA-1 and CBP also coimmunoprecipitate from nuclear extracts of erythroid cells [2].
• Upon activation by tumor necrosis factor, NF-kappaB binds to the distal regulatory region and recruits CBP and p300 [17].
• An N-terminal 36 amino acids of CIITA mediates suppression of the collagen alpha(2)(I) promoter via binding to CREB-binding protein (CBP) [18].
• Furthermore, electrophoretic mobility shift assays and immunoprecipitations demonstrated that the presence of Ets1 was necessary for a CBP/p53 complex to be formed [19].

Enzymatic interactions of Crebbp

• We used mice carrying p300flox and a CBP conditional knockout allele (CBPflox) in conjunction with an Lck-Cre transgene to delete CBP and p300 starting at the CD4- CD8- double-negative thymocyte stage of T-cell development [20].

Regulatory relationships of Crebbp

• These results suggest that p300/CBP is a critical control point in NF-kappaB-dependent transcriptional regulation of cytoprotective genes by cytokines [21].
• A mutant CBP lacking the N terminus failed to stimulate p53-dependent transactivation [22].
• Prevention of PU.1-induced growth inhibition and apoptosis but not differentiation block in murine erythroleukemia cells by overexpression of CBP [23].
• In the absence of Wnt signaling, LEF-1/TCF proteins repress transcription in association with Groucho and CBP [24].
• These results indicate that the constitutive and inducible activation properties of c-Myb and CREB reflect secondary structural characteristics of their corresponding activating regions that influence the thermodynamics of formation of a complex with CBP [25].

Other interactions of Crebbp

• Pcaf is thought to participate in many of the cellular processes regulated by p300/CBP (refs 2-8), but the functions of Gcn5 are unknown in mammalian cells [26].
• Physical and functional interactions between the transcription factor PU.1 and the coactivator CBP [27].
• Classically, binding of phosphorylated CREB to cis-acting cAMP-responsive elements (5'-TGACGTCA-3') within target gene promoters leads to recruitment of the coactivator CREB binding protein (CBP) [28].
• Although expressions of RXRalpha and CBP in livers of vitamin A-sufficient and vitamin A-depleted fetal mice did not differ, the level of HNF4alpha was consistently lower in the latter [29].
• It has been reported that both CBP and p300 are significant for the activation of peroxisome proliferator-activated receptor gamma (PPARgamma), which is a crucial nuclear receptor in adipogenesis [12].

Analytical, diagnostic and therapeutic context of Crebbp

• Sequence analysis reveals that both zones are well conserved in all vertebrate p300/CBP proteins, suggesting their functional importance [30].
• Furthermore, by interaction studies in vivo (a mammalian two-hybrid assay) and in vitro (a pulldown assay), p300/CBP was found to directly bind CRX through their C-terminal domains [31].
• Microinjection of p300/CBP antibodies into myoblasts blocks terminal differentiation, cell fusion, and transcriptional activity of myogenic bHLH proteins [32].
• Also found at the array by immunofluorescence were two different steroid receptor coactivators (SRC1 and CBP) with acetyltransferase activity, a chromatin remodeler (BRG1), and two transcription factors (NFI and AP-2) [33].
• Co-immunoprecipitation experiments using cell extracts showed that p67(SRF) could be retained with antibodies directed against the CREB-binding protein, suggesting that the two proteins form a multimolecular complex in live cells [34].

References