CREB-binding protein and E1A binding protein p300 (CBP (for CREB-binding protein), p300 (for E1A binding protein p300))

Molecular Classification

Enzyme (Specifically, lysine acetyltransferase/histone acetyltransferase, HAT), Transcriptional coactivator, Chromatin remodeler, Histone code "writer"

Other Names

CBP, CREB-binding protein, KAT3A, RSTS, p300, EP300, KAT3B, E1A binding protein p300

Disease Roles

Cancer (mutations, abnormal acetylation, tumorigenesis)Neurodevelopmental and neurodegenerative diseaseCardiovascular disease

CREB-binding protein and E1A binding protein p300 Overview

CREB-binding protein (CBP) and E1A binding protein p300 (p300) are highly conserved transcriptional coactivators and histone acetyltransferases (KAT3A/B) that regulate gene expression by both enzymatic acetylation and protein-protein interaction scaffolding. They bridge DNA-binding transcription factors and the general transcription machinery, acetylate histones to remodel chromatin structure, and also acetylate non-histone proteins, including transcription factors and DNA repair enzymes[1][3][5]. CBP/p300 have distinct and overlapping functions in development and disease, acting as critical nodes (“hubs”) in cellular regulatory networks with hundreds of protein interaction partners[6]. They are considered key "writers" of the histone code, primarily responsible for acetylation at histone H3K18 and H3K27, marks strongly associated with active gene transcription[1][6][4][8]. Mutations, deletions, or dysregulation of CBP/p300 are implicated in various cancers, inflammatory diseases, and developmental syndromes, rendering them important yet challenging therapeutic targets due to their essential roles in normal cell function[1][5][4][8]. CBP/p300 are classically targeted by histone acetyltransferase inhibitors in anti-cancer research, and their chromatin marks (e.g., H3K27ac) serve as biomarkers for gene regulatory activity. Inhibition strategies must be approached carefully due to broad impacts on gene expression and potential safety risks, reflected in knockout models which demonstrate their necessity for embryogenesis[5][1]. Their collective designation as CBP/p300 is common, but distinct biology in specific contexts continues to be uncovered[5][4].

Mechanism of Action

Inhibition of histone acetyltransferase activity, reducing chromatin accessibility and silencing transcription. Disruption of CBP/p300 interaction motifs or binding to KIX/Bromodomain, blocking recruitment of transcriptional machinery.

Biological Functions

Transcriptional activation (by bridging transcription factors and the general transcription machinery)

Chromatin remodeling (by acetylating histones, altering DNA accessibility)

Epigenetic regulation (propagating and reading/writing histone acetylation for gene expression inheritance)

Cell cycle regulation

DNA repair (by acetylating DNA repair proteins)

Cell differentiation

Disease Associations

Cancer (mutations, abnormal acetylation, tumorigenesis)

Neurodevelopmental and neurodegenerative disease

Cardiovascular disease

Rheumatoid arthritis and other inflammation

Developmental disorders (e.g., Rubinstein-Taybi syndrome)

Safety Considerations

Risk of broad transcriptional disruption due to central regulatory functions (potential embryonic lethality with loss, as observed in knockout models)
Impaired DNA repair and cell cycle regulation (may promote genomic instability)
Adverse effects related to alteration of multiple physiological systems (e.g., differentiation, proliferation)

Interacting Drugs

Inhibitors and modulators of CBP/p300 HAT activity (e.g., A-485, CCS1477; clinical/research compounds primarily targeting cancer)

HDAC inhibitors affect pathways involving CBP/p300

Associated Biomarkers

Biomarker
Histone acetylation marks (e.g., H3K18ac, H3K27ac; reduced globally by CBP/p300 loss)
Mutations or expression levels of CREBBP or EP300 in tumors