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1
Shikama, Noriko, Ho Man Chan, Marija Krstic-Demonacos, Linda Smith, Chang-Woo Lee, William Cairns, and Nicholas B. La Thangue. "Functional Interaction between Nucleosome Assembly Proteins and p300/CREB-Binding Protein Family Coactivators." Molecular and Cellular Biology 20, no. 23 (December 1, 2000): 8933–43. http://dx.doi.org/10.1128/mcb.20.23.8933-8943.2000.
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ABSTRACT The p300/CREB-binding protein (CBP) family of proteins consists of coactivators that influence the activity of a wide variety of transcription factors. Although the mechanisms that allow p300/CBP proteins to achieve transcriptional control are not clear, it is believed that the regulation of chromatin is an important aspect of the process. Here, we describe a new level of p300-dependent control mediated through the functional interaction between p300/CBP and members of the family of nucleosome assembly proteins (NAP), which includes NAP1, NAP2, and TAF1. We find that NAP proteins, which have previously been implicated in the regulation of transcription factor binding to chromatin, augment the activity of different p300 targets, including p53 and E2F, through a process that is likely to involve the physical interaction between p300 and NAP. NAP proteins can form oligomers, and the results show that NAP proteins can bind to both core histones and p300 coactivator proteins, perhaps in a multicomponent ternary complex. We also provide data in support of the idea that histones can influence the interaction between p300 and NAP protein. These results argue that NAP is a functionally important component of the p300 coactivator complex and suggest that NAP may serve as a point of integration between transcriptional coactivators and chromatin.
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Kaida, Atsushi, Yasuo Ariumi, Keiko Baba, Masami Matsubae, Toshifumi Takao, and Kunitada Shimotohno. "Identification of a novel p300-specific-associating protein, PRS1 (phosphoribosylpyrophosphate synthetase subunit 1)." Biochemical Journal 391, no. 2 (October 10, 2005): 239–47. http://dx.doi.org/10.1042/bj20041308.
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CBP [CREB (cAMP-response-element-binding protein)-binding protein] and p300 play critical roles in transcriptional co-activation, cell differentiation, proliferation and apoptosis. Multiple transcription factors associate with CBP/p300. With the exception of the SYT oncoprotein, no proteins have been identified that specifically associate with p300, but not CBP. In the present study, we isolated a novel p300-associated protein for which no interaction with CBP was observed by GST (glutathione S-transferase) pull-down assay using Jurkat cell lysates metabolically labelled with [35S]methionine. This protein bound the KIX (kinase-inducible) domain of p300. Following resolution by two-dimensional acrylamide gel electrophoresis, we identified the KIX-domain-bound protein by MS analysis as PRS1 (phosphoribosylpyrophosphate synthetase subunit 1), a protein essential for nucleoside biosynthesis. This is the first report to demonstrate the existence of a p300 KIX-domain-specific-interacting protein that does not interact with CBP. Thus p300 may play a role in the regulation of DNA synthesis through interactions with PRS1.
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Dallas, Peter B., Ian Wayne Cheney, Da-Wei Liao, Valerie Bowrin, Whitney Byam, Stephen Pacchione, Ryuji Kobayashi, Peter Yaciuk, and Elizabeth Moran. "p300/CREB Binding Protein-Related Protein p270 Is a Component of Mammalian SWI/SNF Complexes." Molecular and Cellular Biology 18, no. 6 (June 1, 1998): 3596–603. http://dx.doi.org/10.1128/mcb.18.6.3596.
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ABSTRACT p300 and the closely related CREB binding protein (CBP) are transcriptional adaptors that are present in intracellular complexes with TATA binding protein (TBP) and bind to upstream activators including p53 and nuclear hormone receptors. They have intrinsic and associated histone acetyltransferase activity, suggesting that chromatin modification is an essential part of their role in regulating transcription. Detailed characterization of a panel of antibodies raised against p300/CBP has revealed the existence of a 270-kDa cellular protein, p270, distinct from p300 and CBP but sharing at least two independent epitopes with p300. The subset of p300/CBP-derived antibodies that cross-reacts with p270 consistently coprecipitates a series a cellular proteins with relative molecular masses ranging from 44 to 190 kDa. Purification and analysis of various proteins in this group reveals that they are components of the human SWI/SNF complex and that p270 is an integral member of this complex.
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Kadeppagari, Ravi-Kumar, Natesan Sankar, and Bayar Thimmapaya. "Adenovirus Transforming Protein E1A Induces c-Myc in Quiescent Cells by a Novel Mechanism." Journal of Virology 83, no. 10 (March 11, 2009): 4810–22. http://dx.doi.org/10.1128/jvi.02145-08.
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ABSTRACT Previously we showed that the E1A binding proteins p300 and CBP negatively regulate c-Myc in quiescent cells and that binding of E1A to p300 results in the induction of c-Myc and thereby induction of S phase. We demonstrated that p300 and HDAC3 cooperate with the transcription factor YY1 at an upstream YY1 binding site and repress the Myc promoter. Here we show that the small E1A protein induces c-Myc by interfering with the protein-protein interaction between p300, YY1, and HDAC3. Wild-type E1A but not the E1A mutants that do not bind to p300 interfered in recruitment of YY1, p300, and HDAC3 to the YY1 binding site. As E1A started to accumulate after infection, it transiently associated with promoter-bound p300. Subsequently, YY1, p300, and HDAC3 began to dissociate from the promoter. Later in infection, E1A dissociated from the promoter as well as p300, YY1, and HDAC3. Removal of HDAC3 from the promoter correlated with increased acetylation of Myc chromatin and induction. In vivo E1A stably associated with p300 and dissociated YY1 and HDAC3 from the trimolecular complex. In vitro protein-protein interaction studies indicated that E1A initially binds to the p300-YY1-HDAC3 complex, briefly associates with it, and then dissociates the complex, recapitulating somewhat the in vivo situation. Thus, E1A binding to the C-terminal region of p300 disrupts the important corepressor function provided by p300 in repressing c-Myc. Our results reveal a novel mechanism by which a viral oncoprotein activates c-Myc in quiescent cells and raise the possibility that the oncoproteins encoded by the small-DNA tumor viruses may use this mechanism to induce c-Myc, which may be critical for cell transformation.
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Sánchez-Molina, Sara, José Luis Oliva, Susana García-Vargas, Ester Valls, José M. Rojas, and Marian A. Martínez-Balbás. "The histone acetyltransferases CBP/p300 are degraded in NIH 3T3 cells by activation of Ras signalling pathway." Biochemical Journal 398, no. 2 (August 15, 2006): 215–24. http://dx.doi.org/10.1042/bj20060052.
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The CBP [CREB (cAMP-response-element-binding protein)-binding protein]/p300 acetyltransferases function as transcriptional co-activators and play critical roles in cell differentiation and proliferation. Accumulating evidence shows that alterations of the CBP/p300 protein levels are linked to human tumours. In the present study, we show that the levels of the CBP/p300 co-activators are decreased dramatically by continuous PDGF (platelet-derived growth factor) and Ras signalling pathway activation in NIH 3T3 fibroblasts. This effect occurs by reducing the expression levels of the CBP/p300 genes. In addition, CBP and p300 are degraded by the 26 S proteasome pathway leading to an overall decrease in the levels of the CBP/p300 proteins. Furthermore, we provide evidence that Mdm2 (murine double minute 2), in the presence of active H-Ras or N-Ras, induces CBP/p300 degradation in NIH 3T3 cells. These findings support a novel mechanism for modulating other signalling transduction pathways that require these common co-activators.
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Lee, J. S., R. H. See, T. Deng, and Y. Shi. "Adenovirus E1A downregulates cJun- and JunB-mediated transcription by targeting their coactivator p300." Molecular and Cellular Biology 16, no. 8 (August 1996): 4312–26. http://dx.doi.org/10.1128/mcb.16.8.4312.
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Transcription factors and cofactors play critical roles in cell growth and differentiation. Alterations of their activities either through genetic mutations or by viral oncoproteins often result in aberrant cell growth and tumorigenesis. The transcriptional cofactor p300 has recently been shown to be complexed with transcription factors YY1 and CREB. Adenovirus E1A oncoproteins target these transcription complexes via physical interactions with p300, resulting in alterations of transcription mediated by these transcription factors. Here we show that p300 is also critical for repression by E1A of the activities of cJun and JunB, two members of the AP-1 transcriptional complexes. This repressive effect of E1A is dependent on the p300-binding domain of E1A and can be relieved by overexpression of p300. These results suggest that p300 serves as a mediator protein for downregulation of AP-1 activity by E1A. This hypothesis was further supported by the following observations: (i) in the absence of E1A, overexpression of p300 stimulated transcription both through an AP-1 site present in the collagenase promoter and through Jun proteins in GAL4 fusion protein-based assays; and (ii) overexpression of a mutant p300 lacking the E1A-interacting domain reduced the responsiveness of Jun-dependent transcription to E1A repression. As predicted from the functional results, p300 physically interacted with the Jun proteins. These findings thus established that p300 is a cofactor for cJun and JunB. We propose that p300 is a common mediator protein through which E1A gains control over multiple transcriptional regulatory pathways in the host cells.
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Thompson, Paul R., Hisanori Kurooka, Yoshihiro Nakatani, and Philip A. Cole. "Transcriptional Coactivator Protein p300." Journal of Biological Chemistry 276, no. 36 (July 9, 2001): 33721–29. http://dx.doi.org/10.1074/jbc.m104736200.
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Kasper, Lawryn H., Tomofusa Fukuyama, Michelle A. Biesen, Fayçal Boussouar, Caili Tong, Antoine de Pauw, Peter J. Murray, Jan M. A. van Deursen, and Paul K. Brindle. "Conditional Knockout Mice Reveal Distinct Functions for the Global Transcriptional Coactivators CBP and p300 in T-Cell Development." Molecular and Cellular Biology 26, no. 3 (February 1, 2006): 789–809. http://dx.doi.org/10.1128/mcb.26.3.789-809.2006.
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ABSTRACT The global transcriptional coactivators CREB-binding protein (CBP) and the closely related p300 interact with over 312 proteins, making them among the most heavily connected hubs in the known mammalian protein-protein interactome. It is largely uncertain, however, if these interactions are important in specific cell lineages of adult animals, as homozygous null mutations in either CBP or p300 result in early embryonic lethality in mice. Here we describe a Cre/LoxP conditional p300 null allele (p300 flox ) that allows for the temporal and tissue-specific inactivation of p300. We used mice carrying p300 flox and a CBP conditional knockout allele (CBP flox ) 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. Loss of either p300 or CBP led to a decrease in CD4+ CD8+ double-positive thymocytes, but an increase in the percentage of CD8+ single-positive thymocytes seen in CBP mutant mice was not observed in p300 mutants. T cells completely lacking both CBP and p300 did not develop normally and were nonexistent or very rare in the periphery, however. T cells lacking CBP or p300 had reduced tumor necrosis factor alpha gene expression in response to phorbol ester and ionophore, while signal-responsive gene expression in CBP- or p300-deficient macrophages was largely intact. Thus, CBP and p300 each supply a surprising degree of redundant coactivation capacity in T cells and macrophages, although each gene has also unique properties in thymocyte development.
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Asahara, Hiroshi, Sophie Tartare-Deckert, Takeya Nakagawa, Tsuyoshi Ikehara, Fumiko Hirose, Tony Hunter, Takashi Ito, and Marc Montminy. "Dual Roles of p300 in Chromatin Assembly and Transcriptional Activation in Cooperation with Nucleosome Assembly Protein 1 In Vitro." Molecular and Cellular Biology 22, no. 9 (May 1, 2002): 2974–83. http://dx.doi.org/10.1128/mcb.22.9.2974-2983.2002.
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ABSTRACT In a yeast two-hybrid screen to identify proteins that bind to the KIX domain of the coactivator p300, we obtained cDNAs encoding nucleosome assembly protein 1 (NAP-1), a 60-kDa histone H2A-H2B shuttling protein that promotes histone deposition. p300 associates preferentially with the H2A-H2B-bound form of NAP-1 rather than with the unbound form of NAP-1. Formation of NAP-1-p300 complexes was found to increase during S phase, suggesting a potential role for p300 in chromatin assembly. In micrococcal nuclease and supercoiling assays, addition of p300 promoted efficient chromatin assembly in vitro in conjunction with NAP-1 and ATP-utilizing chromatin assembly and remodeling factor; this effect was dependent in part on the intrinsic histone acetyltransferase activity of p300. Surprisingly, NAP-1 potently inhibited acetylation of core histones by p300, suggesting that efficient assembly requires acetylation of either NAP-1 or p300 itself. As p300 acted cooperatively with NAP-1 in stimulating transcription from a chromatin template in vitro, our results suggest a dual role of NAP-1-p300 complexes in promoting chromatin assembly and transcriptional activation.
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Kannan, Srinivasaraghavan, Anthony W. Partridge, David P. Lane, and Chandra S. Verma. "The Dual Interactions of p53 with MDM2 and p300: Implications for the Design of MDM2 Inhibitors." International Journal of Molecular Sciences 20, no. 23 (November 28, 2019): 5996. http://dx.doi.org/10.3390/ijms20235996.
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Proteins that limit the activity of the tumour suppressor protein p53 are increasingly being targeted for inhibition in a variety of cancers. In addition to the development of small molecules, there has been interest in developing constrained (stapled) peptide inhibitors. A stapled peptide ALRN_6924 that activates p53 by preventing its interaction with its negative regulator Mdm2 has entered clinical trials. This stapled peptide mimics the interaction of p53 with Mdm2. The chances that this peptide could bind to other proteins that may also interact with the Mdm2-binding region of p53 are high; one such protein is the CREB binding protein (CBP)/p300. It has been established that phosphorylated p53 is released from Mdm2 and binds to p300, orchestrating the transcriptional program. We investigate whether molecules such as ALRN_6924 would bind to p300 and, to do so, we used molecular simulations to explore the binding of ATSP_7041, which is an analogue of ALRN_6924. Our study shows that ATSP_7041 preferentially binds to Mdm2 over p300; however, upon phosphorylation, it appears to have a higher affinity for p300. This could result in attenuation of the amount of free p300 available for interacting with p53, and hence reduce its transcriptional efficacy. Our study highlights the importance of assessing off-target effects of peptide inhibitors, particularly guided by the understanding of the networks of protein-protein interactions (PPIs) that are being targeted.
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Chan, Ho Man, and Nicholas B. La Thangue. "p300/CBP proteins: HATs for transcriptional bridges and scaffolds." Journal of Cell Science 114, no. 13 (July 1, 2001): 2363–73. http://dx.doi.org/10.1242/jcs.114.13.2363.
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p300/CBP transcriptional co-activator proteins play a central role in co-ordinating and integrating multiple signal-dependent events with the transcription apparatus, allowing the appropriate level of gene activity to occur in response to diverse physiological cues that influence, for example, proliferation, differentiation and apoptosis. p300/CBP activity can be under aberrant control in human disease, particularly in cancer, which may inactivate a p300/CBP tumour-suppressor-like activity. The transcription regulating-properties of p300 and CBP appear to be exerted through multiple mechanisms. They act as protein bridges, thereby connecting different sequence-specific transcription factors to the transcription apparatus. Providing a protein scaffold upon which to build a multicomponent transcriptional regulatory complex is likely to be an important feature of p300/CBP control. Another key property is the presence of histone acetyltransferase (HAT) activity, which endows p300/CBP with the capacity to influence chromatin activity by modulating nucleosomal histones. Other proteins, including the p53 tumour suppressor, are targets for acetylation by p300/CBP. With the current intense level of research activity, p300/CBP will continue to be in the limelight and, we can be confident, yield new and important information on fundamental processes involved in transcriptional control.
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García-Rodríguez, Carmen, and Anjana Rao. "Nuclear Factor of Activated T Cells (NFAT)-dependent Transactivation Regulated by the Coactivators p300/CREB-binding Protein (CBP)." Journal of Experimental Medicine 187, no. 12 (June 15, 1998): 2031–36. http://dx.doi.org/10.1084/jem.187.12.2031.
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p300 and cAMP response element–binding protein (CREB)–binding protein (CBP) are members of a family of coactivators involved in the regulation of transcription and chromatin. We show that transcription factors of the nuclear factor of activated T cells (NFAT) family bind p300/CBP and recruit histone acetyltransferase activity from T cell nuclear extracts. The NH2-terminal transactivation domain of NFAT1 and the phospho-CREB- and E1A-binding sites of p300/CBP are involved in the interaction. The viral oncoprotein E1A inhibits NFAT-dependent transactivation in a p300-dependent manner. Recruitment of the coactivators p300/CBP by the transactivation domains of NFAT proteins is likely to play a critical role in NFAT-dependent gene expression during the immune response.
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Müller, Andreas, Andreas Ritzkowsky, and Gertrud Steger. "Cooperative Activation of Human Papillomavirus Type 8 Gene Expression by the E2 Protein and the Cellular Coactivator p300." Journal of Virology 76, no. 21 (November 1, 2002): 11042–53. http://dx.doi.org/10.1128/jvi.76.21.11042-11053.2002.
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ABSTRACT The E2 proteins of papillomaviruses (PV) bind to the coactivator CBP/p300 as do many other transcription factors, but the precise role of CBP/p300 in E2-specific functions is not yet understood. We show that the E2 protein of human PV type 8 (HPV8) directly binds to p300. Activation of HPV8 gene expression by low amounts of HPV8 E2 was stimulated up to sevenfold by coexpression of p300. The interaction between E2 and p300 may play a role in differentiation-dependent activation of PV gene expression, since we can show that the expression level of p300 increases during keratinocyte differentiation. Surprisingly, sequence-specific binding of E2 to its recognition sites within the regulatory region of HPV8 is not necessary for this cooperation, indicating that E2 can be recruited to the promoter via protein-protein interaction. HPV8 E2 binds via its N-terminal activation domain (AD), its C-terminal DNA binding domain (DBD), and its internal hinge region to p300 in vitro. Transient-transfection assays revealed that the AD is necessary and sufficient for cooperative activation with p300. However, we provide evidence that the interaction of the hinge and the DBD of HPV8 E2 with p300 may contribute. Our data suggest an important role of p300 in regulation of HPV8 gene expression and reveal a new mechanism by which E2 may be recruited to a promoter to activate transcription without sequence specific DNA binding.
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Qiu, Yi, Min Guo, Suming Huang, and Roland Stein. "Insulin Gene Transcription Is Mediated by Interactions between the p300 Coactivator and PDX-1, BETA2, and E47." Molecular and Cellular Biology 22, no. 2 (January 15, 2002): 412–20. http://dx.doi.org/10.1128/mcb.22.2.412-420.2002.
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ABSTRACT Pancreatic β-cell-type-specific expression of the insulin gene requires both ubiquitous and cell-enriched activators, which are organized within the enhancer region into a network of protein-protein and protein-DNA interactions to promote transcriptional synergy. Protein-protein-mediated communication between DNA-bound activators and the RNA polymerase II transcriptional machinery is inhibited by the adenovirus E1A protein as a result of E1A’s binding to the p300 coactivator. E1A disrupts signaling between the non-DNA-binding p300 protein and the basic helix-loop-helix DNA-binding factors of insulin’s E-element activator (i.e., the islet-enriched BETA2 and generally distributed E47 proteins), as well as a distinct but unidentified enhancer factor. In the present report, we show that E1A binding to p300 prevents activation by insulin’s β-cell-enriched PDX-1 activator. p300 interacts directly with the N-terminal region of the PDX-1 homeodomain protein, which contains conserved amino acid sequences essential for activation. The unique combination of PDX-1, BETA2, E47, and p300 was shown to promote synergistic activation from a transfected insulin enhancer-driven reporter construct in non-β cells, a process inhibited by E1A. In addition, E1A inhibited the level of PDX-1 and BETA2 complex formation in β cells. These results indicate that E1A inhibits insulin gene transcription by preventing communication between the p300 coactivator and key DNA-bound activators, like PDX-1 and BETA2:E47.
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Rikitake, Y., and E. Moran. "DNA-binding properties of the E1A-associated 300-kilodalton protein." Molecular and Cellular Biology 12, no. 6 (June 1992): 2826–36. http://dx.doi.org/10.1128/mcb.12.6.2826-2836.1992.
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One of the major E1A-associated cellular proteins is a 300-kDa product (p300) that binds to the N-terminal region of the E1A products. The p300 binding site is distinct from sequences involved in binding the retinoblastoma product and other E1A-associated cellular products such as p60-cyclin A and p107. p300 binding to E1A is linked genetically to the enhancer repression function of E1A and the other E1A-mediated gene-regulating functions as well as to the transforming functions of E1A. However, the biochemical properties of p300 have not yet been characterized. We report here that p300 has an intrinsic DNA-binding activity and shows a preferential affinity for specific DNA sequences. The sequences selectively bound by p300 are related to those of a series of enhancer elements that are recognized by NF-kappa B. The direct physical interaction of p300 with enhancer elements provides a biochemical basis for the genetic evidence linking the E1A-mediated enhancer repression function with the p300-binding activity of E1A.
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Rikitake, Y., and E. Moran. "DNA-binding properties of the E1A-associated 300-kilodalton protein." Molecular and Cellular Biology 12, no. 6 (June 1992): 2826–36. http://dx.doi.org/10.1128/mcb.12.6.2826.
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One of the major E1A-associated cellular proteins is a 300-kDa product (p300) that binds to the N-terminal region of the E1A products. The p300 binding site is distinct from sequences involved in binding the retinoblastoma product and other E1A-associated cellular products such as p60-cyclin A and p107. p300 binding to E1A is linked genetically to the enhancer repression function of E1A and the other E1A-mediated gene-regulating functions as well as to the transforming functions of E1A. However, the biochemical properties of p300 have not yet been characterized. We report here that p300 has an intrinsic DNA-binding activity and shows a preferential affinity for specific DNA sequences. The sequences selectively bound by p300 are related to those of a series of enhancer elements that are recognized by NF-kappa B. The direct physical interaction of p300 with enhancer elements provides a biochemical basis for the genetic evidence linking the E1A-mediated enhancer repression function with the p300-binding activity of E1A.
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Geng, Hao, Qiong Liu, Changhui Xue, Larry L. David, Tomasz M. Beer, George V. Thomas, Mu-Shui Dai, and David Z. Qian. "HIF1α Protein Stability Is Increased by Acetylation at Lysine 709." Journal of Biological Chemistry 287, no. 42 (August 20, 2012): 35496–505. http://dx.doi.org/10.1074/jbc.m112.400697.
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Lysine acetylation regulates protein stability and function. p300 is a component of the HIF-1 transcriptional complex and positively regulates the transactivation of HIF-1. Here, we show a novel molecular mechanism by which p300 facilitates HIF-1 activity. p300 increases HIF-1α (HIF1α) protein acetylation and stability. The regulation can be opposed by HDAC1, but not by HDAC3, and is abrogated by disrupting HIF1α-p300 interaction. Mechanistically, p300 specifically acetylates HIF1α at Lys-709, which increases the protein stability and decreases polyubiquitination in both normoxia and hypoxia. Compared with the wild-type protein, a HIF1α K709A mutant protein is more stable, less polyubiquitinated, and less dependent on p300. Overexpression of the HIF1α wild-type or K709A mutant in cancer cells lacking the endogenous HIF1α shows that the K709A mutant is transcriptionally more active toward the HIF-1 reporter and some endogenous target genes. Cancer cells containing the K709A mutant are less sensitive to hypoxia-induced growth arrest than the cells containing the HIF1α wild-type. Taken together, these data demonstrate a novel biological consequence upon HIF1α-p300 interaction, in which HIF1α can be stabilized by p300 via Lys-709 acetylation.
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Chen, Jihong, Jonathan R. St-Germain, and Qiao Li. "B56 Regulatory Subunit of Protein Phosphatase 2A Mediates Valproic Acid-Induced p300 Degradation." Molecular and Cellular Biology 25, no. 2 (January 15, 2005): 525–32. http://dx.doi.org/10.1128/mcb.25.2.525-532.2005.
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ABSTRACT Transcriptional coactivator p300 is required for embryonic development and cell proliferation. Valproic acid, a histone deacetylase inhibitor, is widely used in the therapy of epilepsy and bipolar disorder. However, it has intrinsic teratogenic activity through unidentified mechanisms. We report that valproic acid stimulates proteasome-dependent p300 degradation through augmentation of gene expression of the B56γ regulatory subunits of protein phosphatase 2A. The B56γ3 regulatory and catalytic subunits of protein phosphatase 2A interact with p300. Overexpression of the B56γ3 subunit leads to proteasome-mediated p300 degradation and represses p300-dependent transcriptional activation, which requires the B56γ3 interaction domain of p300. Conversely, silencing of the B56γ subunit expression by RNA interference increases the stability and transcriptional activity of the coactivator. Our study establishes the functional interaction between protein phosphatase 2A and p300 activity and provides direct evidence for signal-dependent control of p300 function.
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Deng, Wu-Guo, Ying Zhu, and Kenneth K. Wu. "Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators." Blood 103, no. 6 (March 15, 2004): 2135–42. http://dx.doi.org/10.1182/blood-2003-09-3131.
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Abstract Coactivators p300 and CREB (cyclic adenosine monophosphate [cAMP]–response element binding protein)–binding protein (CBP) serve as an integrator for gene transcription. Their relative involvement in regulating cyclooxygenase-2 (COX-2) promoter activity had not been characterized. Using fibroblast and macrophage COX-2 transcription as a model, we determined p300 and CBP levels in nuclear extracts and their binding to a COX-2 promoter probe. CBP level was barely detectable and there was little CBP binding. In contrast, p300 was detectable in nucleus and its binding to a COX-2 promoter probe was enhanced by phorbol 12-myristate 13-acetate (PMA), interleukin-1β (IL-1β), or lipopolysaccharide (LPS). Binding of p300/CBP-associated factor (PCAF) was also up-regulated. COX-2 proteins and promoter activities induced by these agonists were augmented by p300 overexpression. Early region 1A (E1A), but not its deletion mutant, abrogated COX-2 expression induced by inflammatory mediators and with or without p300 overexpression. Molecular analysis of p300 revealed the requirement of multiple domains, including histone acetyltransferase (HAT) for COX-2 transactivation. Furthermore, roscovitine, an indirect inhibitor of p300 HAT, and histone deacetylase-1 transfection completely abolished COX-2 promoter activity. We conclude that p300 is the predominant coactivator that is essential for COX-2 transcriptional activation by proinflammatory mediators.
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Xiong, Ying, Mingming Zhang, and Yingxia Li. "Recent Advances in the Development of CBP/p300 Bromodomain Inhibitors." Current Medicinal Chemistry 27, no. 33 (October 8, 2020): 5583–98. http://dx.doi.org/10.2174/0929867326666190731141055.
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CBP and p300 are two closely related Histone Acetyltransferases (HATs) that interact with numerous transcription factors and act to increase the expression of their target genes. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important in binding of CBP/p300 to chromatin, which offers an opportunity to develop protein-protein interaction inhibitors. Since their discovery in 2006, CBP/p300 bromodomains have attracted much interest as promising new epigenetic targets for diverse human diseases, including inflammation, cancer, autoimmune disorders, and cardiovascular disease. Herein, we present a comprehensive review of the structure, function, and inhibitors of CBP/p300 bromodomains developed in the last several years, which is expected to be beneficial to relevant studies.
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Cougot, Delphine, Yuanfei Wu, Stefano Cairo, Julie Caramel, Claire-Angélique Renard, Laurence Lévy, Marie Annick Buendia, and Christine Neuveut. "The Hepatitis B Virus X Protein Functionally Interacts with CREB-binding Protein/p300 in the Regulation of CREB-mediated Transcription." Journal of Biological Chemistry 282, no. 7 (December 11, 2006): 4277–87. http://dx.doi.org/10.1074/jbc.m606774200.
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The hepatitis B virus infects more than 350 million people worldwide and is a leading cause of liver cancer. The virus encodes a multifunctional regulator, the hepatitis B virus X protein (HBx), that is essential for virus replication. HBx is involved in modulating signal transduction pathways and transcription mediated by various factors, notably CREB that requires the recruitment of the co-activators CREB-binding protein (CBP)/p300. Here we investigated the role of HBx and its potential interaction with CBP/p300 in regulating CREB transcriptional activity. We show that HBx and CBP/p300 synergistically enhanced CREB activity and that CREB phosphorylation by protein kinase A was a prerequisite for the cooperative action of HBx and CBP/p300. We further show that HBx interacted directly with CBP/p300 in vitro and in vivo. Using chromatin immunoprecipitation, we provide evidence that HBx physically occupied the CREB-binding domain of CREB-responsive promoters of endogenous cellular genes such as interleukin 8 and proliferating cell nuclear antigen. Moreover expression of HBx increased the recruitment of p300 to the interleukin 8 and proliferating cell nuclear antigen promoters in cells, and this is associated with increased gene expression. As recruitment of CBP/p300 is known to represent the limiting event for activating CREB target genes, HBx may disrupt this cellular regulation, thus predisposing cells to transformation.
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Poizat, Coralie, Pier Lorenzo Puri, Yan Bai, and Larry Kedes. "Phosphorylation-Dependent Degradation of p300 by Doxorubicin-Activated p38 Mitogen-Activated Protein Kinase in Cardiac Cells." Molecular and Cellular Biology 25, no. 7 (April 1, 2005): 2673–87. http://dx.doi.org/10.1128/mcb.25.7.2673-2687.2005.
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ABSTRACT p300 and CBP are general transcriptional coactivators implicated in different cellular processes, including regulation of the cell cycle, differentiation, tumorigenesis, and apoptosis. Posttranslational modifications such as phosphorylation are predicted to select a specific function of p300/CBP in these processes; however, the identification of the kinases that regulate p300/CBP activity in response to individual stimuli and the physiological significance of p300 phosphorylation have not been elucidated. Here we demonstrate that the cardiotoxic anticancer agent doxorubicin (adriamycin) induces the phosphorylation of p300 in primary neonatal cardiomyocytes. Hyperphosphorylation precedes the degradation of p300 and parallels apoptosis in response to doxorubicin. Doxorubicin-activated p38 kinases α and β associate with p300 and are implicated in the phosphorylation-mediated degradation of p300, as pharmacological blockade of p38 prevents p300 degradation. p38 phosphorylates p300 in vitro at both the N and C termini of the protein, and enforced activation of p38 by the constitutively active form of its upstream kinase (MKK6EE) triggers p300 degradation. These data support the conclusion that p38 mitogen-activated protein kinase regulates p300 protein stability and function in cardiomyocytes undergoing apoptosis in response to doxorubicin.
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Eckner, R., J. W. Ludlow, N. L. Lill, E. Oldread, Z. Arany, N. Modjtahedi, J. A. DeCaprio, D. M. Livingston, and J. A. Morgan. "Association of p300 and CBP with simian virus 40 large T antigen." Molecular and Cellular Biology 16, no. 7 (July 1996): 3454–64. http://dx.doi.org/10.1128/mcb.16.7.3454.
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p300 and the CREB-binding protein CBP are two large nuclear phosphoproteins that are structurally highly related. Both function, in part, as transcriptional adapters and are targeted by the adenovirus E1A oncoprotein. We show here that p300 and CBP interact with another transforming protein, the simian virus 40 large T antigen (T). This interaction depends on the integrity of a region of T which is critical for its transforming and mitogenic properties and includes its LXCXE Rb-binding motif. T interferes with normal p300 and CBP function on at least two different levels. The presence of T alters the phosphorylation states of both proteins and inhibits their transcriptional activities on certain promoters. Although E1A and T show little sequence similarity, they interact with the same domain of p300 and CBP, suggesting that this region exhibits considerable flexibility in accommodating diverse protein ligands.
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Labalette, Charlotte, Claire-Angélique Renard, Christine Neuveut, Marie-Annick Buendia, and Yu Wei. "Interaction and Functional Cooperation between the LIM Protein FHL2, CBP/p300, and β-Catenin." Molecular and Cellular Biology 24, no. 24 (December 15, 2004): 10689–702. http://dx.doi.org/10.1128/mcb.24.24.10689-10702.2004.
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ABSTRACT Transcriptional activation of gene expression by Wnt signaling is driven by the association of β-catenin with TCF/LEF factors and the recruitment of transcriptional coactivators. It has been shown that the LIM protein FHL2 and the acetyltransferase CBP/p300 individually stimulate β-catenin transactivating activity and that β-catenin is acetylated by p300. Here, we report that FHL2 and CBP/p300 synergistically enhanced β-catenin/TCF-mediated transcription from Wnt-responsive promoters and that the acetyltransferase activity of CBP/p300 was involved in the cooperation. CBP/p300 interacted directly with FHL2, predominantly through the CH3 domain but not the histone acetyltransferase domain, and different regions of CBP/p300 were involved in FHL2 and β-catenin binding. We provided evidence for the formation of a ternary complex by FHL2, CBP/p300, and β-catenin and for colocalization of the three proteins in the nucleus. In murine FHL2−/− embryo fibroblasts, the transactivation activity of β-catenin/TCF was markedly reduced, and this defect could be restored by exogenous expression of FHL2. However, CBP/p300 were still able to coactivate the β-catenin/TCF complex in FHL2−/− cells, suggesting that FHL2 is dispensable for the coactivator function of CBP/p300 on β-catenin. Furthermore, we found that FHL2 significantly increased acetylation of β-catenin by p300 in vivo. Finally, we showed that FHL2, CBP/p300, and β-catenin could synergistically activate androgen receptor-mediated transcription, indicating that the synergistic coactivator function is not restricted to TCF/LEF.
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LUCA, Antonio De, Anna SEVERINO, Paola De PAOLIS, Giuliano COTTONE, Luca De LUCA, Maria De FALCO, Antonio PORCELLINI, Massimo VOLPE, and Gianluigi CONDORELLI. "p300/cAMP-response-element-binding-protein ('CREB')-binding protein (CBP) modulates co-operation between myocyte enhancer factor 2A (MEF2A) and thyroid hormone receptor-retinoid X receptor." Biochemical Journal 369, no. 3 (February 1, 2003): 477–84. http://dx.doi.org/10.1042/bj20020057.
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Thyroid hormone receptors (TRs) and members of the myocyte enhancer factor 2 (MEF2) family are involved in the regulation of muscle-specific gene expression during myogenesis. Physical interaction between these two factors is required to synergistically activate gene transcription. p300/cAMP-response-element-binding-protein ('CREB')-binding protein (CBP) interacting with transcription factors is able to increase their activity on target gene promoters. We investigated the role of p300 in regulating the TR—MEF2A complex. To this end, we mapped the regions of these proteins involved in physical interactions and we evaluated the expression of a chloramphenicol acetyltransferase (CAT) reporter gene in U2OS cells under control of the α-myosin heavy chain promoter containing the thyroid hormone response element (TRE). Our results suggested a role of p300/CBP in mediating the transactivation effects of the TR—retenoid X receptor (RxR)—MEF2A complex. Our findings showed that the same C-terminal portion of p300 binds the N-terminal domains of both TR and MEF2A, and our in vivo studies demonstrated that TR, MEF2A and p300 form a ternary complex. Moreover, by the use of CAT assays, we demonstrated that adenovirus E1A inhibits activation of transcription by TR—RxR—MEF2A—p300 but not by TR—RxR—MEF2A. Our data suggested that p300 can bind and modulate the activity of TR—RxR—MEF2A at TRE. In addition, it is speculated that p300 might modulate the activity of the TR—RxR—MEF2A complex by recruiting a hypothetical endogenous inhibitor which may act like adenovirus E1A.
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Zhang, Weiqing, John W. Nisbet, Bjorn Albrecht, Wei Ding, Fatah Kashanchi, Joshua T. Bartoe, and Michael D. Lairmore. "Human T-Lymphotropic Virus Type 1 p30IIRegulates Gene Transcription by Binding CREB Binding Protein/p300." Journal of Virology 75, no. 20 (October 15, 2001): 9885–95. http://dx.doi.org/10.1128/jvi.75.20.9885-9895.2001.
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ABSTRACT The highly conserved coadapters CREB binding protein (CBP) and p300 form complexes with CREB as well as other DNA binding transcription factors to modulate chromatin remodeling and thus transcription. Human T-lymphotropic virus type 1 (HTLV-1) transcription is controlled, in part, by the CREB/ATF family of transcription factors which bind promoter sequences and function as complexes with the viral oncogenic protein Tax. We have reported that the nuclear localizing protein p30II of HTLV-1 functions as a transcription factor, differentially modulates CREB-responsive promoters, and is critical for maintenance of proviral loads in rabbits. In this study, we tested whether p30IIdirectly interacts with CBP/p300 to modulate gene transcription. Gal4(BD)-p30II-mediated transactivation was enhanced following exogenous expression of p300 and was competitively repressed by the p300 binding protein, adenovirus E1A, and E1ACR2 (mutated for retinoblastoma binding but retaining p300 binding). In contrast, E1ACR1 (mutated for p300 binding) failed to alter Gal4(BD)-p30II-mediated transactivation. In addition, Gal4(BD)-p30II-mediated transactivation was competitively inhibited by the cotransfection of CMV-p30II-HA and CMV-Tax but could be rescued by exogenous p300. Importantly, we demonstrate that p30II colocalizes with p300 in cell nuclei and directly binds to CBP/p300 in cells. Deletion mutants of CBP/p300 were used to localize the site critical for binding p30II to a highly conserved KIX region. DNA binding assays confirmed the interference of p30II with the assembly of CREB-Tax-p300/CBP multiprotein complexes on 21-bp repeat oligonucleotides in vitro. Collectively, our results demonstrate that CBP/p300 is a cellular protein target for HTLV-1 p30II and mediates its transcriptional effects in vivo.
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Papoutsopoulou, Stamatia, and Ralf Janknecht. "Phosphorylation of ETS Transcription Factor ER81 in a Complex with Its Coactivators CREB-Binding Protein and p300." Molecular and Cellular Biology 20, no. 19 (October 1, 2000): 7300–7310. http://dx.doi.org/10.1128/mcb.20.19.7300-7310.2000.
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ABSTRACT The ETS protein ER81 is a DNA-binding factor capable of enhancing gene transcription and is implicated in cellular transformation, but presently the mechanisms of its actions are unclear. In this report, ER81 is shown to coimmunoprecipitate with the transcriptional coactivator CREB-binding protein (CBP) and the related p300 protein (together referred to as CBP/p300). Moreover, confocal laser microscopic studies demonstrated that ER81 and p300 colocalized to nuclear speckles. In vitro and in vivo interaction studies revealed that ER81 amino acids 249 to 429, which encompass the ETS DNA-binding domain, are responsible for binding to CBP/p300. However, mutation of a putative protein-protein interaction motif, LXXLL, in the ETS domain of ER81 did not affect interaction with CBP/p300, whereas DNA binding of ER81 was abolished. Furthermore, two regions within CBP, amino acids 451 to 721 and 1891 to 2175, are capable of binding to ER81. Consistent with the physical interaction between ER81 and the coactivators CBP and p300, ER81 transcriptional activity was potentiated by CBP/p300 overexpression. Moreover, an ER81-associated protein kinase activity was enhanced upon p300 overexpression. This protein kinase phosphorylates ER81 on serines 191 and 216, and mutation of these phosphorylation sites increased ER81 transcriptional activity in Mv1Lu cells but not in HeLa cells. Altogether, our data elucidate the mechanism of how ER81 regulates gene transcription, through interaction with the coactivators CBP and p300 and an associated kinase that may cell type specifically modulate the ability of ER81 to activate gene transcription.
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MATT, Theresia, Maria A. MARTINEZ-YAMOUT, H. Jane DYSON, and Peter E. WRIGHT. "The CBP/p300 TAZ1 domain in its native state is not a binding partner of MDM2." Biochemical Journal 381, no. 3 (July 27, 2004): 685–91. http://dx.doi.org/10.1042/bj20040564.
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The transcriptional co-activator CBP [CREB (cAMP-response-element-binding protein)-binding protein] and its paralogue p300 play a key role in the regulation of both activity and stability of the tumour suppressor p53. Degradation of p53 is mediated by the ubiquitin ligase MDM2 (mouse double minute protein) and is also reported to be regulated by CBP/p300. Direct protein–protein interaction between a central domain of MDM2 and the TAZ1 (transcriptional adaptor zinc-binding domain) [C/H1 (cysteine/histidine-rich region 1)] domain of p300 and subsequent formation of a ternary complex including p53 have been reported previously. We expressed and purified the proposed binding domains of HDM2 (human homologue of MDM2) and CBP, and examined their interactions using CD spectroscopy. The binding studies were extended by using natively purified GST (glutathione S-transferase)–p300 TAZ1 and GST–p53 fusion proteins, together with in vitro translated HDM2 fragments, under similar solution conditions to those in previous studies, but omitting added EDTA, which causes unfolding and aggregation of the zinc-binding TAZ1 domain. Comparing the binding properties of the known TAZ1 interaction partners HIF-1α (hypoxia-inducible factor 1), CITED2 (CBP/p300-interacting transactivator with glutamic- and aspartic-rich tail) and STAT2 (signal transducer and activator of transcription 2) with HDM2, our data suggest that TAZ1 in its native state does not serve as a specific recognition domain of HDM2. Rather, unfolded TAZ1 and HDM2 proteins have a high tendency to aggregate, and non-specific protein complexes are formed under certain conditions.
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Oswald, Franz, Birgitt Täuber, Thomas Dobner, Soizic Bourteele, Ulrike Kostezka, Guido Adler, Susanne Liptay, and Roland M. Schmid. "p300 Acts as a Transcriptional Coactivator for Mammalian Notch-1." Molecular and Cellular Biology 21, no. 22 (November 15, 2001): 7761–74. http://dx.doi.org/10.1128/mcb.21.22.7761-7774.2001.
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ABSTRACT Notch-1 belongs to a family of transmembrane receptor proteins that direct the decisions as to various cell fates. After ligand binding, a proteolytic cleavage step occurs and the intracellular part of Notch-1, Notch-1-IC, translocates into the nucleus, where it targets the DNA binding protein RBP-Jκ/CBF1. RBP-Jκ mediates repression through recruitment of a histone deacetylase-containing complex. The Notch-1-IC/RBP-Jκ complex overcomes repression and activates the transcription of Notch target genes. We have identified a novel domain in Notch-1-IC, the EP domain, which is indispensable for full transcriptional activation. This transactivation domain is localized adjacent to the ankyrin repeats of Notch-1-IC. In cotransfection experiments, Notch-1-IC-mediated transcriptional activation was inhibited by E1A12S and p53, two proteins, which interfere with the function of the common coactivator p300. Protein-protein interaction assays demonstrated the association of Notch-1-IC and the CH3 region of p300. In addition, the interaction of mammalian Notch-1-IC with p300 was destabilized after deletion of the EP domain of Notch-1-IC. Based on physical interaction with Notch-1-IC and coactivator functions of p300, we propose a model for Notch-1-mediated gene regulation via p300.
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Bhaumik, Prasenjit, Jamaine Davis, Joseph E. Tropea, Scott Cherry, Peter F. Johnson, and Maria Miller. "Structural insights into interactions of C/EBP transcriptional activators with the Taz2 domain of p300." Acta Crystallographica Section D Biological Crystallography 70, no. 7 (June 29, 2014): 1914–21. http://dx.doi.org/10.1107/s1399004714009262.
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Members of the C/EBP family of transcription factors bind to the Taz2 domain of p300/CBP and mediate its phosphorylation through the recruitment of specific kinases. Short sequence motifs termed homology boxes A and B, which comprise their minimal transactivation domains (TADs), are conserved between C/EBP activators and are necessary for specific p300/CBP binding. A possible mode of interaction between C/EBP TADs and the p300 Taz2 domain was implied by the crystal structure of a chimeric protein composed of residues 1723–1818 of p300 Taz2 and residues 37–61 of C/EBP∊. The segment corresponding to the C/EBP∊ TAD forms two orthogonally disposed helices connected by a short linker and interacts with the core structure of Taz2 from a symmetry-related molecule. It is proposed that other members of the C/EBP family interact with the Taz2 domain in the same manner. The position of the C/EBP∊ peptide on the Taz2 protein interaction surface suggests that the N-termini of C/EBP proteins are unbound in the C/EBP–p300 Taz2 complex. This observation is in agreement with the known location of the docking site of protein kinase HIPK2 in the C/EBPβ N-terminus, which associates with the C/EBPβ–p300 complex.
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Yang, Hongmei, Wei Wei, Michael Menconi, and Per-Olof Hasselgren. "Dexamethasone-induced protein degradation in cultured myotubes is p300/HAT dependent." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 1 (January 2007): R337—R334. http://dx.doi.org/10.1152/ajpregu.00230.2006.
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Muscle proteolysis during sepsis and other catabolic conditions is, at least in part, regulated by glucocorticoids. Dexamethasone-treated myotubes are a commonly used in vitro model of muscle wasting. We reported recently that treatment of cultured L6 myotubes with dexamethasone resulted in increased gene and protein expression of the nuclear cofactor p300 but it is not known whether glucocorticoids upregulate p300 histone acetyl transferase (HAT) activity in muscle and whether p300/HAT activity regulates glucocorticoid-induced muscle proteolysis. Here, we found that treatment of cultured L6 myotubes with dexamethasone resulted in increased nuclear p300/HAT activity. Treatment of myotubes with p300 siRNA or transfection of muscle cells with a plasmid expressing p300 that was mutated in its HAT activity domain blocked the dexamethasone-induced increase in protein degradation, supporting a role of p300/HAT in glucocortiocoid-induced muscle proteolysis. In addition to increased HAT activity, treatment of the myotubes with dexamethasone resulted in reduced nuclear expression and activity of histone deacetylases (HDACs) 3 and 6. When myotubes were treated with the HDAC inhibitor trichostatin A, protein degradation increased to the same degree as in dexamethasone-treated myotubes. The results suggest that glucocorticoids increase HAT and decrease HDAC activities in muscle, changes that both favor hyperacetylation. The results also provide evidence that dexamethasone-induced protein degradation in cultured myotubes is, at least in part, regulated by p300/HAT activity.
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Ida, Kohmei, Issay Kitabayashi, Tomohiko Taki, Masafumi Taniwaki, Keiko Noro, Masao Yamamoto, Misao Ohki, and Yasuhide Hayashi. "Adenoviral E1A-Associated Protein p300 Is Involved in Acute Myeloid Leukemia With t(11; 22)(q23; q13)." Blood 90, no. 12 (December 15, 1997): 4699–704. http://dx.doi.org/10.1182/blood.v90.12.4699.
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Abstract p300, which was originally cloned as a nuclear binding target of the adenovirus E1A oncoprotein, forms a family with cyclic-AMP response element binding protein (CREB)-binding protein (CBP). p300/CBP are considered to be transcriptional coactivators that connect the basal transcriptional machinery to various DNA-binding transcriptional factors. p300/CBP are implicated in both cell differentiation and regulation of cell-cycle. We identify here that the p300 gene is fused to the MLL gene and that in-frame MLL-p300 fusion protein is generated in acute myeloid leukemia (AML) with t(11; 22)(q23; q13). These findings suggest that the basis for the leukemogenesis of t(11; 22)-AML is the inability of p300 to regulate cell-cycle and cell differentiation after fusion with MLL.
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Ida, Kohmei, Issay Kitabayashi, Tomohiko Taki, Masafumi Taniwaki, Keiko Noro, Masao Yamamoto, Misao Ohki, and Yasuhide Hayashi. "Adenoviral E1A-Associated Protein p300 Is Involved in Acute Myeloid Leukemia With t(11; 22)(q23; q13)." Blood 90, no. 12 (December 15, 1997): 4699–704. http://dx.doi.org/10.1182/blood.v90.12.4699.4699_4699_4704.
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p300, which was originally cloned as a nuclear binding target of the adenovirus E1A oncoprotein, forms a family with cyclic-AMP response element binding protein (CREB)-binding protein (CBP). p300/CBP are considered to be transcriptional coactivators that connect the basal transcriptional machinery to various DNA-binding transcriptional factors. p300/CBP are implicated in both cell differentiation and regulation of cell-cycle. We identify here that the p300 gene is fused to the MLL gene and that in-frame MLL-p300 fusion protein is generated in acute myeloid leukemia (AML) with t(11; 22)(q23; q13). These findings suggest that the basis for the leukemogenesis of t(11; 22)-AML is the inability of p300 to regulate cell-cycle and cell differentiation after fusion with MLL.
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Xiang, Qiuping, Yang Zhou, Yan Zhang, and Yong Xu. "CBP/p300 bromodomain: new promising epigenetic target." Visualized Cancer Medicine 3 (2022): 3. http://dx.doi.org/10.1051/vcm/2022004.
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CREB (cAMP responsive element binding protein) binding protein (CBP) and adenovirus E1A-associated 300 kDa protein (p300) are histone acetyltransferases, which are necessary for multiple cellular processes. Thus, CBP/p300 are promising potential antitumor targets. To date, despite various small molecule inhibitors of CBP/p300 bromodomain (BRD) having been reported, no specific inhibitor was approved by U.S. Food and Drug Administration (FDA). In this review, we described the discovery, optimization, binding mode evaluation, selectivity and potency evaluation, and therapeutic opportunities of our CBP/p300 bromodomain inhibitors, aiming to inspire new inhibitor design and advance drug discovery research in this field. One video presents the development of CBP/p300 bromodomain inhibitors.
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Sartorelli, V., J. Huang, Y. Hamamori, and L. Kedes. "Molecular mechanisms of myogenic coactivation by p300: direct interaction with the activation domain of MyoD and with the MADS box of MEF2C." Molecular and Cellular Biology 17, no. 2 (February 1997): 1010–26. http://dx.doi.org/10.1128/mcb.17.2.1010.
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By searching for molecules that assist MyoD in converting fibroblasts to muscle cells, we have found that p300 and CBP, two related molecules that act as transcriptional adapters, coactivate the myogenic basic-helix-loop-helix (bHLH) proteins. Coactivation by p300 involves novel physical interactions between p300 and the amino-terminal activation domain of MyoD. In particular, disruption of the FYD domain, a group of three amino acids conserved in the activation domains of other myogenic bHLH proteins, drastically diminishes the transactivation potential of MyoD and abolishes both p300-mediated coactivation and the physical interaction between MyoD and p300. Two domains of p300, at its amino and carboxy terminals, independently function to both mediate coactivation and physically interact with MyoD. A truncated segment of p300, unable to bind MyoD, acts as a dominant negative mutation and abrogates both myogenic conversion and transactivation by MyoD, suggesting that endogenous p300 is a required coactivator for MyoD function. The p300 dominant negative peptide forms multimers with intact p300. p300 and CBP serve as coactivators of another class of transcriptional activators critical for myogenesis, myocyte enhancer factor 2 (MEF2). In fact, transactivation mediated by the MEF2C protein is potentiated by the two coactivators, and this phenomenon is associated with the ability of p300 to interact with the MADS domain of MEF2C. Our results suggest that p300 and CBP may positively influence myogenesis by reinforcing the transcriptional autoregulatory loop established between the myogenic bHLH and the MEF2 factors.
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Shen, Xing, Patrick Pei-chih Hu, Nicole T. Liberati, Michael B. Datto, Joshua P. Frederick, and Xiao-Fan Wang. "TGF-β–induced Phosphorylation of Smad3 Regulates Its Interaction with Coactivator p300/CREB-binding Protein." Molecular Biology of the Cell 9, no. 12 (December 1998): 3309–19. http://dx.doi.org/10.1091/mbc.9.12.3309.
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Smads are intermediate effector proteins that transduce the TGF-β signal from the plasma membrane to the nucleus, where they participate in transactivation of downstream target genes. We have shown previously that coactivators p300/CREB-binding protein are involved in TGF-β–mediated transactivation of two Cdk inhibitor genes, p21 and p15. Here we examined the possibility that Smads function to regulate transcription by directly interacting with p300/CREB-binding protein. We show that Smad3 can interact with a C-terminal fragment of p300 in a temporal and phosphorylation-dependent manner. TGF-β–mediated phosphorylation of Smad3 potentiates the association between Smad3 and p300, likely because of an induced conformational change that removes the autoinhibitory interaction between the N- and C-terminal domains of Smad3. Consistent with a role for p300 in the transcription regulation of multiple genes, overexpression of a Smad3 C-terminal fragment causes a general squelching effect on multiple TGF-β–responsive reporter constructs. The adenoviral oncoprotein E1A can partially block Smad-dependent transcriptional activation by directly competing for binding to p300. Taken together, these findings define a new role for phosphorylation of Smad3: in addition to facilitating complex formation with Smad4 and promoting nuclear translocation, the phosphorylation-induced conformational change of Smad3 modulates its interaction with coactivators, leading to transcriptional regulation.
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Marsh, Graham P., Sean Goggins, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, and Hannah J. Maple. "Abstract 3841: Development of p300-targeting PROTAC degraders with enhanced selectivity and onset of degradation." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3841. http://dx.doi.org/10.1158/1538-7445.am2023-3841.
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Abstract CREB-binding protein (CBP, CREBBP, KAT3A) and E1A-binding protein (EP300, p300, KAT3B) are paralogous multi-domain proteins that act as chromatin regulators and transcriptional co-activators. They contain a histone acetyltransferase (HAT) domain that catalyzes the histone H3, lysine 27 acetylation (H3K27ac) mark at regulatory elements such as enhancers and promoters. Transcription factors associate with stretches of H3K27ac marks (known as ‘super-enhancer’ elements) and result in gene transcription that ultimately establishes cell identity and fate. They are implicated in cancer pathology, and small molecule inhibition of the bromodomain (BRD) or HAT domain of CBP/p300 are considered promising therapeutic strategies for a number of cancer types. CBP and p300 are highly homologous but have distinct roles that have to date been hard to delineate, since small molecule inhibitors developed to date are unable to selectively target each protein independently. Additionally, small molecule inhibitors that target individual domains are unable to entirely abrogate the full functionality of CBP/p300. A bromodomain-recruiting dual CBP/p300 PROTAC Degrader ‘dCBP1’ was therefore recently developed to provide a chemical tool to explore the phenotypic consequences of CBP/p300 chemical knockdown. A further study demonstrated that it is possible to degrade p300 with some selectivity by converting a CBP/p300 dual HAT-domain inhibitor into a PROTAC, called ‘JQAD1’. We have used a different HAT-domain recruiting ligand to develop novel PROTACs that elicit proteasome-mediated degradation of p300 with significantly enhanced selectivity over CBP, compared with JQAD1. We additionally demonstrate a faster onset of degradation for lead PROTAC molecules and present data exploring the consequences of selective p300 degradation in CIC-DIX4 sarcoma. Citation Format: Graham P. Marsh, Sean Goggins, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, Hannah J. Maple. Development of p300-targeting PROTAC degraders with enhanced selectivity and onset of degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3841.
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Manning, E. Tory, Tsuyoshi Ikehara, Takashi Ito, James T. Kadonaga, and W. Lee Kraus. "p300 Forms a Stable, Template-Committed Complex with Chromatin: Role for the Bromodomain." Molecular and Cellular Biology 21, no. 12 (June 15, 2001): 3876–87. http://dx.doi.org/10.1128/mcb.21.12.3876-3887.2001.
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ABSTRACT The nature of the interaction of coactivator proteins with transcriptionally active promoters in chromatin is a fundamental question in transcriptional regulation by RNA polymerase II. In this study, we used a biochemical approach to examine the functional association of the coactivator p300 with chromatin templates. Using in vitro transcription template competition assays, we observed that p300 forms a stable, template-committed complex with chromatin during the transcription process. The template commitment is dependent on the time of incubation of p300 with the chromatin template and occurs independently of the presence of a transcriptional activator protein. In studies examining interactions between p300 and chromatin, we found that p300 binds directly to chromatin and that the binding requires the p300 bromodomain, a conserved 110-amino-acid sequence found in many chromatin-associated proteins. Furthermore, we observed that the isolated p300 bromodomain binds directly to histones, preferentially to histone H3. However, the isolated p300 bromodomain does not bind to nucleosomal histones under the same assay conditions, suggesting that free histones and nucleosomal histones are not equivalent as binding substrates. Collectively, our results suggest that the stable association of p300 with chromatin is mediated, at least in part, by the bromodomain and is critically important for p300 function. Furthermore, our results suggest a model for p300 function that involves distinct activator-dependent targeting and activator-independent chromatin binding activities.
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Borger, Darrell R., and James A. DeCaprio. "Targeting of p300/CREB Binding Protein Coactivators by Simian Virus 40 Is Mediated through p53." Journal of Virology 80, no. 9 (May 1, 2006): 4292–303. http://dx.doi.org/10.1128/jvi.80.9.4292-4303.2006.
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ABSTRACT The primary transforming functions of simian virus 40 large T antigen (SV40 LT) are conferred primarily through the binding and inactivation of p53 and the retinoblastoma family members. Normal p53 function requires an association with the CREB binding protein (CBP)/p300 coactivators, and a ternary complex containing SV40 LT, p53, and CBP/p300 has been identified previously. In this report, we have evaluated a secondary function of p53 bound to the SV40 LT complex in mediating the binding of human CBP/p300. We demonstrate that p53 associated with SV40 LT was posttranslationally modified in a manner consistent with the binding of CBP/p300. Furthermore, expression of SV40 LT induced the proportion of p53 phosphorylated on S15. An essential function for p53 in bridging the interaction between SV40 LT and CBP/p300 was identified through the reconstitution of the SV40 LT-CBP/p300 complex upon p53 reexpression in p53-null cells. In addition, the SV40 LT-CBP/p300 complex was disrupted through RNA interference-mediated depletion of endogenous p53. We also demonstrate that SV40 LT was acetylated in a p300- and p53-dependent manner, at least in part through the CH3 domain of p300. Therefore, the binding of p53 serves to modify SV40 LT by targeting CBP and p300 binding to direct the acetylation of SV40 LT.
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Poizat, Coralie, Vittorio Sartorelli, Gene Chung, Robert A. Kloner, and Larry Kedes. "Proteasome-Mediated Degradation of the Coactivator p300 Impairs Cardiac Transcription." Molecular and Cellular Biology 20, no. 23 (December 1, 2000): 8643–54. http://dx.doi.org/10.1128/mcb.20.23.8643-8654.2000.
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ABSTRACT The transcription of tissue-specific genes is controlled by regulatory factors and cofactors and is suppressed in cardiac cells by the antineoplastic agent doxorubicin. Here we show that exposure of cultured cardiomyocytes to doxorubicin resulted in the rapid depletion of transcripts for MEF2C, dHAND, and NKX2.5, three pivotal regulators of cardiac gene expression. Delivery of exogenous p300, a coactivator of MEF2C and NKX2.5 in cardiomyocytes, restored cardiac transcription despite the presence of doxorubicin. Furthermore, p300 also restored the accumulation of transcripts for MEF2C itself. Importantly, cardiocytes exposed to doxorubicin displayed reduced levels of p300 proteins. This was not due to alterations in the level of p300 transcripts; rather, and surprisingly, doxorubicin promoted selective degradation of p300 mediated by the 26S-proteasome machinery. Doxorubicin had no effect on the general level of ubiquitinated proteins or on the levels of β-catenin, a protein known to be degraded by proteasome-mediated degradation. These results provide evidence for a new mechanism of transcriptional repression caused by doxorubicin in which the selective degradation of p300 results in reduced p300-dependent transcription, including production of MEF2C mRNA.
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Chen, Shali, Biao Feng, Biju George, Rana Chakrabarti, Megan Chen, and Subrata Chakrabarti. "Transcriptional coactivator p300 regulates glucose-induced gene expression in endothelial cells." American Journal of Physiology-Endocrinology and Metabolism 298, no. 1 (January 2010): E127—E137. http://dx.doi.org/10.1152/ajpendo.00432.2009.
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Sustained hyperglycemia in diabetes causes alteration of a large number of transcription factors and mRNA transcripts, leading to tissue damage. We investigated whether p300, a transcriptional coactivator with histone acetyl transferase activity, regulates glucose-induced activation of transcription factors and subsequent upregulation of vasoactive factors and extracellular matrix (ECM) proteins in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated in varied glucose concentrations and were studied after p300 small interfering RNA (siRNA) transfection, p300 overexpression, or incubation with the p300 inhibitor curcumin. Histone H2AX phosphorylation and lysine acetylation were examined for oxidative DNA damage and p300 activation. Screening for transcription factors was performed with the Luminex system. Alterations of selected transcription factors were validated. mRNA expression of p300, endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and fibronectin (FN) and its splice variant EDB+FN and FN protein production were analyzed. HUVECs in 25 mmol/l glucose showed increased p300 production accompanied by increased binding of p300 to ET-1 and FN promoters, augmented histone acetylation, H2AX phosphorylation, activation of multiple transcription factors, and increased mRNA expression of vasoactive factors and ECM proteins. p300 overexpression showed a glucose-like effect on the mRNA expression of ET-1, VEGF, and FN. Furthermore, siRNA-mediated p300 blockade or chemical inhibitor of p300 prevented such glucose-induced changes. Similar mRNA upregulation was also seen in the organ culture of vascular tissues, which was prevented by p300 siRNA transfection. Data from these studies suggest that glucose-induced p300 upregulation is an important upstream epigenetic mechanism regulating gene expression of vasoactive factors and ECM proteins in endothelial cells and is a potential therapeutic target for diabetic complications.
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Kirfel, Phillipp, Andreas Vilcinskas, and Marisa Skaljac. "Lysine Acetyltransferase p300/CBP Plays an Important Role in Reproduction, Embryogenesis and Longevity of the Pea Aphid Acyrthosiphon pisum." Insects 11, no. 5 (April 26, 2020): 265. http://dx.doi.org/10.3390/insects11050265.
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CREB-binding protein (p300/CBP) is a universal transcriptional co-regulator with lysine acetyltransferase activity. Drosophila melanogaster p300/CBP is a well-known regulator of embryogenesis, and recent studies in beetles and cockroaches have revealed the importance of this protein during post-embryonic development and endocrine signaling. In pest insects, p300/CBP may therefore offer a useful target for control methods based on RNA interference (RNAi). We investigated the role of p300/CBP in the pea aphid (Acyrthosiphon pisum), a notorious pest insect used as a laboratory model for the analysis of complex life-history traits. The RNAi-based attenuation of A. pisum p300/CBP significantly reduced the aphid lifespan and number of offspring, as well as shortening the reproductive phase, suggesting the manipulation of this gene contributes to accelerated senescence. Furthermore, injection of p300/CBP dsRNA also reduced the number of viable offspring and increased the number of premature nymphs, which developed in abnormally structured ovaries. Our data confirm the evolutionarily conserved function of p300/CBP during insect embryogenesis and show that the protein has a critical effect on longevity, reproduction and development in A. pisum. The potent effect of p300/CBP silencing indicates that this regulatory protein is an ideal target for RNAi-based aphid control.
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Chakraborty, Raja, Allison C. Ostriker, Yi Xie, Jui M. Dave, Ana Gamez-Mendez, Payel Chatterjee, Yaw Abu, et al. "Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity." Circulation 145, no. 23 (June 7, 2022): 1720–37. http://dx.doi.org/10.1161/circulationaha.121.057599.
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Background: Vascular smooth muscle cell (VSMC) phenotypic switching contributes to cardiovascular diseases. Epigenetic regulation is emerging as a key regulatory mechanism, with the methylcytosine dioxygenase TET2 acting as a master regulator of smooth muscle cell phenotype. The histone acetyl-transferases p300 and CREB-binding protein (CBP) are highly homologous and often considered to be interchangeable, and their roles in smooth muscle cell phenotypic regulation are not known. Methods: We assessed the roles of p300 and CBP in human VSMC with knockdown, in inducible smooth muscle–specific knockout mice (inducible knockout [iKO]; p300 iKO or CBP iKO ), and in samples of human intimal hyperplasia. Results: P300, CBP, and histone acetylation were differently regulated in VSMCs undergoing phenotypic switching and in vessel remodeling after vascular injury. Medial p300 expression and activity were repressed by injury, but CBP and histone acetylation were induced in neointima. Knockdown experiments revealed opposing effects of p300 and CBP in the VSMC phenotype: p300 promoted contractile protein expression and inhibited migration, but CBP inhibited contractile genes and enhanced migration. p300 iKO mice exhibited severe intimal hyperplasia after arterial injury compared with controls, whereas CBP iKO mice were entirely protected. In normal aorta, p300 iKO reduced, but CBP iKO enhanced, contractile protein expression and contractility compared with controls. Mechanistically, we found that these histone acetyl-transferases oppositely regulate histone acetylation, DNA hydroxymethylation, and PolII (RNA polymerase II) binding to promoters of differentiation-specific contractile genes. Our data indicate that p300 and TET2 function together, because p300 was required for TET2-dependent hydroxymethylation of contractile promoters, and TET2 was required for p300-dependent acetylation of these loci. TET2 coimmunoprecipitated with p300, and this interaction was enhanced by rapamycin but repressed by platelet-derived growth factor (PDGF) treatment, with p300 promoting TET2 protein stability. CBP did not associate with TET2, but instead facilitated recruitment of histone deacetylases (HDAC2, HDAC5) to contractile protein promoters. Furthermore, CBP inhibited TET2 mRNA levels. Immunostaining of cardiac allograft vasculopathy samples revealed that p300 expression is repressed but CBP is induced in human intimal hyperplasia. Conclusions: This work reveals that p300 and CBP serve nonredundant and opposing functions in VSMC phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with TET2 or HDACs. Targeting specific histone acetyl-transferases may hold therapeutic promise for cardiovascular diseases.
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Lee, Jee H., Jamie L. Volinic, Constanze Banz, Kwok-Ming Yao, and Melissa K. Thomas. "Interactions with p300 enhance transcriptional activation by the PDZ-domain coactivator Bridge-1." Journal of Endocrinology 187, no. 2 (November 2005): 283–92. http://dx.doi.org/10.1677/joe.1.06305.
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Transcriptional coactivators are essential mediators of signal amplification in the regulation of gene expression in response to hormones and extracellular signals. We previously identified Bridge-1 (PSMD9) as a PDZ-domain coregulator that augments insulin gene transcription via interactions with the basic helix-loop-helix transcription factors E12 and E47, and that increases transcriptional activation by the homeodomain transcription factor PDX-1. In these studies, we find that transcriptional activation by Bridge-1 can be regulated via interactions with the histone acetyltransferase and nuclear receptor coactivator p300. In transfection assays, transcriptional activation by Bridge-1 is increased by the inhibition of endogenous histone deacetylase activity with trichostatin A, indicating that the transcriptional activation function of Bridge-1 can be regulated by histone modifications. The exogenous expression of p300 enhances the transcriptional activation by Bridge-1 in a dose-dependent manner. In contrast, the sequestration of p300 by the overexpression of the adenoviral protein E1A, but not by an E1A mutant protein that is unable to interact with p300, suppresses the transcriptional activation by Bridge-1. We demonstrate that p300 and Bridge-1 proteins interact in immunopre-cipitation and glutathione-S-transferase (GST) pull-down assays. Bridge-1 interacts directly with multiple regions within p300 that encompass C/H1 or C/H2 cysteine- and histidine-rich protein interaction domains and the histone acetyltransferase domain. Deletion or point mutagenesis of the Bridge-1 PDZ domain substantially reduces transcriptional activation by Bridge-1 and interrupts interactions with p300. We propose that p300 interactions with Bridge-1 can augment the transcriptional activation of regulatory target genes by Bridge-1.
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Feng, Biao, Shali Chen, Jane Chiu, Biju George, and Subrata Chakrabarti. "Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level." American Journal of Physiology-Endocrinology and Metabolism 294, no. 6 (June 2008): E1119—E1126. http://dx.doi.org/10.1152/ajpendo.00029.2008.
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Diabetic cardiomyopathy, structurally characterized by cardiomyocyte hypertrophy and increased extracellular matrix (ECM) protein deposition, eventually leads to heart failure. We investigated the role of transcriptional coactivator p300 and its interaction with myocyte enhancer factor 2 (MEF2) in diabetes-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed to variable levels of glucose. Cardiomyocytes were analyzed with respect to their size. mRNA expression of p300, MEF2A, MEF2C, atrial natriuretic polypeptide (ANP), brain natriuretic polypeptide (BNP), angiotensinogen (ANG), cAMP-responsive element binding protein-binding protein (CBP), and protein analysis of MEF2 were done with or without p300 blockade. We investigated the hearts of STZ-induced diabetic rats and compared them with age- and sex-matched controls after 1 and 4 mo of followup with or without treatment with p300 blocker curcumin. The results were that cardiomyocytes, exposed to 25 mM glucose for 48 h, showed cellular hypertrophy and augmented mRNA expression of ANP, BNP, and ANG, molecular markers of cardiac hypertrophy. Glucose caused a duration-dependent increase of mRNA and protein expression in MEF2A and MEF2C and transcriptional coactivator p300. Curcumin, a p300 blocker, and p300 siRNA prevented these abnormalities. Similarly, ANP, BNP, and ANG mRNA expression was significantly higher in the hearts of diabetic rats compared with the controls, in association with increased p300, MEF2A, and MEF2C expression. Treatment with p300 blocker curcumin prevented diabetes-induced upregulation of these transcripts. We concluded that data from these studies demonstrate a novel glucose-induced epigenetic mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes.
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Mink, S., B. Haenig, and K. H. Klempnauer. "Interaction and functional collaboration of p300 and C/EBPbeta." Molecular and Cellular Biology 17, no. 11 (November 1997): 6609–17. http://dx.doi.org/10.1128/mcb.17.11.6609.
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Transcriptional coactivators such as p300 and CREB-binding protein (CBP) function as important elements in the transcription factor network, linking individual transactivators via protein-protein interactions to the basal transcriptional machinery. We have investigated whether p300 plays a role in transactivation mediated by C/EBPbeta, a conserved member of the C/EBP family. We show that C/EBPbeta-dependent transactivation is strongly inhibited by adenovirus E1A but not by E1A mutants defective in p300 binding. Ectopic expression of p300 reverses the E1A-dependent inhibition and increases the transactivation potential of C/EBPbeta. Furthermore, we show that C/EBPbeta and p300 interact with each other and demonstrate that the sequences responsible for interaction map to the E1A binding region of p300 and the amino terminus of C/EBPbeta. Finally, we show that the minimal C/EBPbeta binding site of p300 acts as a dominant-negative inhibitor of C/EBPbeta. These observations identify p300 as a bona fide coactivator for C/EBPbeta. C/EBPbeta is highly expressed in the myelomonocytic lineage of the hematopoietic system and cooperates with Myb to activate mim-1, a gene specifically expressed during myelomonocytic differentiation. Recent evidence has shown that Myb recruits CBP (and presumably p300) as a coactivator and, in contrast to C/EBPbeta, interacts with the CREB binding site of p300-CBP. We show that p300 not only stimulates the activity of Myb and C/EBPbeta individually but also increases the synergy between them. Thus, our results reveal a novel function of p300: in addition to linking specific transcription factors to the basal transcriptional machinery, p300 also mediates the cooperation between transactivators interacting with different domains of p300.
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Katavolos, Paula, Gary Cain, Cindy Farman, F. Anthony Romero, Steven Magnuson, Justin Q. Ly, Edna F. Choo, Anand Kumar Katakam, Roxanne Andaya, and Jonathan Maher. "Preclinical Safety Assessment of a Highly Selective and Potent Dual Small-Molecule Inhibitor of CBP/P300 in Rats and Dogs." Toxicologic Pathology 48, no. 3 (March 3, 2020): 465–80. http://dx.doi.org/10.1177/0192623319898469.
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Cyclic adenosine monophosphate-response element (CREB)-binding protein (CBP) and EP300E1A-binding protein (p300) are members of the bromodomain and extraterminal motif (BET) family. These highly homologous proteins have a key role in modulating transcription, including altering the status of chromatin or through interactions with or posttranslational modifications of transcription factors. As CBP and p300 have known roles for stimulating c-Myc oncogenic activity, a small-molecule inhibitor, GNE-781, was developed to selectively and potently inhibit the CBP/p300 bromodomains (BRDs). Genetic models have been challenging to develop due to embryonic lethality arising from germline homozygous mutations in either CBP or P300. Hence, the purpose of this study was to characterize the role of dual inhibition of these proteins in adult rats and dogs. Repeat dose toxicity studies were conducted, and toxicologic and pathologic end points were assessed. GNE-781 was generally tolerated; however, marked effects on thrombopoiesis occurred in both species. Evidence of inhibition of erythroid, granulocytic, and lymphoid cell differentiation was also present, as well as deleterious changes in gastrointestinal and reproductive tissues. These findings are consistent with many preclinical (and clinical) effects reported with BET inhibitors targeting BRD proteins; thus, the current study findings indicate a likely important role for CBP/p300 in stem cell differentiation.
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Yaciuk, P., and E. Moran. "Analysis with specific polyclonal antiserum indicates that the E1A-associated 300-kDa product is a stable nuclear phosphoprotein that undergoes cell cycle phase-specific modification." Molecular and Cellular Biology 11, no. 11 (November 1991): 5389–97. http://dx.doi.org/10.1128/mcb.11.11.5389-5397.1991.
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Binding of a 300-kDa host cell protein (p300) is tightly correlated with the ability of the adenovirus E1A products to induce quiescent baby rat kidney cells to proliferate. We have generated rabbit polyclonal antibodies against p300 to characterize this protein further. We have found p300 to be a nuclear phosphoprotein that is actively synthesized in both quiescent and proliferating baby rat kidney cells. In partially purified mitotic cell populations, we observe a form of p300 with decreased electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels that shares a nearly identical partial proteolytic digest pattern with p300. The slower-migrating form of p300 is greatly reduced by treating immune complexes with potato acid phosphatase. The relative stability and presence of p300 even in resting cells suggests that p300 has a basal cell function, but the appearance of differentially modified forms during the cell cycle suggests the possibility that p300 function is modulated specifically in growing cells.
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Yaciuk, P., and E. Moran. "Analysis with specific polyclonal antiserum indicates that the E1A-associated 300-kDa product is a stable nuclear phosphoprotein that undergoes cell cycle phase-specific modification." Molecular and Cellular Biology 11, no. 11 (November 1991): 5389–97. http://dx.doi.org/10.1128/mcb.11.11.5389.
Full textAbstract:
Binding of a 300-kDa host cell protein (p300) is tightly correlated with the ability of the adenovirus E1A products to induce quiescent baby rat kidney cells to proliferate. We have generated rabbit polyclonal antibodies against p300 to characterize this protein further. We have found p300 to be a nuclear phosphoprotein that is actively synthesized in both quiescent and proliferating baby rat kidney cells. In partially purified mitotic cell populations, we observe a form of p300 with decreased electrophoretic mobility in sodium dodecyl sulfate-polyacrylamide gels that shares a nearly identical partial proteolytic digest pattern with p300. The slower-migrating form of p300 is greatly reduced by treating immune complexes with potato acid phosphatase. The relative stability and presence of p300 even in resting cells suggests that p300 has a basal cell function, but the appearance of differentially modified forms during the cell cycle suggests the possibility that p300 function is modulated specifically in growing cells.
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Xu, Wu, Tomofusa Fukuyama, Paul A. Ney, Demin Wang, Jerold Rehg, Kelli Boyd, Jan M. A. van Deursen, and Paul K. Brindle. "Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B cells." Blood 107, no. 11 (June 1, 2006): 4407–16. http://dx.doi.org/10.1182/blood-2005-08-3263.
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Abstract CREB-binding protein (CBP) and its para-log p300 are transcriptional coactivators that physically or functionally interact with over 320 mammalian and viral proteins, including 36 that are essential for B cells in mice. CBP and p300 are generally considered limiting for transcription, yet their roles in adult cell lineages are largely unknown since homozygous null mutations in either gene or compound heterozygosity cause early embryonic lethality in mice. We tested the hypotheses that CBP and p300 are limiting and that each has unique properties in B cells, by using mice with Cre/LoxP conditional knockout alleles for CBP (CBPflox) and p300 (p300flox), which carry CD19Cre that initiates floxed gene recombination at the pro–B-cell stage. CD19Cre-mediated loss of CBP or p300 led to surprisingly modest deficits in B-cell numbers, whereas inactivation of both genes was not tolerated by peripheral B cells. There was a moderate decrease in B-cell receptor (BCR)–responsive gene expression in CBP or p300 homozygous null B cells, suggesting that CBP and p300 are essential for this signaling pathway that is crucial for B-cell homeostasis. These results indicate that individually CBP and p300 are partially limiting beyond the pro-B-cell stage and that other coactivators in B cells cannot replace their combined loss.