Disease relevance of Ep300

• In mice homozygous for point mutations in the KIX domain of p300 designed to disrupt the binding surface for the transcription factors c-Myb and CREB, multilineage defects occur in haematopoiesis, including anaemia, B-cell deficiency, thymic hypoplasia, megakaryocytosis and thrombocytosis [1].
• Furthermore, in chimeric mice, hematologic malignancies emerged from both CBP(-/-) and p300(-/-) cell populations [2].
• These findings suggest that p300-mediated nuclear acetylation plays a critical role in the development of myocyte hypertrophy and represents a pathway that leads to decompensated heart failure [3].
• cAMP regulatory element-binding protein (CREB)-binding protein (CBP) and its functional homolog, the adenovirus E1A -associated 300-kDa protein (p300) are nuclear coactivators and histone acetyltransferases that integrate signals from disparate pathways by bridging specific transcription factors to the basal transcription apparatus [4].
• Their role in patterning and development was suggested by studies in mice in which CBP and p300 expression was disrupted and by the human Rubinstein-Taybi syndrome, which is associated with mutations of CBP [4].

Psychiatry related information on Ep300

• Differential Role for CBP and p300 CREB-Binding Domain in Motor Skill Learning [5].

High impact information on Ep300

• 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 [6].
• The transcriptional coactivator and integrator p300 and its closely related family member CBP mediate multiple, signal-dependent transcriptional events [7].
• Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300 [7].
• Animals nullizygous for p300 died between days 9 and 11.5 of gestation, exhibiting defects in neurulation, cell proliferation, and heart development [7].
• Surprisingly, p300 heterozygotes also manifested considerable embryonic lethality [7].

Chemical compound and disease context of Ep300

• CITED1 was strongly expressed in nulliparous mouse mammary epithelial cells and, when expressed in ER-positive MCF-7 breast cancer cells by transduction, exogenous CITED1 enhanced sensitivity of MCF-7 cells to estrogen, stabilizing the estrogen-dependent interaction between p300 and ERalpha [8].
• Despite their similarities, p300 and CBP have distinct functions during retinoic acid-induced differentiation of mouse F9 embryonal carcinoma cells [9].

Biological context of Ep300

• A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis [1].
• Here we show that the protein-binding KIX domains of CBP and p300 have nonredundant functions in mice [1].
• These data reveal a specific requirement for p300 and its AT activity in the induction of MRF gene expression and myogenic cell fate determination in vivo [10].
• In this report we provide genetic evidence that p300 but not CBP acetyltransferase (AT) activity is required for myogenesis in the mouse and in embryonic stem (ES) cells [10].
• In vitro glutathione S-transferase pulldown competition experiments revealed the SHP-mediated repression of Smad3 transactivation through competition with its co-activator p300 [11].

Anatomical context of Ep300

• 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 [10].
• The CBP/p300-binding Py mutants are able to transform established rat embryo fibroblasts but are restricted in their ability to induce tumors in the newborn mouse, indicating that interaction of large T with the co-activators may be essential for virus replication and spread in the intact host [12].
• However, it remains unclear whether CBP and/or p300 is physiologically essential to the activation of PPARgamma in adipocytes and adipocyte differentiation [13].
• Transcriptional regulation of dentin matrix protein 1 by JunB and p300 during osteoblast differentiation [14].
• Later in neural development, CBP and p300 proteins could also be found in subsets of ventral neurons, including motor neurons and oligodendrocytes [15].

Associations of Ep300 with chemical compounds

• 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].
• CBP, but not p300, is phosphorylated at serine 436 in response to insulin action [17].
• 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 [13].
• Consistent with results from cellular systems, we demonstrate that maximal levels of transactivation in vitro require both p300 and pCAF, as well as the cofactor acetyl CoA [18].
• In primary cardiac myocytes derived from neonatal rats, we show that stimulation with phenylephrine increased an acetylated form of GATA-4 and its DNA-binding activity, as well as expression of p300 [3].
• P300 down-regulation altered expression of other metabolic FXR target genes involved in lipoprotein and glucose metabolism, such that beneficial lipid and glucose profiles would be expected [19].

Physical interactions of Ep300

• 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 [1].
• Hyper-phosphorylated CIITA interacts with co-activator p300, RFX5 and CIITA itself, which in turn results in induction of MHC class II promoter activity [20].
• cAMP response element binding protein (CREB)-binding protein (CBP) and p300 are two structurally related transcriptional co-activators that activate expression of many eukaryotic genes [21].
• Together these data support a model whereby CREB and multiple NF-kappaB complexes bind to the Igamma1 promoter and recruit p300 [22].
• Chromatin immunoprecipitation assays showed that IRF-2 interacted with p300 and bound to the endogenous H4 promoter only in growing cells, although the levels of total IRF-2 were comparable in both growing and growth-arrested cells [23].

Enzymatic interactions of Ep300

• 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 [24].

Regulatory relationships of Ep300

• Intrinsic histone acetyltransferase activity of p300 also plays a critical role in regulating DMP1 gene expression [14].
• Also similar to the GLalpha promoter, overexpression of p300 enhances Smad3/4-mediated promoter activity, whereas E1A represses promoter activity [25].
• Histone acetyltransferase activity of p300 enhances the activation of IL-18 promoter [26].
• RESULTS: In normal fibroblasts, TGFbeta induced an increase in the levels of p300 [27].
• Collectively, our results show that p300 plays an important role in the differentiation process of ES cells and provide the first evidence for the involvement of p300 in regulating Nanog expression during differentiation, probably through epigenetic modification of histone on Nanog [28].

Other interactions of Ep300

• Together, these results indicate that PARP-1 acts synergistically with p300 and plays an essential regulatory role in NF-kappaB-dependent gene expression [29].
• Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma [13].
• Using mutagenesis and mass spectrometry, we identified two conserved lysine residues in ERalpha (Lys266 and Lys268) that are the primary targets of p300-mediated acetylation [30].
• PU.1 served as a substrate for p300 and was acetylated on lysine residues 170, 171, 206, and 208 [31].
• Thus c-Myb, through interaction with p300, controls the proliferation and differentiation of hematopoietic stem and progenitor cells [32].

Analytical, diagnostic and therapeutic context of Ep300

• Immunoprecipitation and chromatin immunoprecipitation analysis demonstrate the interaction of JunB and p300 in vivo [14].
• Dissection of the steps leading to transcription initiation revealed that the activities of p300 and pCAF are not redundant [18].
• Direct physical interactions between the N- and C-zinc finger domains of GATA-4 and the cysteine/histidine-rich region 3 (C/H3) of p300 were identified in immunoprecipitation and glutathione S-transferase pull-down experiments [33].
• Sequence analysis reveals that both zones are well conserved in all vertebrate p300/CBP proteins, suggesting their functional importance [34].
• 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 [35].

References