Selected-GenAtlas references	SOURCE	GeneCards	NCBI Gene	Swiss-Prot	Orphanet	Ensembl
	HGNC	UniGene	Nucleotide	OMIM		UCSC

Home Page

FLASH GENE

Symbol

CREB1

contributors: mct/shn - updated : 08-06-2016

HGNC name	cAMP responsive element binding protein 1
HGNC id	2345

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	2q33.3      Physical location : 208.394.615 - 208.470.282
Synonym name	active transcription factor CREB
	transactivator protein
Synonym symbol(s)	CREB, MGC9284, CREB-1

DNA

TYPE	functioning gene
STRUCTURE	75.67 kb     9 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

Map	cen - D2S325 - D2S2321 - CREB1 - D2S2242 - D2S2208 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004379 8 splicing 2964 NP_004370 35 327 - 2009 19632997 also called CREB1-IA NM_134442 9 splicing 9794 NP_604391 36.7 341 - 2009 19632997 also called CREB1-IB

EXPRESSION

Type

widely

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 Cardiovascular heart       moderately Digestive liver       moderately Endocrine pancreas       moderately Lymphoid/Immune lymph node       highly Nervous brain       moderately Reproductive male system testis     highly Respiratory lung       moderately Urinary bladder       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow     highly Connective bone       Epithelial secretory glandular endocrine   Epithelial secretory glandular exocrine   Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Visual ganglion cell

cell lineage
cell lines
fluid/secretion	sperm

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a NH2-terminal acidic region containing a potential transcriptional activation domain
	basic leucine zipper (bZIP) protein
	a COOH-terminal basic region

conjugated

PhosphoP

mono polymer

heteromer , dimer

HOMOLOGY

interspecies	ortholog to Creb1, Mus musculus
	ortholog to Creb1, rattus norvegicus
	ortholog to CREB1, Pan troglodytes
	ortholog to creb1, Danio rerio

Homologene

FAMILY

BZIP family

CATEGORY

regulatory , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria,matrix
	intracellular,nucleus,nucleoplasm
text	present in the mitochondrial matrix of neurons

basic FUNCTION	important regulator of cardiac myocyte function
	role in hippocampus-dependent learning
	crucial for the consolidation of long-term conditioned fear memories, but not for encoding, storage or retrieval of these memories
	acting as a transcription regulator, with a role in survival of neurons (inhibition of neuronal suicide)
	involved in spermatogenesis
	playing a role in neuronal protection
	decreasing the protein level of RCAN1
	role of CREB1 and CREM in stimulus-dependent transcription and neuronal homeostasis
	has a context-dependent role in activity-regulated transcription and maintains neuronal cholesterol homeostasis
	acts as a negative regulator of CCN1/CYR61 transcription
	acting as a positive regulator of MMP2 expression and melanoma cell invasion (these effects can be explained, in part, by the CREB1-mediated inhibition of CCN1/CYR61 expression)
	photoreceptors degeneration leads to phosphorylation and increase expression of CREB1/ATF1 complex which is associated with a neuroprotective outcome in photoreceptors
	central intracellular regulator in several signaling pathways and influences a variety of neural processes
	required for acquisition of ischemic tolerance, an endogenous neuroprotective mechanism whereby prior exposure to brief ischemia produces resilience to subsequent normally injurious ischemia
	functions in concert with a family of latent cytoplasmic co-activators called cAMP-regulated transcriptional co-activators (CRTCs), which are activated through dephosphorylation
	CREB1 and CRTCs mediate the effects of fasting and feeding signals on the expression of metabolic programmes in insulin-sensitive tissues
	is a novel protein target of PTEN phosphatase, which contributes to better understanding of PTEN function in the nucleus
	integrates potentially neurotrophic and metabolic signals in the orchestration of complex neuroprotective responses that oppose brain aging
	effector of neurotrophins involved in several age-associated neurodegenerative diseases, mediates at least some brain responses to dietary restriction
	nuclear transcription factor that is critical for normal and neoplastic hematopoiesis
	SOX4 and CREB1 cooperate and contribute to increased proliferation of hematopoietic progenitor cells

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

CREB1-CRTC1 pathway mediates the central effects of hormones and nutrients on energy balance and fertility

a component	component of an heterodimer with ATF
	important component of the CREB1 regulatory circuit acting by placing a constraint on calcineurin activity

INTERACTION

DNA	binds directly to cyclic AMP response elements (CREs) found within the mitochondrial genome

RNA

small molecule

protein	activating transcription factor-1, ATF1
	YY1 transcription factor, YY1
	Abelson murine leukemia virus, v-Abl
	serum response factor, SRF
	homeoprotein LFB3
	GLI family zinc finger 2, GLI2
	Tat interactive protein 60 kDa, TIP60
	Histone binding protein RbAp48
	CCAAT/enhancer binding protein (C/EBP) beta, CEBPB
	MECT1-MAML2 complex
	PSEN1
	bound CRTC1 (to regulate CARTPT and KISS1 gene expression through a direct mechanism)
	is a critical regulator of human GRPR expression in gastrointestinal cancer and might be activated through different upstream intracellular pathways
	binding to HDAC8 (inactivating CREB1 activation and decreasing CREB1 mediated gene transcription)
	SRY (sex determining region Y)-box 9, SOX9
	binding partner for LYL1 but not for TAL1
	interaction with CCDC6 reduces CREB1 binding to AREG promoter
	CREB1, SP1, and TFAP4 play roles in modulating PPP2R2B expression
	interacting with TOX3
	SIK2 plays critical roles in neuronal survival, is modulated by CaMKI/IV, and regulates CREB1 via CRTC1
	protein target of PTEN phosphatase and PTEN deficiency leads to CREB1 phosphorylation independent of the PI3K/AKT pathway
	CREB1 gene silencing decreased IL13-induced transcription of eotaxin-3 (CCL26)
	new role for TIRAP as a key upstream regulator of CREB1 and as a contributor to the expression of both pro- and anti-inflammatory genes
	RCAN1 acting as an important regulatory component in the control of CREB1 signaling
	BDNF uses CREB1 and EGR3 to regulate NMDA receptor levels in cortical neurons
	complex interplay between CREB1 and SIRT1: CREB1 directly regulates the transcription of the sirtuin in neuronal cells by binding to SIRT1 chromatin and, in turn, is recruited by CREB1 to DNA
	NR4A2 is a downstream target of CREB1 and it is responsible for the NMDA-mediated increase in BDNF, which is necessary for the NMDA-mediated prosurvival effect on neurons
	SOX4 transcription factor is a gene that cooperates with CREB1 in myeloid leukemogenesis
	CREB1 has been postulated to regulate TRH expression
	overactivation of CAPN1 caused by calcium overload proteolyses CREB1, resulting in a reduction of SLC2A3 expression and consequently impairing glucose uptake and metabolism in AD brain
	CREB1 mediates the PRKAA-stimulated degradation of GRIP1 through protein-protein interaction and stimulation of proteasomal degradation of ubiquitinated GRIP1
	is necessary for the specific maintenance of the GRIA1 subunit and for its trafficking within the post-synaptic densities (PSD) during the occurrence of learning
	CREB1 regulates TIGAR expression via a CRE-binding site at the TIGAR promoter
	IGF1 regulates MSTN expression via CREB1 transcription factor during muscle cell differentiation
	negative regulation of CREB1 activity by endogenous CAMK2D-dependent CREB1-Ser(142) phosphorylation, suggesting a potential mechanism for CAMK2D/CREB1 signaling in modulating proliferation and migration in vascular smooth muscle cells
	KDELR1, KDELR2 activates CREB1 and other transcription factors that upregulate transport-related genes
	is positioned to interact with the MEF2C pathway known to be important in developmental epilepsies and the CREB1 pathway implicated in epilepsy pathogenesis
	CREB1 is a negative regulator of the TNFAIP1 gene
	depletion of CREB1 decreased the expression of ERN1 and EIF2AK3, two critical UPR signaling molecules, and CREB1 binds to the promoter region of these genes and regulates their expression
	GSK3A is regulated by CREB1 in lung cancer and is required for the cell viability
	SMIM20 acts through GPR173 to activate the cAMP/protein kinase A pathway through CREB1, for a stimulatory effect on reproductive function
	SMIM20 acts through its receptor, G protein-coupled receptor 173 (GPR173), to activate the cAMP/PKA pathway leading to the phosphorylation of CREB1

cell & other

REGULATION

activated by	MAPK14 (role for MAPK14 in activating CREB1 metabolic pathway in the events leading to erythroid differentiation)
	intracellular HIV-1 Tat protein
	Calmodulin-dependent protein kinase II
	fear memory expression

inhibited by

thyroid hormone receptor

repressed by

CCDC6 (represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes)

Other	phosphorylated by ataxia telangiectasia mutated in response to genotoxic stress
	transactivated by epidermal growth factor (EGF)
	phosphorylated by MSK1 and MSK2 in response to to both mitogenic and stress stimuli (Wiggin 2002)
	can be phosphorylated by erum/glucocorticoid-inducible kinase
	phosphorylated by testis-specific serine/threonine kinase 5

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function decreased mitochondrial CREB activity contributes to the mitochondrial dysfunction and neuronal loss associated with neurodegenerative disorders constitutional germinal mutation       a p.D116G mutation in CREB1 leads to novel multiple malformation syndrome

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed mental retardation trisomy   identification of direct endogenous CREB1 target genes may have important insight into the causes and treatments of Down syndrome pathogenesis cancer lung   CREB1-GSK3A axis is a novel therapeutic target for lung cancer treatment

ANIMAL & CELL MODELS

	transgenic mice expressing a dominant-negative form of the CREB1 develop dilated cardiomyopathy associated with hepatic congestion and peripheral edema, intracardiac thrombi, and premature mortality
	CREB null mice are smaller, display a strong reduction in the corpus callosum and the anterior commissures in brain and die immediately after birth from respiratory distress
	mice with a disruption of CREB1exhibit fasting hypoglycaemia and reduced expression of gluconeogenic enzymes
	disrupted Creb1 and Crem in brain of developing and adult mice using the Cre/loxP system leads to progressive neurodegeneration in the hippocampus and in the dorsolateral striatum
	mice harboring a null mutation in the Creb gene, sensory neurons exhibit excess apoptosis and degeneration, and display impaired axonal growth and projections
	mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-gamma (ID: 14614508)
	mice expressing a dominant-negative CREB transgene exhibit a dystrophic phenotype along with reduced MEF2 activity