Fact-checked by Grok 2 weeks ago

CREB-binding protein

CREB-binding protein (CBP), also known as KAT3A, encoded by the CREBBP gene on chromosome 16p13.3 in humans, is a ubiquitously expressed nuclear protein that functions as a transcriptional coactivator and lysine acetyltransferase, essential for regulating gene expression through chromatin remodeling and interactions with transcription factors. CBP is closely related to its paralog p300 (KAT3B), with which it shares significant sequence homology and functional similarities.^[1]^[2] Weighing approximately 265 kDa and comprising 2442 amino acids, CBP was first identified for its binding to the phosphorylated cAMP response element-binding protein (CREB), but it interacts with a broad array of signaling molecules to integrate diverse cellular pathways.^[3]^[4] Structurally, CBP features multiple functional domains, including the nuclear receptor interaction domain, KIX domain for CREB binding, cysteine-histidine-rich (CH) domains, a bromodomain for acetylated histone recognition, a catalytic KAT (lysine acetyltransferase) domain spanning 380 residues, and the NCBD/IBiD domain for protein-protein interactions.^[2] These domains enable CBP to serve as a molecular scaffold, recruiting components of the basal transcription machinery, such as RNA polymerase II, and facilitating the assembly of multiprotein complexes at gene promoters and enhancers.^[5] Its acetyltransferase activity targets both histones—promoting an open chromatin conformation for transcription—and non-histone proteins like p53 and E2F, thereby modulating their stability and activity.^[6]^[7] CBP plays pivotal roles in cellular processes, including embryonic development, cell proliferation, differentiation, and homeostasis, by coupling signal transduction to transcriptional responses.^[1] In hematopoiesis, it regulates blood cell formation through coactivation and acetylation, while in the nervous system, it influences stress responses and synaptic plasticity via CREB-mediated pathways.^[2] Dysregulation of CBP is implicated in several diseases; heterozygous mutations cause Rubinstein-Taybi syndrome, a developmental disorder characterized by intellectual disability and distinctive physical features, and chromosomal translocations involving CREBBP contribute to acute myeloid leukemia.^[1]^[8] Additionally, CBP's involvement in super-enhancers at oncogenes makes it a target for cancer therapies, with inhibitors such as CCS1477 and inobrodib in clinical trials as of 2025 for hematologic and other malignancies.^[9]^[10]

Overview

Definition and discovery

The CREB-binding protein (CBP), also known as CREBBP, is a multifunctional transcriptional coactivator that specifically interacts with the phosphorylated form of the cAMP response element-binding protein (CREB) to facilitate gene expression.^[11] As a histone acetyltransferase (HAT), CBP catalyzes the acetylation of lysine residues on histones, which promotes chromatin relaxation and enhances transcriptional activation, while also acetylating non-histone proteins such as transcription factors to modulate their activity.^[12]^[13] This dual role positions CBP as a critical integrator in signal transduction pathways that regulate cellular processes like proliferation, differentiation, and survival.^[13] CBP was first discovered in 1993 through a yeast two-hybrid screening approach designed to identify nuclear proteins that bind to CREB phosphorylated by protein kinase A (PKA), a key mediator of cAMP signaling.^[11] In this seminal study by Chrivia et al., CBP was characterized as a 265 kDa nuclear protein that specifically associates with the kinase-inducible domain (KID) of phosphorylated CREB, thereby linking cAMP-responsive signals to transcriptional machinery.^[11] This interaction was shown to be essential for CREB's ability to activate transcription from promoters containing cAMP response elements (CREs).^[11] The human CREBBP gene, which encodes CBP, is located on the short arm of chromosome 16 at position 16p13.3 and spans approximately 159 kb with 31 exons.^[14] It produces a protein consisting of 2442 amino acids, resulting in a molecular weight of about 265 kDa, consistent with its identification as a large multifunctional regulator.^[14]^[15] Early investigations following its discovery established CBP's pivotal role in CRE-mediated transcription, demonstrating that its recruitment by phosphorylated CREB is required for efficient activation of cAMP-inducible genes, such as those involved in metabolic adaptation and neuronal signaling.^[11] These foundational studies highlighted CBP's selectivity for phosphorylated CREB over its unphosphorylated form, underscoring its function as a signal-dependent coactivator in the cAMP pathway.^[11]

Nomenclature and relation to p300

The CREB-binding protein (CBP), encoded by the CREBBP gene, derives its name from its specific interaction with the phosphorylated form of the cAMP response element-binding protein (CREB), a transcription factor activated by protein kinase A. This binding was first demonstrated in 1993, when CBP was isolated as a 265-kDa nuclear protein that associates with the kinase-inducible domain (KID) of CREB to facilitate transcriptional activation.^[11]^[16] In 1994, p300 was identified as a distinct 300-kDa protein that interacts with the adenoviral E1A oncoprotein, serving as a transcriptional adaptor. Shortly thereafter, sequence analysis revealed that p300 and CBP share approximately 63% amino acid identity across their entire lengths, establishing them as highly homologous paralogs arising from an ancient gene duplication event estimated to have occurred over 450 million years ago. Due to this homology and their overlapping roles as transcriptional coactivators, p300 and CBP are frequently referred to collectively as p300/CBP in the literature.90127-9)^[17] While both proteins exhibit broad expression, subtle tissue-specific differences exist: CBP shows higher levels in neuronal tissues, whereas p300 is more ubiquitously distributed across cell types. These patterns contribute to context-dependent functions, though early studies often used the terms interchangeably owing to their redundant activities in many signaling pathways, leading to historical ambiguities in attributing specific effects to either protein.^[18]^[19]^[20]

Structure

Zinc finger and cysteine-histidine rich domains

The transitional adapter (Taz) zinc finger domains of CREB-binding protein (CBP), namely Taz1 and Taz2, are specialized C2HC-type zinc fingers that mediate protein-protein interactions essential for transcriptional adapter functions. These domains, located in the N-terminal and central regions of CBP, respectively, facilitate the recruitment of transcription factors by providing structured binding surfaces that stabilize disordered activation domains. Taz1 and Taz2 each coordinate multiple zinc ions through cysteine and histidine residues, forming compact helical bundles that act as versatile scaffolds for complex assembly.^[21] Taz1, encompassing residues approximately 340–439, exhibits a triangular architecture with four α-helices stabilized by three zinc-binding sites, each featuring an HCCC motif involving one histidine and three cysteines. This domain interacts with transcription factors such as HIF-1α, inducing folding of the partner’s C-terminal activation domain (CTAD) through extensive hydrophobic contacts and serving as a scaffold for hypoxic signal transduction. In contrast, Taz2, spanning residues approximately 1764–1855, adopts a similar four-helix bundle but with a rotated fourth helix, enabling binding to the kinase-inducible domain (KID) of CREB and the transactivation domain (TAD) of STAT1; these interactions are enhanced by phosphorylation-induced conformational changes in the transcription factors, promoting signal-responsive recruitment.^[21]^[22] The cysteine-histidine rich regions (CH1, CH2, CH3) of CBP represent multi-domain motifs with inherent zinc-binding capacity, functioning as integrated scaffolds for the assembly of transcriptional complexes. CH1 corresponds to the Taz1 domain, while CH3 encompasses Taz2 along with adjacent ZZ-type zinc-binding elements; both exhibit robust Zn²⁺ coordination essential for structural integrity and partner engagement. CH2, positioned centrally between CH1 and CH3, comprises PHD and ZZ subdomains that also bind zinc ions, contributing to adapter versatility by linking upstream signaling inputs to downstream coactivator recruitment without direct histone recognition. These regions collectively enable CBP's role in signal transduction by undergoing dynamic conformational shifts that accommodate phosphorylated ligands, thereby facilitating ordered assembly of multiprotein complexes at promoters.^[21]^[23]^[24]

Kinase-inducible and bromodomains

The kinase-inducible domain (KIX) of CREB-binding protein (CBP), spanning approximately residues 586 to 672 in the human protein, functions as an amphipathic helix-binding motif that selectively interacts with phosphorylated kinase-inducible domains (KIDs) of various transcription factors, including CREB. This domain, a compact three-helix bundle of about 90 amino acids, serves as a critical docking site for signal-dependent transcriptional activation.^[25] Upon stimulation by cAMP-dependent protein kinase A (PKA), phosphorylation of CREB at serine 133 within its KID triggers a conformational change, enabling the KID to form an α-helical structure that binds to a hydrophobic groove on the KIX surface. The binding interface involves key hydrophobic residues from both KIX and the phosphorylated KID, stabilizing the complex and recruiting CBP to promoter regions to enhance transcription.^[25] Structural studies using nuclear magnetic resonance (NMR) spectroscopy have elucidated the binding mechanism, revealing that the phosphorylated serine 133 forms hydrogen bonds with conserved tyrosine residues (e.g., Tyr658) in KIX, while the amphipathic helix of KID nestles into the groove formed by helices II and III of KIX. This interaction is highly specific to the phosphorylated state, as unphosphorylated KID exhibits low affinity, ensuring that CBP recruitment is tightly regulated by signaling pathways like cAMP/PKA.^[26] The KIX domain's plasticity allows it to accommodate similar motifs from other activators, such as c-Myb, underscoring its role in integrating diverse signals for gene expression.^[26] The bromodomain of CBP, comprising approximately residues 1085 to 1165 and consisting of about 110 amino acids, acts as a specialized module for recognizing acetylated lysine residues on histone tails, thereby facilitating epigenetic readout during transcription.^[27] This domain adopts a conserved left-handed four-helix bundle fold (αZ, αA, αB, αC), with variable ZA and BC loops that form a shallow pocket for binding acetyl-lysines, such as H4K8ac and H3K14ac, through hydrophobic and hydrogen-bonding interactions.^[27] Crystal and NMR structures demonstrate that the acetyl group is anchored by a conserved asparagine residue (Asn1168) in the BC loop, which donates a hydrogen bond to the carbonyl oxygen, while surrounding hydrophobic pockets accommodate the lysine side chain.^[28] These interactions promote CBP's association with acetylated chromatin, aiding in the recruitment of coactivators to active promoters.^[27]

Acetyltransferase and coactivator binding domains

The lysine acetyltransferase (KAT) domain of CREB-binding protein (CBP), spanning approximately residues 1342–1648 and also referred to as the histone acetyltransferase (HAT) domain, catalyzes the transfer of acetyl groups from acetyl-CoA to the ε-amino groups of lysine residues on histones and transcription factors, thereby modulating chromatin structure and transcriptional activity. This intrinsic enzymatic function was first identified in 1996 through in vitro assays demonstrating CBP's ability to acetylate all four core histones (H2A, H2B, H3, and H4). The domain's catalytic core includes conserved sequence motifs, such as motif A (containing the YGNKG pentapeptide) and the B-loop, which are critical for acetyl-CoA binding, substrate recognition, and nucleophilic attack by the substrate lysine, ensuring efficient acetyl transfer. These motifs contribute to CBP's substrate specificity, with a preference for acetylating histone H3 at lysines 14 and 18 (H3K14, H3K18) and histone H4 at lysines 5, 8, 12, and 16 (H4K5, H4K8, H4K12, H4K16), as determined by steady-state kinetic analyses using synthetic histone peptides and nucleosomes.^[29] The nuclear receptor coactivator binding domain (NCBD) of CBP, encompassing approximately residues 2059–2117, functions as an intrinsically disordered region that transiently forms α-helical structures to recruit coactivators bearing LXXLL motifs, such as steroid receptor coactivator-1 (SRC-1), thereby facilitating multiprotein assembly at promoters.^[30] In its unbound state, NCBD exhibits characteristics of a molten globule, with residual secondary structure, compact conformation, and high flexibility due to a dynamic hydrophobic core lacking stable packing. Crystal and NMR structures of NCBD in complex with ligands like the SRC-1 activation domain (ACTR) reveal an induced-fit mechanism, where binding stabilizes three amphipathic helices in NCBD, reorganizing its interface to accommodate diverse partners through hydrophobic and electrostatic interactions. This plasticity enables NCBD's role in coactivator recruitment while maintaining low-affinity, transient interactions in the absence of ligands.^[31]

Molecular interactions

Binding to transcription factors

The CREB-binding protein (CBP) primarily interacts with the transcription factor CREB through its KIX domain, which recognizes the kinase-inducible domain (KID) of CREB following phosphorylation at serine 133 by protein kinase A (PKA) in response to cAMP signaling. This phosphorylation-dependent binding enables CBP recruitment to CRE-dependent gene promoters, such as that of c-fos, facilitating transcriptional activation. The interaction involves a coupled folding and binding mechanism where the intrinsically disordered KID folds into two α-helices upon binding to the globular KIX domain, with binding affinities for the phosphorylated KID typically in the range of 0.5–3 μM, though multi-site interactions and cellular context can enhance specificity and effective affinity to the low nanomolar range. Seminal structural studies have elucidated this interface, highlighting hydrophobic contacts between KID residues (e.g., Leu144, Leu147) and KIX helices as critical for high-affinity recognition. CBP also binds to components of the AP-1 complex, including c-Jun and c-Fos, primarily through its C-terminal region and KIX domain, integrating mitogen-activated protein kinase (MAPK) signaling with transcriptional responses. This interaction potentiates AP-1 activity at promoters involved in cell proliferation and stress responses, with CBP acting as a bridge for coactivator assembly. In interferon-γ (IFN-γ) signaling, CBP interacts with STAT1 via two distinct contact regions: the N-terminal domain of STAT1 binds the KIX domain of CBP, while the C-terminal transactivation domain associates with the E1A-binding domain, promoting IFN-γ-responsive gene expression. Similarly, CBP engages the p65 (RelA) subunit of NF-κB through bivalent interactions involving the Rel homology domain and transactivation domain, enhancing NF-κB-driven transcription in inflammatory contexts; phosphorylation of p65 by PKA further strengthens this association. Under hypoxic conditions, CBP is recruited by HIF-1α via its C-terminal transactivation domain (CAD), which binds the CH1 domain of CBP, stabilizing the HIF-1α/ARNT heterodimer at hypoxia-response elements. Beyond these, CBP is recruited to MyoD during skeletal muscle differentiation, where it interacts with the basic helix-loop-helix domain of MyoD to support myogenic gene expression. In the DNA damage response, CBP binds the N-terminal transactivation domain of p53, particularly following phosphorylation at serine 15, which increases affinity and promotes p53-dependent apoptosis and cell cycle arrest.

Interactions with chromatin modifiers

The CREB-binding protein (CBP) often functions cooperatively with its paralog p300, facilitating cooperative regulation of chromatin accessibility through their homologous acetyltransferase domains. This cooperation enhances the overall histone acetyltransferase (HAT) activity at target loci, allowing for more efficient acetylation of histones and non-histone proteins. Structural studies indicate that the CH1 and CH3 regions of CBP and p300 contribute to stable complex formation by serving as docking sites for shared binding partners, thereby amplifying enzymatic output in multi-subunit assemblies.^[20]^[32] CBP also associates with the SWI/SNF chromatin remodeling complex, particularly through the BRG1 ATPase subunit, to promote nucleosome mobilization and repositioning at enhancers and promoters. This binding enables SWI/SNF to facilitate the exposure of DNA for subsequent modifications, with CBP providing acetyltransferase activity that stabilizes open chromatin states.^[33] Similarly, CBP interacts with the Mediator complex, a multi-subunit coactivator that bridges transcription factors and RNA polymerase II, coordinating nucleosome remodeling with transcriptional initiation. These associations ensure synergistic effects on chromatin dynamics, where SWI/SNF and Mediator work in concert with CBP to mobilize nucleosomes and sustain gene activation.^[34] In addition to p300, CBP forms complexes with other HATs such as PCAF and GCN5, contributing to the assembly of enhanceosomes—multi-protein hubs at regulatory elements that integrate diverse signals for precise transcriptional control. These interactions allow CBP to collaborate with PCAF/GCN5 in sequential acetylation events, where CBP often initiates broad histone modifications followed by substrate-specific actions from GCN5/PCAF. CBP further recruits histone deacetylases (HDACs), including HDAC1 and HDAC2, to establish dynamic acetylation cycles that toggle chromatin between active and poised states, preventing sustained hyperacetylation and enabling rapid responses to cellular cues.^[35] This recruitment balances HAT and deacetylase activities, supporting cyclical modifications essential for processes like cell cycle progression.^[36] Notable multi-protein assemblies involving CBP include ternary complexes with p300 and additional chromatin factors, such as in p53-mediated regulation, where CBP-p300 heterodimers integrate with ubiquitin ligases to fine-tune acetylation and stability at damage sites. In DNA repair contexts, CBP interacts with the TIP60 HAT complex, enhancing acetylation of repair proteins like ATM and promoting efficient double-strand break resolution through coordinated chromatin relaxation.^[37] These specific complexes underscore CBP's role as a central scaffold in epigenetic networks, linking acetylation to broader remodeling efforts.^[38]

Functions

Transcriptional coactivation mechanisms

The CREB-binding protein (CBP) functions as a transcriptional coactivator by bridging sequence-specific transcription factors to the basal transcription machinery, thereby stabilizing the pre-initiation complex (PIC) at target promoters. This bridging occurs through direct interactions with components such as TBP and TFIIB, as well as recruitment of the Mediator complex, which integrates signals from enhancers to RNA polymerase II (Pol II).^[39] In this capacity, CBP enhances the assembly and stability of the PIC, promoting efficient transcription initiation without directly contacting Pol II.^[40] A key aspect of CBP's coactivation involves post-translational modification of non-histone targets, particularly transcription factors. For instance, following phosphorylation of CREB at Ser133 by protein kinase A (PKA), CBP binds to phospho-CREB via its KIX domain and subsequently acetylates CREB at lysine residues 91, 94, and 136 within the activation domain. This acetylation enhances CREB's transactivation potential, increasing CREB-dependent transcription by approximately 4-fold in cellular assays, independent of effects on DNA binding affinity.^[41] Similar acetylation events on other factors, such as p53 and STAT3, amplify their transcriptional output by modulating protein stability and cofactor recruitment.^[42] CBP's multidomain architecture and large molecular weight (approximately 265 kDa) enable it to act as a scaffold for chromatin looping, facilitating physical proximity between distal enhancers and promoters over distances of tens to hundreds of kilobases. By simultaneously binding enhancer-associated transcription factors and promoter-proximal elements, CBP stabilizes these loops, often in coordination with Mediator, to boost enhancer-promoter communication.^[43] This structural role contributes to quantitative enhancements in transcription, with CBP overexpression driving 80- to 90-fold increases in reporter gene activity in mammalian cells.^[40] Additionally, CBP promotes the release of promoter-proximal paused Pol II into productive elongation by acetylating histones near the transcription start site and interacting with pausing factors like TFIIB, preventing Pol II backlog and accelerating elongation rates; inhibition of CBP reduces paused Pol II occupancy by up to 80% within an hour.^[44]

Role in chromatin modification and cell cycle

The CREB-binding protein (CBP) plays a pivotal role in chromatin modification through its intrinsic histone acetyltransferase (HAT) activity, primarily targeting core histones H3 and H4. Acetylation of these histones by CBP neutralizes their positive charge, thereby reducing the affinity between histones and negatively charged DNA, which loosens nucleosome structure and facilitates an open chromatin conformation conducive to transcriptional activation.^[45]^[46] This modification is essential for establishing euchromatic regions that allow access for transcription factors and other regulatory proteins. Additionally, CBP undergoes autoacetylation, a self-modification process that significantly enhances its own HAT activity, thereby amplifying its capacity to acetylate histones and maintain dynamic chromatin states.^[47] In the context of cell cycle regulation, CBP contributes to key transitions by acetylating critical regulators. Specifically, CBP acetylates the tumor suppressor p53 at lysine 382 (K382), a modification that stabilizes p53, enhances its DNA-binding affinity, and promotes transcriptional activation of genes such as p21, leading to G1/S phase arrest in response to cellular stress.^[48] Conversely, CBP interacts with E2F transcription factors, serving as a coactivator that facilitates their recruitment to promoters of S-phase genes, thereby promoting entry into the S phase during normal cell proliferation.^[49]^[50] This dual role is exemplified in the activation of the cyclin E promoter, where CBP, through its HAT activity, acetylates histones to enable E2F-dependent transcription and progression through the G1/S checkpoint.^[51]^[50] CBP also contributes to epigenetic memory by depositing histone H3 lysine 27 acetylation (H3K27ac) marks at active enhancers, which sustain gene expression patterns during development. These H3K27ac modifications, catalyzed by CBP's HAT domain, distinguish active from poised enhancers and propagate transcriptional competence across cell generations, ensuring stable epigenetic landscapes in differentiating tissues.^[52]^[53] Dysregulation of CBP's chromatin-modifying functions disrupts these balanced controls, often resulting in aberrant cell proliferation due to unchecked progression through cell cycle phases.^[50]

Distinction from p300

The CREB-binding protein (CBP) and p300, also known as EP300, are paralogous transcriptional coactivators that share approximately 63% amino acid sequence identity and conserved functional domains, including the histone acetyltransferase (HAT) domain, bromodomain, and zinc finger motifs, enabling partial redundancy in acetylation activities.^[54] However, they exhibit notable structural differences outside these core regions, with CBP possessing unique extensions in its C-terminal glutamine-rich domains that facilitate distinct protein-protein interactions.^[55] In terms of expression patterns, CBP is preferentially enriched in neuronal and hematopoietic tissues, reflecting its specialized roles in these systems, whereas p300 displays broader ubiquitous expression, particularly in epithelial and cardiac tissues.^[6]^[56] This divergence influences their tissue-specific contributions to development and homeostasis. Functionally, CBP plays a more prominent role in CREB-mediated processes, such as neuronal synaptic plasticity and long-term memory formation, where its HAT activity is essential for activity-dependent gene expression in the hippocampus.^[57] In contrast, p300 is predominantly involved in interactions with viral oncoproteins, including adenovirus E1A and human papillomavirus E7, which hijack p300 to disrupt cellular regulation and promote transformation.^[58] These non-overlapping functions underscore their non-redundant contributions despite shared coactivation capabilities. Genetic studies further highlight their distinctions: homozygous CBP knockout in mice is embryonic lethal and associated with Rubinstein-Taybi syndrome phenotypes in heterozygotes, characterized by growth retardation and skeletal defects, whereas p300 null mice exhibit broader developmental defects, including cardiac malformations and increased hematopoietic stem cell accumulation without proper differentiation.^[59] Despite these differences, evidence from conditional knockouts and double-null cell lines indicates partial redundancy, as each can partially compensate for the loss of the other in histone acetylation and certain transcriptional responses.^[60]

Role in diseases

Rubinstein–Taybi syndrome

Rubinstein–Taybi syndrome (RTS) is a rare autosomal dominant neurodevelopmental disorder primarily caused by heterozygous pathogenic variants in the CREBBP gene, which encodes the CREB-binding protein (CBP), accounting for approximately 50-60% of cases.^[61] The remaining cases are attributed to variants in the homologous EP300 gene, but CREBBP mutations predominate in RTS type 1. These mutations typically include nonsense, frameshift, splice site, and missense variants, often leading to haploinsufficiency through premature truncation or loss of functional protein domains.^[61] Deletions encompassing CREBBP or contiguous gene syndromes at 16p13.3 also contribute, spanning from small intragenic changes to larger genomic rearrangements up to 6.5 Mb.^[62] The prevalence of RTS is estimated at 1 in 100,000 to 125,000 live births.^[61] Clinically, RTS is characterized by moderate to severe intellectual disability (IQ typically 35-50), distinctive craniofacial dysmorphology including downslanting palpebral fissures, a low-hanging columella, and a high-arched palate, as well as broad and angulated thumbs and halluces.^[61] Additional features encompass short stature, growth retardation, congenital heart defects in about one-third of individuals, recurrent infections, and an increased risk of certain tumors.^[61] These manifestations arise during embryonic development, reflecting CBP's critical role in regulating gene expression essential for neuronal differentiation and skeletal morphogenesis.^[63] At the pathophysiological level, CREBBP mutations result in reduced CBP acetyltransferase (HAT) activity, disrupting histone acetylation and chromatin remodeling processes that are vital for transcriptional coactivation of developmental genes.^[61] This haploinsufficiency impairs the expression of target genes involved in neuronal signaling pathways and limb bud formation, leading to the syndrome's core phenotypes.^[64] Mutations within the HAT domain of CREBBP are particularly overrepresented and associated with more pronounced disruptions in these epigenetic mechanisms.^[65] Diagnosis of RTS relies on clinical evaluation followed by molecular genetic testing, such as targeted sequencing of CREBBP and EP300 or multigene panels, with deletion/duplication analysis for unresolved cases.^[61] Recent studies from the 2020s have explored genotype-phenotype correlations, revealing that while overall severity does not strongly correlate with mutation type across large cohorts, variants in the HAT domain or early truncating mutations may contribute to more severe intellectual disability and dysmorphic features in some patients.^[66] For instance, screening of over 200 individuals identified novel variants emphasizing the HAT domain's role, and specific nonsense mutations in exon 5 have been linked to atypical milder outcomes potentially due to alternative isoform expression.^[65]^[66]

Cancer involvement

The CREB-binding protein (CBP), encoded by the CREBBP gene, exhibits a dual role in cancer pathogenesis, functioning as both an oncogene and a tumor suppressor depending on the cellular context and cancer type. Overexpression of CBP is observed in numerous malignancies, where it promotes tumor cell proliferation, survival, and progression by acetylating key oncoproteins such as MYC and β-catenin, thereby enhancing their stability and transcriptional activity. Conversely, loss-of-function mutations or deletions in CREBBP, often involving the 16p13.3 chromosomal locus, impair CBP's acetyltransferase function and act as a tumor suppressor mechanism in other cancers, leading to reduced chromatin acetylation and disrupted gene expression essential for tumor suppression.^[67]^[68]^[69] Mechanistically, CBP drives oncogenesis by enhancing Wnt/β-catenin signaling through direct acetylation of β-catenin at lysine 49, which stabilizes the protein and amplifies its ability to activate downstream target genes involved in cell proliferation and invasion. In prostate cancer, CBP serves as a critical coactivator for the androgen receptor (AR), acetylating AR to prevent its ubiquitin-mediated degradation and sustain AR-dependent transcription that fuels tumor growth and resistance to therapy. These interactions underscore CBP's role in deregulating proliferative pathways across solid tumors.^[70]^[71] Genomic alterations in CREBBP are prevalent in specific cancers, with inactivating mutations occurring in approximately 9% of colorectal cancers based on large-scale sequencing data, often contributing to epigenetic silencing of tumor suppressor genes. In breast cancer, CREBBP amplification is frequently detected in estrogen receptor-positive subtypes (luminal A and B) as well as triple-negative breast cancer, correlating with aggressive disease features and poorer prognosis. Recent studies have highlighted CBP's involvement in the tumor microenvironment, where it coactivates hypoxia-inducible factor 1α (HIF-1α) to promote angiogenesis and metabolic adaptation under hypoxic conditions, further supporting tumor progression.^[72]^[73]^[74] Chromosomal translocations involving CREBBP, particularly t(8;16)(p11;p13) resulting in KAT6A-CREBBP fusion, are associated with a subtype of acute myeloid leukemia (AML) characterized by monocytic or myelomonocytic differentiation (FAB M4/M5) and often eosinophilia. This fusion protein acts as an aberrant transcriptional coactivator, promoting leukemogenesis through disrupted epigenetic regulation, and is linked to poor prognosis.^[75]

Metabolic and neurological disorders

The CREB-binding protein (CBP) plays a critical role in metabolic homeostasis by acetylating sterol regulatory element-binding proteins (SREBPs), which stabilizes these transcription factors and promotes their transcriptional activity in lipid metabolism regulation.^[76] Dysregulation of CBP in the hypothalamus contributes to obesity and diabetes by altering glucose and lipid metabolism profiles.^[77] In hepatic contexts, p300 (a homolog of CBP) suppresses gluconeogenesis through acetylation of PEPCK, which promotes its ubiquitination and degradation, and impairments in this process exacerbate hyperglycemia in diabetic models, as evidenced by metformin-induced CBP phosphorylation that suppresses gluconeogenic gene expression.^[78]^[79] In neurological disorders, polyglutamine-expanded huntingtin in Huntington's disease sequesters CBP into nuclear inclusions, depleting its availability for transcriptional coactivation and histone acetylation, which leads to reduced gene expression and progressive neuronal death.^[80] Similarly, in Alzheimer's disease, hyperactive p300/CBP acetylates tau protein at specific lysine residues, impairing microtubule binding, promoting tau aggregation into neurofibrillary tangles, and enhancing tau secretion and propagation via disrupted autophagy-lysosomal pathways.^[81]^[82] Prenatal ethanol exposure in fetal alcohol spectrum disorders inhibits CBP recruitment to neuronal gene promoters, disrupting histone acetylation and chromatin remodeling essential for neural development, resulting in synaptic plasticity deficits and long-term cognitive impairments.^[83] Recent studies from 2023 to 2025 highlight CBP's involvement in Parkinson's disease, where α-synuclein mutations or overexpression mislocalize cytoplasmic p300/CBP, perturbing acetyl-CoA metabolism and exacerbating dopaminergic neuron vulnerability through altered epigenetic regulation.^[84] Additionally, CBP degradation or dysfunction contributes to circadian rhythm disruptions in sleep disorders, as seen in models where amyloid-β induces CBP loss alongside BMAL1, desynchronizing clock gene expression like PER2 and leading to fragmented sleep-wake cycles.^[85] The CBP KIX domain specifically modulates circadian period length, and its impairment links to broader neurological vulnerabilities in rhythm-related pathologies.^[86]

Therapeutic targeting

CBP inhibitors and development

Small-molecule inhibitors targeting the CREB-binding protein (CBP) have been developed primarily against its histone acetyltransferase (HAT, also known as KAT3B) domain and bromodomain, aiming to disrupt its coactivator function in transcription and chromatin remodeling. These inhibitors typically act by competing with substrates or mimicking regulatory motifs, leading to reduced histone acetylation at key sites such as H3K27ac, which diminishes enhancer activity and gene expression in disease contexts. Early efforts focused on the HAT domain, while more recent advances target the bromodomain for greater selectivity. A prominent HAT inhibitor is C646, a pyrazolone-based compound that competitively binds the HAT domain of CBP (and the related p300), blocking acetyl-CoA substrate access with an IC50 of approximately 5 μM. Developed as one of the first selective probes for CBP/p300, C646 has been widely used in preclinical studies to validate HAT inhibition as a therapeutic strategy. Another potent HAT inhibitor, A-485, exhibits nanomolar potency (IC50 ~0.06 μM for p300 HAT and similar for CBP), acting through allosteric modulation of the catalytic site to prevent lysine acetylation without directly competing with acetyl-CoA. For bromodomain targeting, CCS1477 (also known as inobrodib) serves as a selective inhibitor that mimics acetyl-lysine to occupy the bromodomain binding pocket, disrupting CBP recruitment to acetylated histones with high specificity over other bromodomains. By 2025, CCS1477 has advanced to phase I/II clinical trials for hematological malignancies, including acute myeloid leukemia (AML) and multiple myeloma, evaluating safety and preliminary efficacy in combination regimens. As of September 2025, enrollment has been completed for phase II dose optimization cohorts in relapsed/refractory multiple myeloma.^[87] In preclinical models, CBP inhibitors demonstrate antitumor activity, particularly in AML, where HAT blockade by A-485 or C646 suppresses leukemic cell proliferation and induces differentiation in patient-derived xenografts and mouse models. Bromodomain inhibition with CCS1477 similarly reduces AML burden in orthotopic mouse models by downregulating oncogenes like MYC. Notably, CBP inhibitors synergize with bromodomain and extra-terminal (BET) inhibitors, such as JQ1, enhancing apoptosis and overcoming resistance in AML cells through complementary disruption of super-enhancer networks. Despite promising efficacy, challenges in CBP inhibitor development include off-target effects on the paralog p300, which shares high structural similarity and can lead to unintended inhibition of normal cellular processes. Additionally, dose-limiting toxicity in non-cancerous cells, such as hematopoietic progenitors, arises from broad disruption of acetylation-dependent gene regulation, necessitating optimized dosing or combinations to improve therapeutic windows.

Emerging therapeutic strategies

Emerging therapeutic strategies for modulating CREB-binding protein (CBP) activity extend beyond inhibition to include activation, targeted degradation, and genetic interventions, aiming to address CBP's roles in neurodevelopmental and oncogenic disorders. One promising approach involves small-molecule activators that enhance CBP's histone acetyltransferase (HAT) activity and its interaction with CREB to restore transcriptional function. For instance, CSP-TTK21, a conjugate of the CBP/p300 activator TTK21 with glucose-derived carbon nanospheres, improves blood-brain barrier penetration and ameliorates amyloid-β-induced impairments in long-term potentiation and spatial memory in Alzheimer's disease mouse models by boosting CREB-CBP-mediated gene expression.^[88]^[89] This activation strategy highlights CBP's potential in countering epigenetic deficits in neurodegenerative conditions, with preclinical data showing enhanced neurogenesis and synaptic plasticity.^[88] Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) represents another innovative avenue, particularly for cancer where CBP drives oncogenic enhancer activity. The PROTAC dCBP-1, which recruits the E3 ubiquitin ligase cereblon (CRBN) to CBP/p300, selectively induces ubiquitination and proteasomal degradation of these proteins, potently killing multiple myeloma cells by abolishing MYC-driving enhancers without affecting normal cells at therapeutic doses.^[90] This approach offers superior efficacy over small-molecule inhibitors by achieving complete loss of CBP function, with ongoing development focusing on broader hematologic malignancies. Gene therapy strategies are advancing in preclinical stages to correct CBP deficiencies, such as those in Rubinstein-Taybi syndrome (RTS). Recent developments emphasize combination therapies pairing CBP activators with histone deacetylase (HDAC) inhibitors show synergistic rescue of memory deficits in Alzheimer's models by amplifying global histone acetylation and CREB-CBP signaling, with preclinical evidence of enhanced synaptic gene expression and cognitive performance.^[91] These multimodal strategies underscore CBP's therapeutic versatility across disease contexts.

References

[1]
CREBBP CREB binding lysine acetyltransferase [ (human)] - NCBI
Sep 27, 2025 · The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels.
[2]
CREB-binding Protein - an overview | ScienceDirect Topics
CREB binding protein (CBP) and p300 are critical regulators of hematopoiesis through both their transcriptional coactivator and acetyltransferase activities.
[3]
CBP, a transcriptional coactivator and acetyltransferase - PubMed
CBP is a transcriptional coactivator and acetyltransferase, binding to CREB and acting as a molecular scaffold. It also has acetyltransferase activity.
[4]
p53 Recruitment of CREB Binding Protein Mediated through ... - NIH
CREB binding protein (CBP) is a 270-kDa nuclear protein required for activated transcription of a large number of cellular genes.
[5]
A transcription factor-binding domain of the coactivator CBP is ... - NIH
As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with numerous transcription factors and contains multiple functional domains.
[6]
CREB binding protein (CREBBP): Structure-based perspectives for ...
Aug 18, 2025 · The main function of CBP is acetylation, which includes the acetylation of histones and other nonhistone proteins (such as p53 and bcl-2). The ...
[7]
Stimulation of CREB Binding Protein Nucleosomal Histone ... - NIH
The transcriptional coactivator CREB binding protein (CBP) possesses intrinsic histone acetyltransferase (HAT) activity that is important for gene regulation.<|control11|><|separator|>
[8]
https://www.ncbi.nlm.nih.gov/omim/180849
[9]
https://www.sciencedirect.com/science/article/pii/S1096719216301226
[10]
Phosphorylated CREB binds specifically to the nuclear protein CBP
Oct 28, 1993 · Here we report that CREB phosphorylated by protein kinase A binds specifically to a nuclear protein of M r 265K which we term CBP (for CREB-binding protein).Missing: discovery | Show results with:discovery
[11]
The CBP co-activator is a histone acetyltransferase - Nature
Dec 26, 1996 · One mechanism by which CBP is thought to stimulate transcription is by recruiting the histone acetyltransferase (HAT) P/CAF to the promoter8.
[12]
CREBBP gene: MedlinePlus Genetics
Jan 1, 2020 · On the basis of this function, CREB binding protein is called a histone acetyltransferase. In addition, CREB binding protein connects other ...
[13]
Entry - *600140 - CREB-BINDING PROTEIN; CREBBP - OMIM
Chrivia et al. (1993) reported the discovery of a nuclear transcriptional coactivator protein, CREB-binding protein (CBP), that binds specifically to the ...
[14]
Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder - NIH
The CBP protein is composed of 2442 amino acids (AA) and has a molecular weight of approximately 265 kDa. The p300 protein is composed of 2414 AA and has a ...
[15]
Phosphorylated CREB binds specifically to the nuclear protein CBP
Here we report that CREB phosphorylated by protein kinase A binds specifically to a nuclear protein of M(r) 265K which we term CBP (for CREB-binding protein).Missing: discovery | Show results with:discovery
[16]
The complex network of p300/CBP regulation - PubMed Central - NIH
Sep 15, 2025 · p300 and CBP are paralogs that diverged as a consequence of gene duplication over 450 million years ago (16). ... homology to the p53 ...
[17]
CBP and p300 Jointly Maintain Neural Progenitor Viability but Play ...
Dec 18, 2022 · RNA-seq data have shown that p300 is less expressed in neurons than CBP in both adult and embryonic brain [3]; however, whether they have ...Missing: ubiquitous | Show results with:ubiquitous
[18]
Developmentally regulated expression of the transcriptional ...
Although it is generally believed that the expression of CBP and p300 is ubiquitous, we report here that they are developmentally regulated during mouse ...
[19]
CBP/p300 in cell growth, transformation, and development
CREB binding protein (CBP) and p300 were both identified initially in protein interaction assays–the former through its association with the transcription ...
[20]
Structural basis for recruitment of CBP/p300 by hypoxia-inducible ...
CH1 and CH3 are homologous Zn2+-binding domains of CBP/p300 containing numerous cysteine and histidine residues (Fig. 1C). The CH2 domain also binds Zn2+ ...
[21]
Recognition of the disordered p53 transactivation domain by ... - PNAS
Mar 14, 2016 · Four domains of CBP/p300 are involved in the interaction with the p53TAD: the folded transcriptional adapter zinc finger (TAZ) 1, KIX, and TAZ2 ...
[22]
The CH2 domain of CBP/p300 is a novel zinc finger - ScienceDirect
Aug 19, 2013 · CBP and p300 have three cysteine/histidine rich zinc-binding domains, termed CH1, CH2 and CH3 [9]. Although the CH1 and CH3 domains have ...
[23]
Four domains of p300 each bind tightly to a sequence ... - PNAS
Its precise boundaries are subject to debate. (B) Domain structure of human p300. Taz1, PHD, and ZZ-Taz2 are also described as CH1, CH2, and CH3, respectively.
[24]
Solution structure of the KIX domain of CBP bound to the ... - PubMed
The phosphate group of the critical phosphoserine residue of pKID forms a hydrogen bond to the side chain of Tyr-658 of KIX. The structure provides a model for ...
[25]
Solution structure of the KIX domain of CBP bound to the ... - PubMed
Mar 26, 2004 · The solution structure of the KIX domain in complex with the activation domain of c-Myb reveals a helical structure very similar to that adopted ...
[26]
Article Structural Basis of Site-Specific Histone Recognition by the ...
Apr 8, 2008 · We report three three-dimensional solution structures of the bromodomains of the human transcriptional coactivators CREB-binding protein (CBP) and p300/CBP- ...
[27]
Structural Mechanism of the Bromodomain of the Coactivator CBP in ...
We report that the conserved bromo-domain of the transcriptional coactivator CBP (CREB binding protein) binds specifically to p53 at the C-terminal acetylated ...
[28]
Differences in Specificity and Selectivity Between CBP and p300 ...
Jul 17, 2013 · Our results show that while p300 and CBP acetylate many common residues on H3 and H4, they do in fact possess very different specificities.
[29]
Graded enhancement of p53 binding to CREB-binding protein (CBP ...
Oct 20, 2010 · The TAZ domains of CBP are highly basic and have a large positive charge at neutral pH (+10.8 for TAZ1, +15.3 for TAZ2). These positively ...
[30]
Article Is a Malleable Protein Necessarily Highly Dynamic? The ...
The nuclear coactivator binding domain of CREB binding protein folds into remarkably different structures in complex with different ligands.
[31]
Structure and chemistry of the p300/CBP and Rtt109 histone ...
p300 and CBP HAT domains have >90% sequence identity and are conserved in ... The promiscuous substrate specificity of p300 relative to other HATs can ...Missing: consensus | Show results with:consensus
[32]
p300/CREB Binding Protein-Related Protein p270 Is a Component ...
We have now identified four of the remaining p300/CBP/p270-associated proteins as members of another important cellular complex: the mammalian SWI/SNF complex.
[33]
Mediator and p300/CBP-Steroid Receptor Coactivator Complexes ...
We demonstrate synergism between Mediator and p300/CBP-SRC during ERα-dependent transcription with chromatin templates, but not with naked DNA.
[34]
CBP/p300 and HDAC activities regulate H3K27 acetylation ...
Oct 10, 2022 · We show that CBP/p300 and HDAC activities play important roles in regulating H3K27ac dynamics and are essential for preimplantation development.
[35]
Dynamics of global histone acetylation and deacetylation in vivo - NIH
ACTR is then acetylated by p300/CBP, resulting in dissociation of the HAT complex from the promoter, and thus self-attenuation of histone acetylation (Chen et ...Missing: seminal papers
[36]
Cooperative regulation of p53 by modulation of ternary complex ...
Apr 21, 2009 · In unstressed cells, CBP/p300, HDM2 and p53 form a ternary complex that promotes polyubiquitination and degradation of p53. After cellular ...
[37]
Involvement of the TIP60 histone acetylase complex in DNA repair ...
Aug 18, 2000 · These results indicate that the histone acetylase TIP60-containing complex plays a role in DNA repair and apoptosis.
[38]
https://pubmed.ncbi.nlm.nih.gov/10966108/
[39]
https://doi.org/10.1074/jbc.R000025200
[40]
https://doi.org/10.1074/jbc.271.45.28138
[41]
https://doi.org/10.1074/jbc.M300546200
[42]
https://doi.org/10.1016/S0092-8674(00)81663-3
[43]
https://doi.org/10.1093/nar/gkac083
[44]
The Transcriptional Coactivators p300 and CBP Are Histone ...
p300/CBP acetylates all four core histones in nucleosomes. These observations suggest that p300/CBP acetylates nucleosomes in concert with PCAF. Introduction.
[45]
Evolving insights to the roles of lysine acetylation in chromatin ...
Jan 10, 2022 · Acetylation of H3 and other histones at promoters and gene bodies can influence accessibility through effects on histone-DNA interactions, inter ...
[46]
Polycomb inhibits histone acetylation by CBP by binding ... - PubMed
Feb 9, 2016 · ... CBP, binding to the previously identified autoregulatory loop, whose autoacetylation greatly enhances HAT activity. We identify a conserved ...
[47]
Acetylation Is Indispensable for p53 Activation - Cell Press
Here we have identified K164 as a new site for in vivo acetylation of p53 by CBP/p300 and evaluated its function in these processes. ... K382, and K386.
[48]
Regulation of E2F transcription by cyclin E-Cdk2 kinase ... - PubMed
The E2F proteins form a family of transcription factors that regulate the transition from the G1 to the S phase in the cell cycle. E2F activity is regulated ...Missing: entry | Show results with:entry
[49]
CBP/p300 histone acetyl-transferase activity is important for the G1 ...
May 11, 2000 · We show that CBP/p300 is required for cell proliferation and has an essential function during the G1/S transition.Missing: coactivator | Show results with:coactivator
[50]
Down-regulation of p300/CBP histone acetyltransferase activates a ...
Down-regulation of p300/CBP histone acetyltransferase ... The cyclin E promoter was activated by p300 and the histone deacetylase inhibitor trichostatin A.
[51]
Epigenetic mechanisms to propagate histone acetylation by p300/CBP
Jul 17, 2023 · We propose a model in which p300/CBP replicates histone N-terminal tail acetylation within the H3-H4 tetramer to inherit epigenetic storage.
[52]
RNA Binding to CBP Stimulates Histone Acetylation and Transcription
Jan 12, 2017 · The enzymatic activity of CBP and p300 is localized in their catalytic histone acetyltransferase (HAT) domain and targets both histones and ...<|control11|><|separator|>
[53]
Genome-wide assessment of differential roles for p300 and CBP in ...
The heterogeneous binding patterns possibly reflect the divergent roles of CBP and p300 in transcriptional regulation. Most of the 16 103 genes were bound by ...Missing: distinctions | Show results with:distinctions
[54]
Glutamine-rich regions of the disordered CREB transactivation ...
Nov 14, 2023 · This work provides insights into the molecular basis by which glutamine-rich transactivation domains support dynamic and transient interactions.
[55]
p300 Acetyltransferase Is a Cytoplasm-to-Nucleus Shuttle ... - PubMed
In the nucleus, TAZ binds to SMAD2/3 to prevent SMAD2/3 nuclear export. However, how TAZ and SMAD2/3 enter the nucleus remains poorly understood because neither ...Missing: differences | Show results with:differences
[56]
The Complex Network of p300/CBP Regulation: Interactions, Post ...
Sep 15, 2025 · One of the most important acetyltransferases is the E1A binding protein p300, encoded by the EP300 gene and its paralog CBP (the cyclic AMP ...
[57]
CBP Histone Acetyltransferase Activity Is a Critical Component of ...
We generated transgenic mice that express CBP in which HAT activity is eliminated. Acquisition of new information and short-term memory is spared in these mice.Missing: discovered | Show results with:discovered
[58]
CREB-binding Protein and p300 in Transcriptional Regulation*
This review deals with some of the more controversial aspects of CBP/p300 function. In particular, we will ask whether. CBP and p300 have distinct functions, ...
[59]
Distinct roles for CREB-binding protein and p300 in hematopoietic ...
A full dose of CBP, but not p300, is crucial for HSC self-renewal. Conversely, p300, but not CBP, is essential for proper hematopoietic differentiation.
[60]
CBP/p300 double null cells reveal effect of coactivator level and ...
Sep 21, 2010 · Transcription in the absence of CBP/p300 correlated with endogenous genes having more CREs, more bound CREB, and more CRTC2 (a non‐HAT ...Results · Histone Acetylation In... · Crtc2 Overexpression...
[61]
Rubinstein-Taybi Syndrome - GeneReviews® - NCBI Bookshelf
Aug 30, 2002 · This condition is caused by missense variants in the last part of exon 30 or the beginning part of exon 31 of CREBBP or the homologous regions ...Diagnosis · Clinical Characteristics · Management · Genetic Counseling
[62]
Spectrum of CREBBP gene dosage anomalies in Rubinstein–Taybi ...
May 2, 2007 · Our data show that gene dosage anomalies of the CREBBP gene span between 3.3 kb and 6.5 Mb, and constitute a more common cause of RTS than was initially ...Missing: review | Show results with:review
[63]
Rubinstein-Taybi syndrome: clinical features, genetic basis ...
Jan 20, 2015 · It has been shown that mutations in the genes encoding the cyclic-AMP-regulated enhancer binding protein (CREBBP) and the E1A-binding protein ...
[64]
Rubinstein-Taybi Syndrome: A Model of Epigenetic Disorder - MDPI
Two genes are currently known to cause RSTS, CREBBP and EP300, mutated in around 55% and 8% of clinically diagnosed cases, respectively. To date, 500 pathogenic ...
[65]
Screening of a large Rubinstein-Taybi cohort identified many novel ...
Aug 21, 2020 · Abstract. Pathogenic variants within the CREBBP and EP300 genes account for the majority of individuals with Rubinstein-Taybi syndrome (RSTS).
[66]
Exploring genotype–phenotype correlations in CREBBP - NIH
May 29, 2023 · Rubinstein-Taybi syndrome (RTS) is a rare, mainly sporadic, autosomal dominant genetic disorder characterized by distinctive facial features ...Missing: 2020s | Show results with:2020s<|control11|><|separator|>
[67]
CREBBP knockdown suppressed proliferation and promoted chemo ...
The aforementioned study demonstrated that CBP could serve as a tumor suppressor or an oncogene in different cancer types. Till now, the role of CBP in ...
[68]
Targeting CBP and p300: Emerging Anticancer Agents - MDPI
CCS1477 was shown to bind CBP and p300 with Kd values of 1.7 and 1.3 nM, respectively, demonstrating only minimal binding to BRD2, 3, 4, 9 in a BROMOscan assay.<|control11|><|separator|>
[69]
The CREBBP Acetyltransferase Is a Haploinsufficient Tumor ...
These findings establish CREBBP as a haploinsufficient tumor-suppressor gene in GC B cells and provide insights into the mechanisms by which its loss ...
[70]
Acetylation of β-Catenin by CREB-binding Protein (CBP)
We show that the CBP-mediated acetylation of β-catenin occurs at a single site, lysine 49. Importantly, this lysine is frequently found mutated in cancer.
[71]
CBP/p300, a promising therapeutic target for prostate cancer
Oct 2, 2025 · CBP/p300 also acetylate AR to prevent its degradation and maintain AR signaling activity [10]. Additionally, CBP/p300 is involved in inducing ...
[72]
Abstract 1605: CERBBP mutation promotes antitumor immunity and ...
Jul 1, 2021 · Results: In total, 8.62% (43/526) of CRC patients in TCGA harboring CREBBP mutation and 2.00% (44/2198) in Chinese cohort, the alternation ...
[73]
The impact of CBP expression in estrogen receptor-positive breast ...
Apr 7, 2021 · This study aims to investigate the value of CBP and GCN5 as markers and/or targets for BC prognosis and therapy.
[74]
Small molecule blockade of transcriptional coactivation ... - Cell Press
Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and ...
[75]
Coactivator-Dependent Acetylation Stabilizes Members of the ...
Members of the SREBP family of transcription factors control cholesterol and lipid homeostasis and play important roles during adipocyte differentiation.
[76]
Role of Hypothalamic Creb-Binding Protein in Obesity and ...
Nov 10, 2016 · Inhibition of hypothalamic Cbp produces a transcriptional profile indicating decreased glucose metabolism and increased lipid metabolism. We ...Missing: SREBP gluconeogenesis PEPCK
[77]
Unraveling the Regulation of Hepatic Gluconeogenesis - Frontiers
... P300 functions as PEPCK acetyltransferase to modulate gluconeogenesis. High-concentration glucose induces P300-catalyzed PEPCK acetylation, which stimulates ...
[78]
Metformin and Insulin Suppress Hepatic Gluconeogenesis through ...
Only metformin is able to stimulate CBP phosphorylation in a mouse obesity model of insulin resistance, suggesting a mechanism for its therapeutic effect.
[79]
Cell death triggered by polyglutamine-expanded huntingtin in a ...
Nuclear inclusions containing polyQ-expanded htt recruit the transcriptional cofactor, CREB-binding protein (CBP). PolyQ toxicity appears to involve alterations ...
[80]
Promoting tau secretion and propagation by hyperactive p300/CBP ...
Jan 6, 2020 · We investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy.
[81]
Article Acetylation of Tau Inhibits Its Degradation and Contributes to ...
Sep 23, 2010 · To demonstrate that tau is acetylated, we incubated recombinant tau with recombinant acetyltransferase p300 or pCAF (p300/CBP-associated factor) ...
[82]
Activity-dependent Signaling and Epigenetic Abnormalities in Mice ...
Nov 10, 2018 · Postnatal ethanol exposure has been shown to cause persistent defects in hippocampal synaptic plasticity and disrupt learning and memory ...
[83]
Alpha-synuclein mutations mislocalize cytoplasmic p300 ...
Jun 18, 2025 · We demonstrate that the PD-causing A53T α-Syn mutation and elevated α-Syn expression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons.
[84]
Aβ-induced degradation of BMAL1 and CBP leads to circadian ...
Mar 19, 2015 · In this study, we investigated the role of Aβ in the regulation of clock molecules and circadian rhythm using an AD mouse model.
[85]
The CBP KIX domain regulates long-term memory and circadian ...
Following this phosphorylation, the kinase inducible domain (KID) of CREB binds to the KIX domain of the cyclic-AMP response element-binding protein (CREB) ...
[86]
A Novel Activator of CBP/p300 Acetyltransferases Promotes ...
Jun 26, 2013 · Although the brain functions of specific acetyltransferases such as the CREB-binding protein (CBP) and p300 have been well documented using ...Missing: ubiquitous | Show results with:ubiquitous
[87]
Glucose derived carbon nanosphere (CSP) conjugated TTK21, an ...
Aug 12, 2022 · Here, we show that p300/CBP activation by a small‐molecule TTK21, conjugated to carbon nanosphere (CSP) ameliorates Aβ‐impaired long‐term ...
[88]
Targeted degradation of the enhancer lysine acetyltransferases CBP ...
Apr 15, 2021 · dCBP-1 is exceptionally potent at killing multiple myeloma cells and can abolish the enhancer that drives MYC oncogene expression.
[89]
Rubinstein-Taybi Syndrome and Epigenetic Alterations - PMC
Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder in humans characterized by growth and psychomotor delay, abnormal gross anatomy, ...
[90]
Transcriptome and acetylome profiling identify crucial steps of ...
Oct 15, 2024 · Rubinstein-Taybi syndrome (RTS) is a rare and severe genetic developmental disorder characterized by multiple congenital anomalies and ...
[91]
Challenges in the Structural–Functional Characterization of ...
In this chapter, we describe the effective expression of CBP and p300 in a eukaryotic host, Sf9 insect cells, followed by their tandem affinity purification.Missing: distinctions | Show results with:distinctions<|control11|><|separator|>
[92]
Unlocking the synergistic potential of HAT activation and HDAC ...
Jan 9, 2025 · Histone acetylation is reduced in Alzheimer's disease (AD) brains, and evidence has shown a synergistic regulation of HDACs and HATs activities.