CREB1

Summary

CREB1 (cAMP responsive element binding protein 1, HGNC:2345) is a protein-coding gene on chromosome 2q33.3, encoding Cyclic AMP-responsive element-binding protein 1 (P16220). Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters.

This gene encodes a transcription factor that is a member of the leucine zipper family of DNA binding proteins. This protein binds as a homodimer to the cAMP-responsive element, an octameric palindrome. The protein is phosphorylated by several protein kinases, and induces transcription of genes in response to hormonal stimulation of the cAMP pathway. Alternate splicing of this gene results in several transcript variants encoding different isoforms.

Source: NCBI Gene 1385 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 37 total
• Regional missense constraint (gnomAD): 1 of 4 regions constrained (≈24% of expected missense variation)
• GTEx eGene: eQTL in 7 tissues, sQTL in 7 (q < 0.05)
• Phenotypes (HPO): 2
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.19 (highly constrained)
• Transcription factor: yes — 494 downstream targets (CollecTRI)
• MANE Select transcript: NM_004379
• Interaction hub: 6,202 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2345
Approved symbol	CREB1
Name	cAMP responsive element binding protein 1
Location	2q33.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000118260
Ensembl biotype	protein_coding
OMIM	123810
Entrez	1385

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 27 protein_coding, 11 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 2 retained_intron

MANE Select: ENST00000353267

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 2, TSL 3: 4, TSL 4: 4, TSL 5: 5

ENST00000353267, ENST00000414681, ENST00000418081, ENST00000421139, ENST00000430624, ENST00000432329, ENST00000445803, ENST00000446449, ENST00000448277, ENST00000451164, ENST00000452474, ENST00000455757, ENST00000457101, ENST00000464407, ENST00000480189, ENST00000494094, ENST00000494983, ENST00000896942, ENST00000896943, ENST00000915136, ENST00000961890, ENST00000961891, ENST00000961892, ENST00001003798, ENST00001003799, ENST00001003800, ENST00001003801, ENST00001027428, ENST00001027429, ENST00001027430, ENST00001063070, ENST00001063071, ENST00001063072, ENST00001063073, ENST00001090836, ENST00001108011, ENST00001108012, ENST00001117703, ENST00001117704, ENST00001117705, ENST00001128516, ENST00001128517, ENST00001129468, ENST00001142570

RefSeq mRNA: 6 — MANE Select: NM_004379 NM_001320793, NM_001371426, NM_001371427, NM_001371428, NM_004379, NM_134442

CCDS: CCDS2374, CCDS2375

Canonical transcript exons

ENST00000353267 — 8 exons

Exon	Start	End
ENSE00001887644	207529962	207530134
ENSE00003553318	207577505	207577655
ENSE00003594653	207560226	207560372
ENSE00003621510	207555628	207555749
ENSE00003656413	207575272	207575454
ENSE00003659734	207567463	207567563
ENSE00003784251	207570179	207570321
ENSE00004801173	207596914	207605988

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 95.90.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.2984 / max 585.8434, expressed in 1824 samples.

Highest expression (Bgee): secondary oocyte, calcaneal tendon, bone marrow cell, superficial temporal artery, trabecular bone tissue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CREB1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 7 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	sqtl	1.3e-08	+0.90	2:207550413:A:G
Whole Blood	eqtl	1.7e-04	-0.09	2:207649177:T:A
Adipose Subcutaneous	sqtl	2.2e-04	-0.36	2:207553213:T:C
Skin Sun Exposed Lower leg	sqtl	9.3e-04	+0.34	2:207619779:GT:G
Lung	sqtl	2.1e-03	-0.38	2:207628851:T:C
Cells Cultured fibroblasts	eqtl	2.6e-03	+0.15	2:206741009:C:T
Skin Sun Exposed Lower leg	eqtl	4.6e-03	+0.13	2:207638550:C:T
Breast Mammary Tissue	eqtl	5.2e-03	-0.41	2:207243804:T:C
Skin Not Sun Exposed Suprapubic	eqtl	9.9e-03	-0.28	2:207572115:A:G
Nerve Tibial	sqtl	1.0e-02	-0.31	2:207565659:C:T
Esophagus Muscularis	sqtl	1.5e-02	+0.32	2:207669676:A:C
Esophagus Gastroesophageal Junction	eqtl	3.6e-02	+0.32	2:208006013:T:C
Minor Salivary Gland	sqtl	3.8e-02	-2.25	2:207194078:CTTTG:C
Pancreas	eqtl	4.6e-02	+0.55	2:207676948:G:C

FANTOM5 promoters

showing 10 of 14 alternative TSS:

Promoter ID	TPM avg	Samples expressed
24877	26.2757	1818
24876	9.2033	1742
24880	7.8425	1523
24878	2.4492	1305
24879	1.5077	912
24881	0.5819	154
24875	0.1358	70
24882	0.0963	26
24874	0.0632	20
24885	0.0544	7

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.90	gold quality
calcaneal tendon	UBERON:0003701	95.06	gold quality
bone marrow cell	CL:0002092	94.26	gold quality
superficial temporal artery	UBERON:0001614	94.16	gold quality
trabecular bone tissue	UBERON:0002483	94.06	gold quality
cortical plate	UBERON:0005343	93.98	gold quality
left testis	UBERON:0004533	93.97	gold quality
ganglionic eminence	UBERON:0004023	93.94	gold quality
skin of hip	UBERON:0001554	93.83	gold quality
embryo	UBERON:0000922	93.70	gold quality
right testis	UBERON:0004534	93.57	gold quality
epithelium of nasopharynx	UBERON:0001951	93.56	gold quality
bone marrow	UBERON:0002371	93.28	gold quality
testis	UBERON:0000473	93.19	gold quality
tonsil	UBERON:0002372	93.18	gold quality
parietal pleura	UBERON:0002400	93.10	gold quality
visceral pleura	UBERON:0002401	92.93	gold quality
colonic epithelium	UBERON:0000397	92.91	gold quality
ventricular zone	UBERON:0003053	92.59	gold quality
islet of Langerhans	UBERON:0000006	92.25	gold quality
germinal epithelium of ovary	UBERON:0001304	92.23	gold quality
upper leg skin	UBERON:0004262	92.22	gold quality
palpebral conjunctiva	UBERON:0001812	92.12	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.11	gold quality
tendon	UBERON:0000043	92.06	gold quality
pleura	UBERON:0000977	92.04	gold quality
blood	UBERON:0000178	91.73	gold quality
lower lobe of lung	UBERON:0008949	91.65	gold quality
penis	UBERON:0000989	91.49	gold quality
mammalian vulva	UBERON:0000997	91.23	gold quality
synovial joint	UBERON:0002217	91.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.00	gold quality
monocyte	CL:0000576	90.90	gold quality
lymph node	UBERON:0000029	90.88	gold quality
gingiva	UBERON:0001828	90.86	gold quality
mononuclear cell	CL:0000842	90.69	gold quality
leukocyte	CL:0000738	90.67	gold quality
gingival epithelium	UBERON:0001949	90.61	gold quality
adrenal tissue	UBERON:0018303	90.60	gold quality
corpus callosum	UBERON:0002336	90.54	gold quality
oral cavity	UBERON:0000167	90.50	gold quality
cauda epididymis	UBERON:0004360	90.48	gold quality
endometrium	UBERON:0001295	90.45	gold quality
esophagus squamous epithelium	UBERON:0006920	90.41	gold quality
tibia	UBERON:0000979	90.30	gold quality
urethra	UBERON:0000057	90.26	gold quality
stromal cell of endometrium	CL:0002255	90.08	gold quality
pericardium	UBERON:0002407	90.06	gold quality
mammary duct	UBERON:0001765	90.04	gold quality
vermiform appendix	UBERON:0001154	89.95	gold quality
nipple	UBERON:0002030	89.95	gold quality
caecum	UBERON:0001153	89.93	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.83	gold quality
pigmented layer of retina	UBERON:0001782	89.68	gold quality
rectum	UBERON:0001052	89.50	gold quality
smooth muscle tissue	UBERON:0001135	89.47	gold quality
squamous epithelium	UBERON:0006914	89.31	gold quality
mammary gland	UBERON:0001911	89.29	gold quality
gall bladder	UBERON:0002110	89.29	gold quality
thoracic mammary gland	UBERON:0005200	89.26	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.22	gold quality
epithelium of mammary gland	UBERON:0003244	89.20	gold quality
saphenous vein	UBERON:0007318	89.13	gold quality
seminal vesicle	UBERON:0000998	89.04	gold quality
sural nerve	UBERON:0015488	89.04	gold quality
urinary bladder	UBERON:0001255	88.69	gold quality
cerebellar vermis	UBERON:0004720	88.69	gold quality
caput epididymis	UBERON:0004358	88.55	gold quality
corpus epididymis	UBERON:0004359	88.47	gold quality
epithelium of esophagus	UBERON:0001976	87.89	gold quality
placenta	UBERON:0001987	87.85	gold quality
buccal mucosa cell	CL:0002336	87.75	gold quality
heart right ventricle	UBERON:0002080	87.73	gold quality
epithelial cell of pancreas	CL:0000083	87.69	silver quality
oocyte	CL:0000023	87.65	gold quality
paraflocculus	UBERON:0005351	87.64	gold quality
superior surface of tongue	UBERON:0007371	87.47	gold quality
blood vessel layer	UBERON:0004797	87.34	gold quality
cartilage tissue	UBERON:0002418	87.24	gold quality
uterus	UBERON:0000995	87.23	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.22	gold quality
jejunum	UBERON:0002115	87.13	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.08	gold quality
thymus	UBERON:0002370	86.99	gold quality
layer of synovial tissue	UBERON:0007616	86.96	gold quality
pylorus	UBERON:0001166	86.92	gold quality
lung	UBERON:0002048	86.91	gold quality
subthalamic nucleus	UBERON:0001906	86.85	gold quality
colonic mucosa	UBERON:0000317	86.78	gold quality
trigeminal ganglion	UBERON:0001675	86.76	gold quality
myocardium	UBERON:0002349	86.76	gold quality
jejunal mucosa	UBERON:0000399	86.67	gold quality
biceps brachii	UBERON:0001507	86.63	gold quality
bronchial epithelial cell	CL:0002328	86.53	gold quality
cardia of stomach	UBERON:0001162	86.46	gold quality
connective tissue	UBERON:0002384	86.41	gold quality
vena cava	UBERON:0004087	86.30	gold quality
amniotic fluid	UBERON:0000173	86.24	gold quality
female reproductive system	UBERON:0000474	86.14	gold quality
adipose tissue	UBERON:0001013	86.13	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Corpus callosum	tissue	42.4
Cerebellum	tissue	39.8	high
Choroid plexus	tissue	38.7
Olfactory bulb	tissue	37.7
Hippocampal formation	tissue	36.3
Midbrain	tissue	35.6
Hypothalamus	tissue	35.0
Prefrontal cortex	tissue	34.3
Cerebral cortex	tissue	34.3	high
Substantia nigra	tissue	33.8
Septum	tissue	33.4
Spinal cord	tissue	33.2
Entorhinal cortex	tissue	33.2
Superior colliculi	tissue	33.0
Periaqueductal gray	tissue	33.0
Motor cortex	tissue	32.9
Thalamus	tissue	32.8
Hippocampus	tissue	32.4	high
Occipital cortex	tissue	32.3
Pons	tissue	32.2
Nucleus accumbens	tissue	32.0
Retrosplenial and cingulate cortex	tissue	32.0
Medulla oblongata	tissue	31.9
Amygdala	tissue	31.6
Somatosensory cortex	tissue	31.4
Insular cortex	tissue	31.3
Putamen	tissue	31.2
Retrosplenial cortex	tissue	31.0
Temporal cortex	tissue	30.9
Locus coeruleus	tissue	30.7
Testis	tissue	30.2	high
Postcentral gyrus	tissue	29.9
Ventral forebrain	tissue	29.9
Basal ganglia	tissue	29.5	high
Thymus	tissue	26.8
Tonsil	tissue	23.4	high
Bone marrow	tissue	21.1	high
Lymph node	tissue	20.6	high
Thyroid gland	tissue	17.0	high
Placenta	tissue	16.9	high
Retina	tissue	16.5
Spleen	tissue	16.1	high
Urinary bladder	tissue	15.7	high
Caudate putamen	tissue	15.5
Ovary	tissue	15.4	high
Smooth muscle	tissue	15.3	high
Cervix	tissue	14.8	high
Endometrium 1	tissue	14.7	high
Parathyroid gland	tissue	14.6	high
Frontal cortex	tissue	14.5
Appendix	tissue	14.5	high
Esophagus	tissue	14.1	high
Breast	tissue	13.8	high
Tongue	tissue	13.6
Rectum	tissue	13.2	high
Gallbladder	tissue	13.1	high
Lung	tissue	12.8	high
Fallopian tube	tissue	12.3	high
Adipose tissue	tissue	12.2	high
Prostate	tissue	12.2	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Cerebellar cortex (50.1), Flocculonodular lobe (46.7), Vermis (45.3), Corpus callosum, splenium (white matter) (43.6), White matter (42.4).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

showing 30 of 494 targets:

Target	Regulation
AANAT	Activation
ABCA1	Activation
ABCB1	Unknown
ACACA	Activation
ACHE	Activation
ACSL4	Unknown
ADAM2
ADARB1	Repression
ADCYAP1	Unknown
ADIPOQ	Unknown
ADM	Activation
ADORA2A
ADRA1A	Unknown
AGER	Activation
AGT	Activation
AGTR1	Unknown
AICDA	Unknown
AKAP8L	Activation
AKT1	Unknown
ALAS2	Unknown
ANG	Activation
ANGPTL2	Repression
AP1	Repression
APEX1	Unknown
AQP2	Activation
AQP3	Unknown
AR	Unknown
AREG	Activation
ARG1	Activation
ARMCX1	Activation

JASPAR motifs

Motif	Name	Family
MA0018.1	CREB1	CREB-related factors
MA0018.2	CREB1	CREB-related factors
MA0018.3	CREB1	CREB-related factors
MA0018.4	CREB1	CREB-related factors
MA0018.5	CREB1	CREB-related factors
UN1154.1	CREB1::ELF1	CREB-related factors,Ets-related
UN1156.1	CREB1::ERG	CREB-related factors,Ets-related
UN1159.1	CREB1::ETV1	CREB-related factors,Ets-related
UN1162.1	CREB1::ETV4	CREB-related factors,Ets-related
UN1165.1	CREB1::FLI1	CREB-related factors,Ets-related
UN1168.1	CREB1::IRF7	CREB-related factors,Interferon-regulatory factors

JASPAR matrix evidence (PMIDs): PMID:8264613, PMID:17916232

Upstream regulators (CollecTRI, top): AP1, ATF1, ATF4, ATF5, ATF6, CEBPA, CREB1, CREBBP, CREM, FOSB, FOXO4, HOXA9, LYL1, NFKB, NR3C1, RELA, SMAD3, SMAD4, SP1, SRF, THRB, TP53, USF1, YY1

miRNA regulators (miRDB)

Targeting CREB1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 437 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.189, missense Z 3.6 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000353267 splits into 4 regions with different missense tolerance; 1 is missense-constrained (≈24% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
2:207,555,636–207,560,253	53 / 57.1	0.93	no
2:207,560,254–207,575,302	66 / 150.8	0.44	no
2:207,575,303–207,577,561	66 / 88.1	0.75	no
2:207,577,562–207,597,055	14 / 93.0	0.15	yes (p 2.5e-16)

Literature-anchored findings (GeneRIF, showing 40)

• review of CREB transcription factor involvment with spermatogenesis (PMID:11988318)
• Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB. (PMID:12091337)
• CREB and sterol regulatory element binding protein cooperate in transactivating CYP51. (PMID:12145339)
• is co-expressed with CREB and CBP in extravillous cytotrophoblasts, revealing the in vivo relevance of this transactivation pathway (PMID:12183445)
• CREB-DNA binding by magnetic fields is dependent on calcium ions. (PMID:12200150)
• hGRP-R activation stimulated sustained cyclic AMP response element binding protein (CREB) phosphorylation and transactivation in duodenal cancer cells through a protein kinase C and partially p38 mitogen-activated protein kinase-dependent pathway. (PMID:12220644)
• Oct-1 potentiates CREB-dependent cyclin D1 transcriptional activity by a phospho-CREB and CREB binding protein-independent mechanism (PMID:12391146)
• CREB1 plays an important role in the trans-activation of the MHC class II trans-activator (CIITA) promoter III in B cells. (PMID:12391222)
• Structurally distinct modes of recognition of the KIX domain of CBP by Jun and CREB (PMID:12437352)
• CREB response to hypoxia is modified by small ubiquitin-related modifier-1 (SUMO-1) (PMID:12552083)
• Here we show that HDAC1 associates with and blocks Ser133 phosphorylation of CREB during pre-stimulus and attenuation phases of the cAMP response (PMID:12567184)
• CREB1 associates with TIF2 and is essential for cell transformation. (PMID:12676584)
• IL1beta and TNFalpha activation of MSK1 and CREB and cAMP-response element signaling cascades occurs via ERK/p38 MAP kinases and are crucial aspects of the intracellular mechanisms that mediate MUC5AC gene expression (PMID:12690113)
• Levels of CREB mRNA in thyroid carcinomas, but not in adenomas, were significantly lower than in corresponding normal tissue. (PMID:12720543)
• Tissue transglutaminase directly regulates adenylyl cyclase resulting in enhanced cAMP-response element-binding protein (CREB) activation. (PMID:12743114)
• The involvement of CREB in STAT5 transactivation was demonstrated by serine-133-mutated CREB, which completely blocked the SCF effect. In addition, the CREB-binding protein CBP/p300 was shown to be essential for EPO- and SCF-mediated STAT5 transactivation (PMID:12829027)
• Sequence variations in the CREB1 promoter and intron 8 have been detected that cosegregate with Mood Disorders, or their absence, in women from these families, identifying CREB1 as a sex-limited susceptibility gene for unipolar Mood Disorders. (PMID:12851637)
• observed CREB phosphorylation via signal pathways and binding of CREB to the cAMP-responsive element after treatment with oxidized phospholipids (PMID:14523007)
• role in assembly of CBP-CREB-HTLV-1 tax coactivator-activator complex (PMID:14580193)
• CREB-binding protein interacts preferentially with the glycosylated form of Stat5 (PMID:14597631)
• activation of BTK and the subsequent phosphorylation of CREB at Ser-133 are important in the neuronal differentiation of hippocampal progenitor cells. (PMID:14597636)
• chronic activation CREB and p90RSK in the epileptic hippocampus may be closely associated with the histopathological changes of Ammon’s horn sclerosis (PMID:14646589)
• CREB-1/CREM-1 have roles as regulators of macrophage differentiation (PMID:14754893)
• CREB is activated by TNF/TNFR1 signaling through a p38MAPK/MSK1 signaling pathway. (PMID:14761884)
• CREB has a role in PPARgamma2 inhibition of cyclin D1 transcription in hepatocytes (PMID:14764597)
• In VSMCs, LDL-induced mitogenesis involves NOR-1 upregulation through a CREB-dependent mechanism. CREB could play a role in the modulation by LDL of key genes (containing CRE sites) involved in atherogenesis. (PMID:14962944)
• CRH plays pathogenic role in modulating inflammatory joint disease with CREB/ATF family of transcription factors as principal effector molecules of proinflammatory mediator action in rheumatoid arthritis. (PMID:15077295)
• identified the in vivo binding sites of CREB1 across the entire human chromosome 22; a large number of potential gene targets for CREB1 have been identified, raising the possibility that it has important roles in a variety of cellular processes (PMID:15082775)
• CREB suppresses the glioblastoma proliferative effect of the stress-induced acetylcholinesterase variant, AChE-R (PMID:15153340)
• Resistance to various antifolates may potentially be associated with impaired activity of Galphas or their coupled receptors, resulting in loss of CREB-1 phosphorylation. (PMID:15340044)
• This review article highlights the current findings on the role of nucleus accumbal and amygdaloid CREB signaling in behavioral consequences of alcohol use and abuse. (PMID:15500908)
• SDF-1/CXCL12 enhanced cell survival in synergy with other cytokines involves activation of CREB and induction of Mcl-1 and c-Fos (PMID:15588513)
• p90 ribosomal S 6 protein kinase 1 (RSK1) mediates the PGE2-induced phosphorylation of cAMP-response element binding protein (PMID:15615708)
• affects the expression of 958 genes in myometrium (PMID:15691874)
• CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter. (PMID:15753290)
• CREB promotes abnormal proliferation and survival of myeloid cells in vitro and in vivo through upregulation of specific target genes and thus is implicated in myeloid cell transformation. (PMID:15837624)
• The contribution of CREB to interferon(IFN)-gamma upregulation is demonstrated in T cells from normal tuberculin reactors, compared to T cells from tuberculosis patients with ineffective immunity, which show reduced CREB activity and low IFN-gamma levels. (PMID:15879136)
• the PI3-kinase/p38(MAPK)/CREB pathway contributes to the EGF activation of NF-IL6beta gene expression (PMID:15901830)
• Pellino3 is a novel upstream regulator of p38 MAPK and activates CREB in a p38-dependent manner (PMID:15917247)
• Results do not support the previous evidence for CREB1 as a major factor contributing to depression. (PMID:15999345)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	creb1b	ENSDARG00000093420
mus_musculus	Creb1	ENSMUSG00000025958
rattus_norvegicus	Creb1	ENSRNOG00000013412
drosophila_melanogaster	Atf6	FBGN0033010
drosophila_melanogaster	CrebB	FBGN0265784
caenorhabditis_elegans		WBGENE00000222
caenorhabditis_elegans		WBGENE00000793

Paralogs (9): CREB3L3 (ENSG00000060566), CREM (ENSG00000095794), CREB3 (ENSG00000107175), ATF6 (ENSG00000118217), ATF1 (ENSG00000123268), CREB3L4 (ENSG00000143578), CREB3L1 (ENSG00000157613), CREB3L2 (ENSG00000182158), ATF6B (ENSG00000213676)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:88494) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 31 distinct phenotype terms.

Mouse phenotype (MP)	Records
small superior cervical ganglion	1
abnormal stellate ganglion morphology	1
small testis	1
abnormal lung development	1
abnormal cued conditioning behavior	1
abnormal spatial learning	1
abnormal temporal memory	1
abnormal contextual conditioning behavior	1
reduced long-term potentiation	1
postnatal lethality	1
abnormal CNS synaptic transmission	1
oligozoospermia	1
decreased vertical activity	1
decreased circulating testosterone level	1
abnormal single cell response	1
small lung	1
abnormal lung vasculature morphology	1
decreased fetal size	1
decreased testis weight	1
decreased seminal vesicle weight	1
decreased epididymis weight	1
impaired lung alveolus development	1
decreased survivor rate	1
abnormal behavioral response to addictive substance	1
decreased behavioral withdrawal response	1

+6 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	P27925	99.7%	Diamond
Hydra viridissima	P51984	94.3%	Diamond
Hydra vulgaris	P51985	94.3%	Diamond
Canis lupus familiaris	P79145	92.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
METTL21A	protein-coding	151194
MIR1302-4	ncRNA	100302130
MYOSLID-AS1	ncRNA	101927865
LINC01802	ncRNA	105373852
MYOSLID	ncRNA	105373853
SAILR	ncRNA	102724714

Protein

Protein identifiers

Cyclic AMP-responsive element-binding protein 1 — P16220 (reviewed: P16220)

All UniProt accessions (11): C9J276, C9J4L5, C9J896, C9JBT4, C9JCI4, E7EWP8, H7C1R5, H7C3I0, P16220, Q53X93, Q5U0J5

UniProt curated annotations — full annotation on UniProt →

Function. Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells. Regulates the expression of apoptotic and inflammatory response factors in cardiomyocytes in response to ERFE-mediated activation of AKT signaling.

Subunit / interactions. Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators CRTC1/TORC1, CRTC2/TORC2 and CRTC3/TORC3. When phosphorylated on Ser-119, binds CREBBP. Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity. Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119. Forms a complex with KMT2A and CREBBP. Interacts with TOX4; CREB1 is required for full induction of TOX4-dependent activity and the interaction is increased by cAMP and inhibited by insulin. (Microbial infection) Interacts with hepatitis B virus/HBV protein X. (Microbial infection) Interacts with HTLV-1 protein Tax.

Subcellular location. Nucleus.

Post-translational modifications. Stimulated by phosphorylation. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion. CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity. Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1. Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-119. Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.

Disease relevance. Angiomatoid fibrous histiocytoma (AFH) [MIM:612160] A distinct variant of malignant fibrous histiocytoma that typically occurs in children and adolescents and is manifest by nodular subcutaneous growth. Characteristic microscopic features include lobulated sheets of histiocyte-like cells intimately associated with areas of hemorrhage and cystic pseudovascular spaces, as well as a striking cuffing of inflammatory cells, mimicking a lymph node metastasis. The gene represented in this entry may be involved in disease pathogenesis. A chromosomal aberration involving CREB1 is found in a patient with angiomatoid fibrous histiocytoma. Translocation t(2;22)(q33;q12) with CREB1 generates a EWSR1/CREB1 fusion gene that is most common genetic abnormality in this tumor type. A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.

Miscellaneous. Highly expressed in adult testis and sperm.

Similarity. Belongs to the bZIP family.

Isoforms (3)

UniProt ID	Names	Canonical?
P16220-2	1, CREB-B	yes
P16220-1	2, CREB-A
P16220-3	3, htCREB

RefSeq proteins (6): NP_001307722, NP_001358355, NP_001358356, NP_001358357, NP_004370, NP_604391 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001630	Leuzip_CREB	Family
IPR003102	CREB1-like_pKID	Domain
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily

Pfam: PF00170, PF02173

UniProt features (38 total): sequence conflict 11, mutagenesis site 6, region of interest 5, modified residue 3, cross-link 3, helix 3, domain 2, splice variant 2, chain 1, sequence variant 1, site 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
7TBH	cryo-EM structure of MBP-KIX-apoferritin complex with peptide 7	ELECTRON MICROSCOPY	2.3
5ZK1	Crystal Structure of the CRTC2(SeMet)-CREB-CRE complex	X-RAY DIFFRACTION	3.05
5ZKO	Crystal structure of the CRTC2-CREB-CRE complex	X-RAY DIFFRACTION	3.05
2LXT	Allosteric communication in the KIX domain proceeds through dynamic re-packing of the …	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16220-F1	62.38	0.18

Human Protein Atlas

Protein class: Predicted intracellular proteins, Transcription factors, Basic domains, Cancer-related genes, Mutational cancer driver genes, Disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; basal body; centrosome; cytosol

Antibody reliability (HPA): IH supported · IF enhanced

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
300	required for binding torcs

Post-translational modifications (6)

Type	Positions
Phosphoserine	128, 257, 119
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	122
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo1)	271, 290

Mutagenesis-validated functional residues (6)

Position	Phenotype
119	does not interact with tox3 and inhibits induction of transcription by tox3. loss of phosphorylation by camk4. loss of phosphorylation by …
141	no effect on sumoylation.
257	impaired phosphorylation by hipk2 and subsequent transactivation.
257	potentiated transactivation.
271	decreased sumoylation, in vivo and in vitro.
290	decreased sumoylation, in vivo and in vitro. loss of nuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

9 curated (TAS) of 27; 4 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

27 pathways:

ID	Pathway	Evidence
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer ⚕	curated
R-HSA-9609690	HCMV Early Events ⚕	curated
R-HSA-198693	AKT phosphorylates targets in the nucleus	curated
R-HSA-199920	CREB phosphorylation	curated
R-HSA-442742	CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	curated
R-HSA-881907	Gastrin-CREB signalling pathway via PKC and MAPK	curated
R-HSA-375165	NCAM signaling for neurite out-growth	curated
R-HSA-9824585	Regulation of MITF-M-dependent genes involved in pigmentation	curated
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity	curated
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production ⚕	electronic
R-HSA-9664323	FCGR3A-mediated IL10 synthesis ⚕	electronic
R-HSA-442720	CREB1 phosphorylation through the activation of Adenylate Cyclase	electronic
R-HSA-442729	CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde	electronic
R-HSA-111932	CaMK IV-mediated phosphorylation of CREB	electronic
R-HSA-9634638	Estrogen-dependent nuclear events downstream of ESR-membrane signaling	electronic
R-HSA-9931509	Expression of BMAL (ARNTL), CLOCK, and NPAS2	electronic
R-HSA-9707616	Heme signaling	electronic
R-HSA-9022699	MECP2 regulates neuronal receptors and channels	electronic
R-HSA-9022707	MECP2 regulates transcription factors	electronic
R-HSA-9022702	MECP2 regulates transcription of neuronal ligands	electronic
R-HSA-9031628	NGF-stimulated transcription	electronic
R-HSA-2197563	NOTCH2 intracellular domain regulates transcription	electronic
R-HSA-111931	PKA-mediated phosphorylation of CREB	electronic
R-HSA-9931510	Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	electronic
R-HSA-9022692	Regulation of MECP2 expression and activity	electronic
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis	electronic
R-HSA-9616222	Transcriptional regulation of granulopoiesis	electronic

MSigDB gene sets: 795 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, GOBP_MEMORY, CREL_01, REACTOME_SIGNALING_BY_NOTCH, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_LUNG_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_COGNITION

GO Biological Process (51): regulation of transcription by RNA polymerase II (GO:0006357), protein phosphorylation (GO:0006468), signal transduction (GO:0007165), transforming growth factor beta receptor signaling pathway (GO:0007179), memory (GO:0007613), circadian rhythm (GO:0007623), visual learning (GO:0008542), response to xenobiotic stimulus (GO:0009410), negative regulation of gene expression (GO:0010629), response to purine-containing compound (GO:0014074), response to activity (GO:0014823), cell differentiation (GO:0030154), positive regulation of transforming growth factor beta3 production (GO:0032916), response to glucagon (GO:0033762), chemotaxis to arachidonate (GO:0034670), response to nicotine (GO:0035094), response to erythropoietin (GO:0036017), cellular response to platelet-derived growth factor stimulus (GO:0036120), response to cocaine (GO:0042220), mRNA transcription by RNA polymerase II (GO:0042789), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), response to morphine (GO:0043278), response to ethanol (GO:0045471), positive regulation of fat cell differentiation (GO:0045600), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of RNA polymerase II transcription preinitiation complex assembly (GO:0045899), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of lipid biosynthetic process (GO:0046889), regulation of fibroblast proliferation (GO:0048145), protein stabilization (GO:0050821), regulation of glial cell proliferation (GO:0060251), cellular response to retinoic acid (GO:0071300), cellular response to fatty acid (GO:0071398), cAMP/PKA signal transduction (GO:0141156), positive regulation of long-term synaptic potentiation (GO:1900273), response to L-glutamate (GO:1902065), response to dehydroepiandrosterone (GO:1903494), positive regulation of membrane depolarization (GO:1904181), cellular response to forskolin (GO:1904322), cellular response to nerve growth factor stimulus (GO:1990090), cellular response to insulin-like growth factor stimulus (GO:1990314), response to hypobaric hypoxia (GO:1990910), regulation of testosterone biosynthetic process (GO:2000224), response to hypoxia (GO:0001666), regulation of DNA-templated transcription (GO:0006355), regulation of apoptotic process (GO:0042981), positive regulation of gluconeogenesis (GO:0045722), rhythmic process (GO:0048511), cellular response to growth factor stimulus (GO:0071363), cellular response to transforming growth factor beta stimulus (GO:0071560)

GO Molecular Function (18): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), transcription coactivator binding (GO:0001223), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), enzyme binding (GO:0019899), Hsp70 protein binding (GO:0030544), histone acetyltransferase binding (GO:0035035), cAMP response element binding (GO:0035497), identical protein binding (GO:0042802), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), arrestin family protein binding (GO:1990763), sequence-specific double-stranded DNA binding (GO:1990837), transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (8): chromatin (GO:0000785), euchromatin (GO:0000791), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrial matrix (GO:0005759), axon (GO:0030424), ATF4-CREB1 transcription factor complex (GO:1990589), transcription regulator complex (GO:0005667)

Reactome top-level categories

14 top-level categories:

Category	Pathways
Transcriptional Regulation by MECP2	4
Post NMDA receptor activation events	3
Calmodulin induced events	2
Nuclear Events (kinase and transcription factor activation)	2
PIP3 activates AKT signaling	1
MAPK targets/ Nuclear events mediated by MAP kinases	1
Mitochondrial biogenesis	1
Signaling by NOTCH2	1
Axon guidance	1
PI3K/AKT Signaling in Cancer	1
G alpha (q) signalling events	1
HCMV Infection	1
Developmental Biology	1
Extra-nuclear estrogen signaling	1

GO top-level categories

showing 60 of 66 GO namespaces:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
protein binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
response to chemical	2
chromatin	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
learning or memory	1
rhythmic process	1
visual behavior	1
associative learning	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
response to nitrogen compound	1
response to stimulus	1
cellular developmental process	1
transforming growth factor beta3 production	1
regulation of transforming growth factor beta3 production	1
positive regulation of transforming growth factor beta production	1
response to peptide hormone	1
chemotaxis	1
response to cytokine	1
response to platelet-derived growth factor	1
cellular response to growth factor stimulus	1
response to alkaloid	1
response to oxygen-containing compound	1
mRNA transcription	1
cis-regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity	1
regulation of transcription by RNA polymerase II	1
transcription coregulator binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription regulator activity	1
heat shock protein binding	1
protein-folding chaperone binding	1
enzyme binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 19 of 78 annotations. The rest are phylogenetic / computational / electronic (IEA).

19 experimentally-supported GO terms:

GO term	NS	Evidence
cAMP/PKA signal transduction	BP	direct assay
cellular response to forskolin	BP	direct assay
mRNA transcription by RNA polymerase II	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	direct assay
protein phosphorylation	BP	direct assay
response to purine-containing compound	BP	direct assay
ATF4-CREB1 transcription factor complex	CC	direct assay
euchromatin	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
DNA-binding transcription activator activity, RNA polymerase II-specific	MF	direct assay
DNA-binding transcription factor activity	MF	direct assay
DNA-binding transcription factor activity, RNA polymerase II-specific	MF	direct assay
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay
RNA polymerase II-specific DNA-binding transcription factor binding	MF	physical interaction
cAMP response element binding	MF	direct assay
enzyme binding	MF	physical interaction
identical protein binding	MF	physical interaction
sequence-specific double-stranded DNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 6,202 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CREB1	BDNF	P23560	953
CREB1	PRKACG	P22612	934
CREB1	PRKACA	P17612	927
CREB1	PRKACB	P22694	927
CREB1	CRTC2	Q53ET0	866
CREB1	FOS	P01100	859
CREB1	CREBBP	Q92793	846
CREB1	CAMK4	Q16566	846
CREB1	CRTC1	Q6UUV9	839
CREB1	JUN	P05412	830
CREB1	EP300	Q09472	822
CREB1	PPARGC1A	Q9UBK2	819
CREB1	BCL2	P10415	819
CREB1	GRIN2B	Q13224	819
CREB1	CALM1	P02593	808

IntAct

Human interaction partners of CREB1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 70 partners by confidence:

Partner	Interaction type	MIscore	Records
ATF1	physical association	0.760	4
TSSK4	physical association	0.690	5
MEIS1	association	0.680	9
CRTC1	physical association	0.670	6
CREBBP	physical association	0.590	2
NFIL3	direct interaction	0.590	2
NFATC1	physical association	0.580	2
HSPA4	proximity	0.570	1
AGR2	physical association	0.560	3
CRTC2	physical association	0.560	3
HTT	physical association	0.560	3
PIAS2	physical association	0.560	3
RNF4	physical association	0.560	3
PASK	phosphorylation reaction	0.560	2
HSPA4L	association	0.530	1
NFATC2	physical association	0.500	1
SGK1	physical association	0.490	2
SMCO1	physical association	0.490	2
HBZ	direct interaction	0.440	2
MDV005	direct interaction	0.440	2
ATR	phosphorylation reaction	0.440	1
BACH1	direct interaction	0.440	1
BRCA1	direct interaction	0.440	1
CREB3L3	direct interaction	0.440	1
RPS6KA1	phosphorylation reaction	0.440	1
NFIX	physical association	0.400	2
PRKACA	physical association	0.400	1
SEC22B	physical association	0.400	1
X	physical association	0.400	1
MTF2	physical association	0.370	1

BioGRID (355 interactions; top human partners by supporting records): CREBBP (Far Western; 33 records), EP300 (Far Western; 13 records), TP53 (Co-localization; 7 records), CCDC6 (Affinity Capture-Western; 5 records), CEBPB (Affinity Capture-Western; 4 records), CTNNB1 (Affinity Capture-Western; 4 records), HDAC1 (Affinity Capture-Western; 4 records), POGZ (Two-hybrid; 4 records), DAXX (Two-hybrid; 3 records), JUN (Affinity Capture-MS; 3 records), NFATC1 (Affinity Capture-MS; 3 records), NFATC2 (Affinity Capture-MS; 3 records), NR5A2 (Two-hybrid; 3 records), ORC6 (Affinity Capture-MS; 3 records), POU2F1 (Affinity Capture-Western; 3 records)

SIGNOR signaling

showing 53 of 88 signaling interactions:

A	Effect	B	Mechanism
CAMK4	“up-regulates activity”	CREB1	phosphorylation
CAMK2A	down-regulates	CREB1	phosphorylation
ATM	“down-regulates activity”	CREB1	phosphorylation
ATM	down-regulates	CREB1	phosphorylation
ATR	down-regulates	CREB1	phosphorylation
CREB1	“down-regulates activity”	FOXO4	binding
TSSK4	up-regulates	CREB1	phosphorylation
CREB1	“up-regulates quantity by expression”	BCL2L1	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	PKM	“transcriptional regulation”
CAMK4	up-regulates	CREB1	phosphorylation
MAPKAPK2	up-regulates	CREB1	phosphorylation
CREB1	“up-regulates quantity by expression”	FOS	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	NR4A3	“transcriptional regulation”
RPS6KA4	up-regulates	CREB1	phosphorylation
HIPK2	up-regulates	CREB1	phosphorylation
MAPKAPK2	“up-regulates activity”	CREB1	phosphorylation
CREB1	“up-regulates quantity by expression”	MYF5	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	MYOD1	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	PAX3	“transcriptional regulation”
PRKACA	“up-regulates activity”	CREB1	phosphorylation
CREB1	up-regulates	Survival
HNF1B	“up-regulates activity”	CREB1	binding
AKT	“up-regulates activity”	CREB1	phosphorylation
RPS6KA3	“up-regulates activity”	CREB1	phosphorylation
CREB1	“up-regulates quantity by expression”	GCH1	“transcriptional regulation”
AKT1	“up-regulates activity”	CREB1	phosphorylation
RPS6K	“up-regulates activity”	CREB1	phosphorylation
CREB1	“down-regulates activity”	FOXO	binding
CREB1	“down-regulates quantity by repression”	PLAT	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	PCSK1	“transcriptional regulation”
CREB1	“down-regulates quantity by repression”	SNAI2	“transcriptional regulation”
CREB1	“down-regulates quantity by repression”	NR2F1	“transcriptional regulation”
CREB1	“down-regulates quantity by repression”	NR2F6	“transcriptional regulation”
CREB1	“down-regulates quantity by repression”	SNAI1	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	CYP19A1	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	MUC4	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	UXT	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	CHGA	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	IL10	“transcriptional regulation”
CRTC2	“up-regulates activity”	CREB1	binding
CREB1	“up-regulates quantity”	G6PC1	“transcriptional regulation”
PKA	“up-regulates activity”	CREB1	phosphorylation
CREB1	“up-regulates quantity”	BDNF	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	SLC5A5	“transcriptional regulation”
CREB1	“up-regulates quantity”	G6P	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	PK	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	POMC	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	IRS2	“transcriptional regulation”
GNAO1	down-regulates	CREB1
CDK5	“up-regulates activity”	CREB1	phosphorylation
DYRK1A	“up-regulates activity”	CREB1	phosphorylation
CREB1	“up-regulates quantity by expression”	BCL2	“transcriptional regulation”
RPS6KA5	up-regulates	CREB1	phosphorylation

Protein complexes (CORUM) (5)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

5 complexes by size:

Complex	Subunits	Members
LMO4-CREB complex	2	CREB1, LMO4
FHL2-CREB complex	2	CREB1, FHL2
FHL3-CREB complex	2	CREB1, FHL3
ATF4-CREB1 complex	2	ATF4, CREB1
★ CREB1-HDAC8 complex	2	CREB1, HDAC8

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 70 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SUMOylation of chromatin organization proteins	5	17.6×	2e-03
Processing of DNA double-strand break ends	5	12.7×	5e-03
Cellular responses to stimuli	8	5.6×	6e-03

Disease & clinical

Genetic variants

Variant evidence for CREB1: 37 ClinVar records (0 pathogenic / likely pathogenic); 2 PharmGKB clinical annotations; 9 GWAS associations.

ClinVar

37 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	1
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 1,146):

Position(s)	Effect	Δscore	Sites
2:207555750–207555751	donor_loss	1.0000	4
2:207560217	acceptor_gain	1.0000
2:207560224–207560225	acceptor_loss	1.0000	6
2:207560373–207560374	donor_loss	1.0000	4
2:207567461–207567462	acceptor_loss	1.0000	6
2:207567564–207567565	donor_loss	1.0000	5
2:207577063	acceptor_gain	1.0000
2:207577076	acceptor_gain	1.0000
2:207577503–207577504	acceptor_loss	1.0000	5
2:207577656–207577657	donor_loss	1.0000	5

AlphaMissense

1,008 missense substitutions predicted likely pathogenic (of 2,096 scored), across 240 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
N308	8	1.000	1.000
N279	8	0.999	1.000
N299	8	0.982	0.999
N306	8	0.979	0.998
D320	8	0.966	0.994
D215	8	0.849	0.990
D106	8	0.772	0.962
E298	7	1.000	1.000
C286	7	0.999	1.000
E305	7	0.999	1.000
E314	7	0.999	1.000
R280	7	0.998	1.000
C296	7	0.998	1.000
R116	7	0.996	1.000
K290	7	0.996	1.000
R117	7	0.995	1.000
I123	7	0.995	1.000
E285	7	0.995	1.000
Q307	7	0.995	1.000
I312	7	0.991	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	8.47e-06
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000109

Disease associations

OMIM: gene MIM:123810 | disease phenotypes:

HPO phenotypes

2 phenotypes (HPO-id order):

HPO	Term
HP:0001442	Typified by somatic mosaicism
HP:0012315	Histiocytoma

GWAS associations

9 associations:

Study	Trait	p-value
GCST004904_19	Body mass index	3e-10
GCST90002390_571	Mean corpuscular hemoglobin	9e-10
GCST007099_199	Systolic blood pressure	2e-8
GCST010002_408	Refractive error	2e-8
GCST002783_487	Body mass index	3e-8
GCST002783_84	Body mass index	8e-8
GCST007094_136	Diastolic blood pressure	1e-7
GCST002518_5	Food antigen IgG levels	1e-6
GCST002783_413	Body mass index	6e-6

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0005844	response to dietary antigen
EFO:0004340	body mass index
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5587 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 8,718 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL8260	BAICALEIN	2	8,718

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

2 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs7569963	Efficacy,Toxicity	3	antidepressants;citalopram	Depression
rs889895	Efficacy	3	antidepressants	Major Depressive Disorder

PharmGKB variants

3 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs889895	CREB1	3	0.50	1	antidepressants
rs4675690	CREB1	3	3.00	1	citalopram
rs7569963	CREB1, METTL21A	3	5.00	1	antidepressants;citalopram

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

3 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs889895	antidepressants	Efficacy	Genotype GG is associated with increased response to antidepressants in people with Depressive Disorder, Major as compared to genotypes AA + AG.	PMID:23537502
rs7569963	citalopram	Toxicity	Allele A is associated with decreased likelihood of treatment-emergent suicidality when treated with citalopram in people with Depressive Disorder, Major as compared to allele G.	PMID:17548750
rs7569963	antidepressants	Efficacy	Genotype GG is associated with increased likelihood of remission when treated with antidepressants in people with Depressive Disorder, Major as compared to genotypes AA + AG.	PMID:20643483

ChEMBL bioactivities

4 potent at pChembl≥5 of 7 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.77	AC50	1700	nM	CHEMBL186490
5.66	AC50	2200	nM	OROXYLIN A
5.37	AC50	4300	nM	CHEMBL434537
5.09	AC50	8200	nM	CHEMBL189339

CTD chemical–gene interactions

233 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Colforsin	decreases reaction, increases phosphorylation, affects binding, increases activity	6
sodium arsenite	decreases response to substance, decreases reaction, increases phosphorylation, affects methylation, affects cotreatment (+3 more)	5
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases reaction, increases phosphorylation, increases expression, increases activity	5
SB 203580	decreases reaction, increases phosphorylation, decreases phosphorylation	5
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases phosphorylation, decreases reaction, increases phosphorylation	5
Valproic Acid	affects expression, affects binding, increases reaction, decreases expression, increases methylation	5
Particulate Matter	decreases phosphorylation, decreases reaction, affects methylation, increases abundance, affects cotreatment (+2 more)	5
Resveratrol	decreases phosphorylation, increases activity, increases phosphorylation, affects binding, decreases reaction	4
Tetradecanoylphorbol Acetate	decreases reaction, increases phosphorylation, increases activity	4
bisphenol A	affects binding, increases reaction, increases activity, increases phosphorylation, decreases reaction	3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases phosphorylation, affects cotreatment, decreases phosphorylation	3
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases phosphorylation, decreases reaction, increases phosphorylation	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression, affects methylation	3
Benzo(a)pyrene	decreases expression, affects reaction, increases expression, affects activity	3
Formaldehyde	decreases reaction, increases phosphorylation, increases expression, decreases expression	3
Hydrogen Peroxide	affects cotreatment, decreases phosphorylation, decreases reaction, affects reaction, decreases expression (+1 more)	3
Rotenone	affects response to substance, decreases expression	3
Tobacco Smoke Pollution	increases phosphorylation, decreases expression, increases expression	3
Cadmium Chloride	decreases reaction, increases phosphorylation, affects phosphorylation, increases reaction	3
666-15 compound	decreases reaction, increases expression, decreases activity	2
methylmercuric chloride	affects cotreatment, affects phosphorylation, affects reaction, affects binding, decreases expression	2
o,p’-DDT	increases phosphorylation, affects localization, increases activity	2
manganese chloride	decreases expression, increases abundance, decreases phosphorylation, decreases reaction	2
4-hydroxy-2-nonenal	increases phosphorylation, decreases expression	2
nickel sulfate	increases secretion, affects expression, increases expression, affects cotreatment, increases reaction	2
epigallocatechin gallate	affects cotreatment, decreases phosphorylation, decreases reaction, affects reaction, decreases expression	2
cordycepin	increases phosphorylation, increases expression, decreases reaction	2
Ro 31-8220	decreases reaction, increases phosphorylation	2
bisindolylmaleimide I	decreases reaction, increases phosphorylation	2
4-tert-octylphenol	affects cotreatment, increases phosphorylation, decreases reaction	2

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3816446	Binding	Induction of degradation of halo-tagged CREB1 (unknown origin) expressed in HEK293 cells at 10 uM by Western blot analysis	Efficient protein knockdown of HaloTag-fused proteins using hybrid molecules consisting of IAP antagonist and HaloTag ligand. — *Bioorg Med Chem*

Cellosaurus cell lines

13 cell lines: 9 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0S0	SEES3-1V human CREB1, clone1	Embryonic stem cell	Male
CVCL_A0S1	SEES3-1V human CREB1, clone2	Embryonic stem cell	Male
CVCL_A0S2	SEES3-1V human CREB1, clone3	Embryonic stem cell	Male
CVCL_B8E1	Abcam HCT 116 CREB1 KO	Cancer cell line	Male
CVCL_B8UA	Abcam MCF-7 CREB1 KO	Cancer cell line	Female
CVCL_B9G9	Abcam A-549 CREB1 KO	Cancer cell line	Male
CVCL_D7MU	Ubigene A-549 CREB1 KO	Cancer cell line	Male
CVCL_D9CA	Ubigene HEK293 CREB1 KO	Transformed cell line	Female
CVCL_E0AU	Ubigene HeLa CREB1 KO	Cancer cell line	Female
CVCL_F6G9	EDITGENE CREB1 Knockout HAP1 Cell Line	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

5 trials:

NCT	Phase	Status	Title
NCT03600649	Phase 1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT02180867	Phase 2/3	COMPLETED	Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Before Surgery in Treating Patients With Newly Diagnosed Non-rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery
NCT05266196	Phase 1/2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	Phase 1/2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT03759327	Not specified	COMPLETED	Angiomatoid Fibrous Histiocytoma: a Single Institution Case-series

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CREB1 across ~30M SureChEMBL compounds — explore on Sugi Predict.