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FLASH GENE

Symbol

CREBBP

contributors: mct/npt/pgu - updated : 21-02-2018

HGNC name	CREB binding protein
HGNC id	2348

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	155.07 kb     31 Exon(s)

10 Kb 5' upstream gene genomic sequence study

motif	repetitive sequence   ALU
text structure	percentage of interspersed repetitive elements (mainly Alu and LINEs in the CREBBP exon 2 region) is significantly higher suggesting that this characteristic may be involved in the region is vulnerability to breaking and nonhomologous pairing

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001079846 30 - 10083 NP_001073315 - 2404 - 1995 7606928 NM_004380 31 - 10197 NP_004371 265 2442 - 1995 7606928

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth tongue     highly Hearing/Equilibrium ear inner cochlea   highly Lymphoid/Immune lymph node       highly   thymus         Reproductive male system testis       Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	cochlea, pancreas

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	three cysteine-histidine rich (C4-H-C3) PHD type zinc finger motifs
	a bromodomain (histone acetyltransferase domain, HAT)
	a nuclear receptor interaction motif (LXXLL), the KIX domain for interaction with MYB
	a highly conserved cysteine/histidine-rich region (CH2) domain that with the preceding bromodomain interact and mutually stabilize each other, implying a cooperative function
	a TAZ1 domain, consisting of four alpha-helices (alpha(1)-alpha(4) stabilized by three zinc atoms (for binding to CITED2)
	C-terminal domain, SID (SRC1 interacting domain) responsible for interaction with SRC1 (NCOA1), and other transcriptional regulators such as E1A, ETS2, IRF3, and p53

HOMOLOGY

interspecies	homolog to murine Crebbp
	homolog to EP300

Homologene

FAMILY

CATEGORY

transcription factor , signaling

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,nucleoplasm,nuclear bodies
	intracellular,nucleus,chromatin/chromosome,heterochromosome
text	colocalizing with PML in special (PML/SP100) nuclear bodies (NB/POD)

basic FUNCTION	playing an important role as a general co-integrator of multiple signaling pathways
	potent histone acetyltransferase
	transcriptional coactivator with EP300 of various nuclear receptors and hypoxia inducible factor 1A (HIF1A)
	associating to PML which increases its localization in POD (promyelocytic oncoprotein domain)
	acting as a potent nuclear receptor coactivator
	playing a pivotal role in embryonic development
	involved in a variety of transcriptional pathways through chromatin remodeling (acetylation of histone protein H3)
	participating in basic cellular functions and acting rarely as classical suppressor of tumor
	regulator with PCAF of involucrin expression in stratified squamous epithelial cells
	promoting nucleosome acetylation at NOTCH enhancers and activating transcription via its binding to MAML1
	dosage-dependent regulator of NFKB1 suppression by the estrogen receptor
	CREBBP and EP300 function as transcriptional coactivators for a large number of DNA-binding transcription factors involved in multiple signalling and developmental pathways, by modifying lysine residues on both histone and non-histone nuclear proteins
	histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioural adaptations to environmental enrichment (EE)(
	important role for CREBBP in cognitive dysfunction in Huntington disease
	CREBBP-dependent transcriptional neuroadaptation is an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics
	CREBBP and KAT5 coordinate histone acetylation at both local and global levels to facilitate RAS-induced transformation
	KMT2C/KMT2D and H3K27 acetyltransferases CREBBP/EP300 are major enhancer epigenomic writers

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

text	MADH4 dependent TGFB transcriptional responses in endothelial cells

PATHWAY

metabolism

signaling

signal transduction

HH signaling transduction pathway

a component

complexing with CITED2 (CBP/p300-interacting transactivator with ED-rich tail), inhibiting the activity of the hypoxia inducible factor (HIF-1alpha)

INTERACTION

DNA	binding to cAMP response element

RNA

small molecule

protein	MADH4
	TGFB
	N4BP2
	binding to GLI activators
	SNIP1
	MAML1
	interacts with a large number of transcription factors and co-factors, through its numerous protein-binding domains
	interacting with TRIP10, ZBTB17, SH3GL1, GAK, EIF2B1 in embryonic orofacial tissue
	interacting with GATA2(CREBPP could increase GATA2 transcriptional activity in the dose-dependent manner)
	MAP3K4 controls the activity of the histone acetyltransferase CREBBP, and acetylation of histones H2A and H2B by CREBBP is required to maintain the epithelial phenotype
	displayed histone H3K9-me1/2 demethylase activity and induced leukemogenic oncogene LMO2 expression via a synergistic interaction with CREBBP
	CREBBP and EP300 play distinct roles in RA-mediated STRA8 gene transcription
	KIX domains of CREBBP, and especially EP300, are principal mediators of MYB-dependent gene activation and repression that is required for definitive hematopoiesis
	TDG, as a new coactivator, promotes CTNNB1/TCFs transactivation and functionally cooperates with CREBBP in canonical WNT signaling
	CREBBP and EP300 cooperate with several key Treg transcription factors that act on the FOXP3 promoter to promote FOXP3 production
	destabilization of CREBBP by downregulation of PPP1R13L
	expression levels appears to represent a molecular mechanism that contributes to chemoresistance in melanoma cells
	AJUBA recruits CREBBP via its LIM domain and facilitates CREBBP binding to PPARG
	complex regulation of CREBBP activity by HIPK2, which might be relevant for the control of specific sets of target genes involved in cellular proliferation, differentiation and apoptosis
	TLX3 directly interacts with the epigenetic co-activator cyclic adenosine monophosphate CREBBP and its homeodomain is essential for this interaction
	CREBBP regulates lung cancer growth by targeting MAPK and CPSF4 signaling pathways 8)
	interplay between the remodeling activity of SMARCAD1 and histone acetylation by CREBBP sheds light on the function of chromatin and the genome-integrity network
	CREBBP and EP300, activate transcription of TP53-regulated stress response genes and stabilize TP53 against ubiquitin-mediated degradation
	DYRK1A functions in enhancer regulation by interacting with EP300/CREBBP and modulating their activity

cell & other

REGULATION

activated by

CREB and CREM after phosphorylation of respectively Ser133 and Ser 117

ASSOCIATED DISORDERS

corresponding disease(s)

RSTS , AMLT3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       with MYST3 in acute myeloid leukemia with translocation t(8;16)(p11;p13), see AML3, and with MLL (HRX) in therapy related acute leukemia with translocation t(11;16)(q23;p13), with MYST4 in AML with t(10;16) (q22;p13) tumoral fusion       fusion genes MYST3-CREBBP in acute myeloid leukemia (AML) by chromosomal translocation tumoral somatic mutation     loss of function in B-cell non-Hodgkin lymphoma tumoral somatic mutation       in relapsed acute lymphoblastic leukaemia, mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes, and may confer resistance to therapy ( tumoral somatic mutation       in hypothalamic hamartoma with gelastic epilepsy

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer hemopathy   use of histone deacetylase inhibitors has a potential therapy in B-cell non-Hodgkin lymphoma cancer hemopathy   promising therapeutic targets across multiple subtypes in acute myeloid leukemia

ANIMAL & CELL MODELS

mice with a deletion mutation in the CBP CH1 (TAZ1) domain have an Rubinstein-Taybi Syndrome (RTS)-like phenotype that includes ASD-relevant repetitive behaviors, hyperactivity, social interaction deficits, motor dysfunction, impaired recognition memory, and abnormal synaptic plasticity