CREBBP (CREB binding protein)

2009-03-01 Cristina Gervasini Affiliation

Division of Medical Genetics, San Paolo School of Medicine, University of Milan, 20142 Milan, Italy

Identity

HGNC

CREBBP

LOCATION

16p13.3

IMAGE

LEGEND

A: CBP (16p22) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

LEGEND

B: Map showing the position of BAC clone RP11-1072J2 (UCSC Genome Browser assembly Mar 2006), centered on CREBBP gene (top) and two images of partial metaphases from normal controls showing, after FISH, CREBBP-specific signals at 16p13.3 (bottom).

LOCUSID

1387

ALIAS

CBP,KAT3A,MKHK1,RSTS,RSTS1

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

The gene spans about 155 kb; transcription from centromere to telomere, number of exons: 31.

Transcription

10 kb mRNA, with a 7.3 kb coding sequence, start codon in exon 1, stop codon in exon 31.

Proteins

Description

2442 amino acids; 265351 Da; predict PI=8.83; Known domains are: KIX= CREB binding , Bromo= Bromodomain, Zn=zinc-finger (corresponding to cysteine-histidine rich regions), HAT= acetyl transferasic, Q= poly Glutaminic stretch. From the carboxy to the N-terminus: Q-Zn-HAT-Zn-Bromo-KIX-Zn. Reported isoform b (2402 aa) lacking aa406-444 (exon 5). Methylation of the KIX domain by CARM1 blocks association with CREB. Phosphorylated upon DNA damage, probably by ATM or ATR.

Expression

Wide expression; expression in the whole embryo as well brain; cDNA sources: mammary gland; lung; placenta; testis; lymph node; thymus; mouth; ear; kidney; embryonic tissue; larynx; pancreas; intestine; blood; heart; amniotic fluid; trachea; liver; thyroid; skin; connective tissue; uterus; eye; prostate; stomach; ovary; salivary gland; muscle; adrenal gland; bone marrow; adipose tissue; spleen; nerve; bone; bladder.

Localisation

Nucleus.

Function

Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes;
Acts as transcription co-activator by: i) enabling the interaction between different TF and RNAPolII complexes, ii) serving as molecular scaffold that brings enzymes to the promoter, iii) remodelling the chromatin favouring the open status, by histone and non-histone proteins acetylation.
Essential role in embryogenesis, cell differentiation, apoptosis, and proliferation;
Involved in the regulation of cell cycle during G1/S transition.

Homology

EP300

Implicated in

Entity name

t(8;16)(p11;p13)/M4 AML --> MOZ/ CREBBP

Disease

Acute non lymphocytic leukemia (AML) and treatment related AML (t-AML).

Prognosis

Poor: remission is obtained in half cases; survival is often less than 1yr.

Cytogenetics

+8 as an additional anomalies in half cases.

Hybrid gene

5 MOZ - 3 CBP.

Fusion protein

N-term finger motifs and acetyl transferase from MOZ fused to most of CBP, with a breakpoint in 5 of the CREB binding domain of CBP.

Entity name

t(10;16)(q22;p13)/M4 AML --> MYST4/ CREBBP

Disease

Acute myeloid leukaemia (AML) M4/M5a and therapy-related myelodysplastic syndromes (MDS). Only 4 cases described.

Prognosis

Poor, bad response to chemotherapy.

Hybrid gene

5 MYST4 - 3 CBP.

Fusion protein

In-frame fusion between MYST4 exon 17 and CREBBP exon 3. Variants fusing MYST4 exon 16 and CREBBP exon 5; MYST4 exon 17 and CREBBP exon 7 have been also described. CREBBP-MYST4 transcripts have been detected.

Entity name

t(11;16)(q23;p13)/t-AML --> KMT2A/ CREBBP

Disease

Therapy related AML (t-AML); should be very close to the t(11;22)(q23;q13).

Prognosis

Likely to be poor.

Hybrid gene

5 MLL - 3CBP.

Fusion protein

N-term AT hook and DNA methyltransferase from MLL fused to most of CBP; variable brakpoint in CBP: either 5 to the CREB binding domain (like in the t(8;16)), or just upstream the bromodomain.

Entity name

Rubinstein-Taybi syndrome

Note

Due to CBP haploinsufficiency.

Disease

Rare autosomal dominant congenital disorder characterized by postnatal growth retardation and psychomotor developmental delay, skeletal anomalies (broad and duplicated distal phalanges of thumbs and halluces are a landmark sign) and specific facial dysmorphisms. The latter include down-slanted palpebral fissures, broad nasal bridge, beaked nose and micrognathia. In addition, patients with RSTS have an increased, although not well documented, risk of tumor formation.

Top: Ideogram of chromosome 16 and chromosomal localisation of the CREBBP gene. Middle: the genomic region including CREBBP (red) and flanking genes is zoomed. Deletions spanning CREBBP and adjacent sequences (accounting for about 10% of CREBBP mutations) are indicated by black lines. Mosaic deletions (only 3 so far detected) are asterisked; dotted lines target low-resolution mapped breakpoints. So far 22 deletions have been reported and the differently sized ones (21) are here diagrammed.

Bottom: structure of CREBBP gene and protein. Different colours are used to link gene exons (pictured by rectangles) and corresponding protein domains. Different reported point mutations (n.108 in Leiden Open Variation Database) are shown: filled circles (nonsense) and dotted circles (frameshift), squares (missense) and triangles (splicing). Most mutations cluster to exons encoding the HAT domain.

Known domains from the carbossi-terminal are: Q= poly Glutaminic stretch, Zn=zinc-finger, HAT= acetyl transferasic, Bromo= Bromodomain, KIX= CREB binding).

Breakpoints

Localization of breakpoints affecting CREBBP and partner genes in leukaemia-associated balanced translocations.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
10828885	2000	CBP/p300 histone acetyl-transferase activity is important for the G1/S transition.	Ait-Si-Ali S et al
15207239	2004	Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration.	Alarcón JM et al
12909086	2003	Ca(2+)/CREB/CBP-dependent gene regulation: a shared mechanism critical in long-term synaptic plasticity and neuronal survival.	Bito H et al
11927640	2002	CBP and p300: versatile coregulators with important roles in hematopoietic gene expression.	Blobel GA et al
8782817	1996	The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein.	Borrow J et al
12747548	2003	The multifunctional role of E1A in the transcriptional regulation of CREB/CBP-dependent target genes.	Brockmann D et al
8960368	1996	p300 and CBP as transcriptional regulators and targets of oncogenic events.	Eckner R et al
17855048	2007	High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.	Gervasini C et al
9177780	1997	Construction of a 1.2-Mb contig surrounding, and molecular analysis of, the human CREB-binding protein (CBP/CREBBP) gene on chromosome 16p13.3.	Giles RH et al
10497301	1999	p300 and CBP: partners for life and death.	Giordano A et al
9238849	1997	The multifunctional role of the co-activator CBP in transcriptional regulation.	Goldman PS et al
11358491	2001	p300/CBP/p53 interaction and regulation of the p53 response.	Grossman SR et al
16868563	2006	Rubinstein-Taybi syndrome.	Hennekam RC et al
11962765	2002	The versatile functions of the transcriptional coactivators p300 and CBP and their roles in disease.	Janknecht R et al
15313412	2004	CBP and p300: HATs for different occasions.	Kalkhoven E et al
17410209	2007	CBP/p300 are bimodal regulators of Wnt signaling.	Li J et al
18273021	2008	The structural basis of protein acetylation by the p300/CBP transcriptional coactivator.	Liu X et al
12168567	2002	Transcriptional control of the inflammatory response: a role for the CREB-binding protein (CBP).	Matt T et al
11467739	2001	CBP, a transcriptional coactivator and acetyltransferase.	McManus KJ et al
10610021	1999	Developmentally regulated expression of the transcriptional cofactors/histone acetyltransferases CBP and p300 during mouse embryogenesis.	Partanen A et al
15313413	2004	Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders.	Rouaux C et al
9238046	1997	MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3).	Sobulo OM et al
9166831	1997	The t(11;16)(q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene.	Taki T et al
17484131	2007	Aberrant forms of histone acetyltransferases in human disease.	Van Beekum O et al
11279224	2001	CREB-binding protein and p300 in transcriptional regulation.	Vo N et al
18657848	2008	t(8;16)(p11;p13) predisposes to a transient but potentially recurring neonatal leukemia.	Wong KF et al
10523850	1999	Function for p300 and not CBP in the apoptotic response to DNA damage.	Yuan ZM et al

Other Information

Locus ID:

NCBI: 1387
MIM: 600140
HGNC: 2348
Ensembl: ENSG00000005339

Variants:

dbSNP: 1387
ClinVar: 1387
TCGA: ENSG00000005339
COSMIC: CREBBP

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000005339	ENST00000262367	Q92793
ENSG00000005339	ENST00000382070	Q92793
ENSG00000005339	ENST00000570939	I3L466
ENSG00000005339	ENST00000571826	I3L293
ENSG00000005339	ENST00000572134	I3L0Q1
ENSG00000005339	ENST00000573517	I3L3I5
ENSG00000005339	ENST00000637492	A0A1B0GUU0

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Cell cycle	KEGG	ko04110
Wnt signaling pathway	KEGG	ko04310
Notch signaling pathway	KEGG	ko04330
TGF-beta signaling pathway	KEGG	ko04350
Adherens junction	KEGG	ko04520
Jak-STAT signaling pathway	KEGG	ko04630
Long-term potentiation	KEGG	ko04720
Melanogenesis	KEGG	ko04916
Huntington's disease	KEGG	ko05016
Renal cell carcinoma	KEGG	ko05211
Prostate cancer	KEGG	ko05215
Cell cycle	KEGG	hsa04110
Wnt signaling pathway	KEGG	hsa04310
Notch signaling pathway	KEGG	hsa04330
TGF-beta signaling pathway	KEGG	hsa04350
Adherens junction	KEGG	hsa04520
Jak-STAT signaling pathway	KEGG	hsa04630
Long-term potentiation	KEGG	hsa04720
Melanogenesis	KEGG	hsa04916
Huntington's disease	KEGG	hsa05016
Pathways in cancer	KEGG	hsa05200
Renal cell carcinoma	KEGG	hsa05211
Prostate cancer	KEGG	hsa05215
Tuberculosis	KEGG	ko05152
Tuberculosis	KEGG	hsa05152
Influenza A	KEGG	ko05164
Influenza A	KEGG	hsa05164
HTLV-I infection	KEGG	ko05166
HTLV-I infection	KEGG	hsa05166
Herpes simplex infection	KEGG	ko05168
Herpes simplex infection	KEGG	hsa05168
Epstein-Barr virus infection	KEGG	hsa05169
Epstein-Barr virus infection	KEGG	ko05169
Viral carcinogenesis	KEGG	hsa05203
Viral carcinogenesis	KEGG	ko05203
Hepatitis B	KEGG	hsa05161
HIF-1 signaling pathway	KEGG	hsa04066
MicroRNAs in cancer	KEGG	hsa05206
MicroRNAs in cancer	KEGG	ko05206
FoxO signaling pathway	KEGG	hsa04068
Thyroid hormone signaling pathway	KEGG	hsa04919
cAMP signaling pathway	KEGG	hsa04024
cAMP signaling pathway	KEGG	ko04024
Glucagon signaling pathway	KEGG	hsa04922
Glucagon signaling pathway	KEGG	ko04922
Organelle biogenesis and maintenance	REACTOME	R-HSA-1852241
Mitochondrial biogenesis	REACTOME	R-HSA-1592230
Transcriptional activation of mitochondrial biogenesis	REACTOME	R-HSA-2151201
Disease	REACTOME	R-HSA-1643685
Diseases of signal transduction	REACTOME	R-HSA-5663202
Signaling by NOTCH1 in Cancer	REACTOME	R-HSA-2644603
Signaling by NOTCH1 PEST Domain Mutants in Cancer	REACTOME	R-HSA-2644602
Constitutive Signaling by NOTCH1 PEST Domain Mutants	REACTOME	R-HSA-2644606
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	REACTOME	R-HSA-2894858
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	REACTOME	R-HSA-2894862
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways	REACTOME	R-HSA-168928
TRAF3-dependent IRF activation pathway	REACTOME	R-HSA-918233
TRAF6 mediated IRF7 activation	REACTOME	R-HSA-933541
Cytosolic sensors of pathogen-associated DNA	REACTOME	R-HSA-1834949
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	REACTOME	R-HSA-3134973
C-type lectin receptors (CLRs)	REACTOME	R-HSA-5621481
CD209 (DC-SIGN) signaling	REACTOME	R-HSA-5621575
Hemostasis	REACTOME	R-HSA-109582
Factors involved in megakaryocyte development and platelet production	REACTOME	R-HSA-983231
Signal Transduction	REACTOME	R-HSA-162582
Signaling by NOTCH	REACTOME	R-HSA-157118
Pre-NOTCH Expression and Processing	REACTOME	R-HSA-1912422
Pre-NOTCH Transcription and Translation	REACTOME	R-HSA-1912408
Signaling by NOTCH1	REACTOME	R-HSA-1980143
NOTCH1 Intracellular Domain Regulates Transcription	REACTOME	R-HSA-2122947
Signaling by Wnt	REACTOME	R-HSA-195721
TCF dependent signaling in response to WNT	REACTOME	R-HSA-201681
Formation of the beta-catenin:TCF transactivating complex	REACTOME	R-HSA-201722
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Notch-HLH transcription pathway	REACTOME	R-HSA-350054
YAP1- and WWTR1 (TAZ)-stimulated gene expression	REACTOME	R-HSA-2032785
Transcriptional Regulation by TP53	REACTOME	R-HSA-3700989
Circadian Clock	REACTOME	R-HSA-400253
BMAL1:CLOCK,NPAS2 activates circadian gene expression	REACTOME	R-HSA-1368108
RORA activates gene expression	REACTOME	R-HSA-1368082
Metabolism	REACTOME	R-HSA-1430728
Metabolism of lipids and lipoproteins	REACTOME	R-HSA-556833
Fatty acid, triacylglycerol, and ketone body metabolism	REACTOME	R-HSA-535734
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)	REACTOME	R-HSA-400206
PPARA activates gene expression	REACTOME	R-HSA-1989781
Regulation of cholesterol biosynthesis by SREBP (SREBF)	REACTOME	R-HSA-1655829
Activation of gene expression by SREBF (SREBP)	REACTOME	R-HSA-2426168
Developmental Biology	REACTOME	R-HSA-1266738
Transcriptional regulation of white adipocyte differentiation	REACTOME	R-HSA-381340
Cellular responses to stress	REACTOME	R-HSA-2262752
Cellular response to hypoxia	REACTOME	R-HSA-2262749
Regulation of Hypoxia-inducible Factor (HIF) by oxygen	REACTOME	R-HSA-1234174
Regulation of gene expression by Hypoxia-inducible Factor	REACTOME	R-HSA-1234158
Cellular response to heat stress	REACTOME	R-HSA-3371556
HSF1-dependent transactivation	REACTOME	R-HSA-3371571
Attenuation phase	REACTOME	R-HSA-3371568
Chromatin organization	REACTOME	R-HSA-4839726
Chromatin modifying enzymes	REACTOME	R-HSA-3247509
HATs acetylate histones	REACTOME	R-HSA-3214847
Activation of HOX genes during differentiation	REACTOME	R-HSA-5619507
Activation of anterior HOX genes in hindbrain development during early embryogenesis	REACTOME	R-HSA-5617472
TP53 Regulates Transcription of Cell Death Genes	REACTOME	R-HSA-5633008
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	REACTOME	R-HSA-6803204
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	REACTOME	R-HSA-8864260
Activation of the TFAP2 (AP-2) family of transcription factors	REACTOME	R-HSA-8866907

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37721116	2024	Molecular insight into CREBBP and TANGO2 variants causing intellectual disability.	1
37864465	2024	NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.	2
38037460	2024	CBP-mediated FOXO4 acetylation facilitates postmenopausal osteoporosis (PMO) progression through the inhibition of the Wnt/β-catenin signaling pathway.	0
38637838	2024	BCOR::CREBBP fusion in malignant neuroepithelial tumor of CNS expands the spectrum of methylation class CNS tumor with BCOR/BCOR(L1)-fusion.	0
37721116	2024	Molecular insight into CREBBP and TANGO2 variants causing intellectual disability.	1
37864465	2024	NOTCH1 and CREBBP co-mutations negatively affect the benefit of adjuvant therapy in completely resected EGFR-mutated NSCLC: translational research of phase III IMPACT study.	2
38037460	2024	CBP-mediated FOXO4 acetylation facilitates postmenopausal osteoporosis (PMO) progression through the inhibition of the Wnt/β-catenin signaling pathway.	0
38637838	2024	BCOR::CREBBP fusion in malignant neuroepithelial tumor of CNS expands the spectrum of methylation class CNS tumor with BCOR/BCOR(L1)-fusion.	0
36477795	2023	SARS-CoV-2 infection activates CREB/CBP in cellular cyclic AMP-dependent pathways.	4
36872777	2023	Hypermethylation at CREBBP Is Associated with Cognitive Impairment in a Mexican American Cohort.	1
36893259	2023	KMT2D acetylation by CREBBP reveals a cooperative functional interaction at enhancers in normal and malignant germinal center B cells.	4
37161136	2023	Identification and verification of FN1, P4HA1 and CREBBP as potential biomarkers in human atrial fibrillation.	0
37314181	2023	Emerging roles of p300/CBP in autophagy and autophagy-related human disorders.	2
37353110	2023	β-catenin/CBP activation of mTORC1 signaling promotes partial epithelial-mesenchymal states in head and neck cancer.	2
37816914	2023	The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels.	1

Citation

Cristina Gervasini

CREBBP (CREB binding protein)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: http://atlasgeneticsoncology.org/gene/42/js/lib/deep-insight-explorer/favicon/manifest.json

Historical Card

2000-07-01 CREBBP (CREB binding protein) by Jean-Loup Huret Affiliation

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France