ATF1

Summary

ATF1 (activating transcription factor 1, HGNC:783) is a protein-coding gene on chromosome 12q13.12, encoding Cyclic AMP-dependent transcription factor ATF-1 (P18846). This protein binds the cAMP response element (CRE) (consensus: 5’-GTGACGT[AC][AG]-3’), a sequence present in many viral and cellular promoters.

This gene encodes an activating transcription factor, which belongs to the ATF subfamily and bZIP (basic-region leucine zipper) family. It influences cellular physiologic processes by regulating the expression of downstream target genes, which are related to growth, survival, and other cellular activities. This protein is phosphorylated at serine 63 in its kinase-inducible domain by serine/threonine kinases, cAMP-dependent protein kinase A, calmodulin-dependent protein kinase I/II, mitogen- and stress-activated protein kinase and cyclin-dependent kinase 3 (cdk-3). Its phosphorylation enhances its transactivation and transcriptional activities, and enhances cell transformation. Fusion of this gene and FUS on chromosome 16 or EWSR1 on chromosome 22 induced by translocation generates chimeric proteins in angiomatoid fibrous histiocytoma and clear cell sarcoma. This gene has a pseudogene on chromosome 6.

Source: NCBI Gene 466 — RefSeq curated summary.

At a glance

• GWAS associations: 28
• Clinical variants (ClinVar): 50 total
• Druggable target: yes
• Transcription factor: yes — 91 downstream targets (CollecTRI)
• MANE Select transcript: NM_005171

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:783
Approved symbol	ATF1
Name	activating transcription factor 1
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	TREB36
Ensembl gene	ENSG00000123268
Ensembl biotype	protein_coding
OMIM	123803
Entrez	466

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 24 protein_coding, 2 nonsense_mediated_decay

ENST00000262053, ENST00000549612, ENST00000551831, ENST00000552487, ENST00000552510, ENST00000862770, ENST00000862771, ENST00000862772, ENST00000862773, ENST00000862774, ENST00000862775, ENST00000862776, ENST00000862777, ENST00000862778, ENST00000862779, ENST00000862780, ENST00000862781, ENST00000862782, ENST00000862783, ENST00000929819, ENST00000929820, ENST00000929821, ENST00000929822, ENST00000929823, ENST00000929824, ENST00000949061

RefSeq mRNA: 25 — MANE Select: NM_005171 NM_001412960, NM_001412961, NM_001412962, NM_001412963, NM_001412964, NM_001412965, NM_001412966, NM_001412967, NM_001412968, NM_001412969, NM_001412970, NM_001412971, NM_001412972, NM_001412973, NM_001412974, NM_001412975, NM_001412976, NM_001412977, NM_001412978, NM_001412979, NM_001412980, NM_001412981, NM_001412982, NM_001412983, NM_005171

CCDS: CCDS8803

Canonical transcript exons

ENST00000262053 — 7 exons

Exon	Start	End
ENSE00000837655	50809456	50809589
ENSE00001295868	50819635	50821162
ENSE00002391770	50764101	50764307
ENSE00003503033	50780140	50780238
ENSE00003675908	50814280	50814439
ENSE00003683463	50795909	50796009
ENSE00003788621	50814010	50814192

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 96.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.5137 / max 164.3490, expressed in 1812 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125456	20.3663	1808
125455	5.6281	1662
125457	0.4247	150
125454	0.0946	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	96.56	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.85	gold quality
parietal pleura	UBERON:0002400	95.74	gold quality
amniotic fluid	UBERON:0000173	95.37	gold quality
biceps brachii	UBERON:0001507	95.24	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.06	gold quality
pleura	UBERON:0000977	94.59	gold quality
visceral pleura	UBERON:0002401	94.50	gold quality
trabecular bone tissue	UBERON:0002483	94.48	gold quality
palpebral conjunctiva	UBERON:0001812	94.28	gold quality
calcaneal tendon	UBERON:0003701	94.13	gold quality
tibia	UBERON:0000979	93.99	gold quality
vastus lateralis	UBERON:0001379	92.44	gold quality
tendon	UBERON:0000043	92.31	gold quality
esophagus squamous epithelium	UBERON:0006920	92.18	gold quality
skeletal muscle tissue	UBERON:0001134	92.08	gold quality
cartilage tissue	UBERON:0002418	91.96	gold quality
quadriceps femoris	UBERON:0001377	91.78	gold quality
mammary duct	UBERON:0001765	91.65	gold quality
epithelium of nasopharynx	UBERON:0001951	91.49	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.46	gold quality
bronchial epithelial cell	CL:0002328	91.38	gold quality
epithelium of mammary gland	UBERON:0003244	91.37	gold quality
muscle organ	UBERON:0001630	91.26	gold quality
skeletal muscle organ	UBERON:0014892	91.26	gold quality
skin of hip	UBERON:0001554	91.13	gold quality
jejunal mucosa	UBERON:0000399	91.09	gold quality
oral cavity	UBERON:0000167	91.02	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.98	gold quality
muscle of leg	UBERON:0001383	90.90	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.61

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

91 targets.

Target	Regulation
ACHE
ADIPOQ	Activation
ALS2
ATF1
ATP1A1	Activation
BCL2	Unknown
CAMK2A
CAT	Unknown
CCNA1	Repression
CCNA2	Unknown
CD44
CD74
CDK3
CEBPA	Activation
CEBPB	Activation
CFTR	Activation
CGA	Unknown
CIITA	Unknown
CNTN2
CREB1
CREBBP	Activation
CYP11B1	Unknown
CYP11B2	Unknown
DBH
DUSP1
EGR1	Activation
ENO1	Unknown
ERBB2	Unknown
ERVW-1
EWSR1

Upstream regulators (CollecTRI, top): ATF1, EWSR1, PIAS3

miRNA regulators (miRDB)

119 targeting ATF1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
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
HSA-MIR-4282	99.99	75.36	6408

Literature-anchored findings (GeneRIF, showing 40)

• Composition and function of AP-1 transcription complexes during muscle cell differentiation (PMID:11877423)
• Molecular genetic characterization of the EWS/ATF1 fusion gene in clear cell sarcoma of tendons and aponeuroses. (PMID:11992546)
• APC inhibited both the binding of NF-kB to target sites and the degradation of I kappa B alpha, and inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. (PMID:12195699)
• ATF1 plays an important role in the trans-activation of the MHC class II trans-activator (CIITA) promoter III in B cells. (PMID:12391222)
• identification of its target genes as a chimeric protein with EWS (PMID:12527906)
• Results demonstrate that c-Src and TRAF6 are key mediators of interleukin-1-induced AP-1 activation and provide evidence of cross talk between c-Src and TRAF6 molecules through PI3 kinase-Akt-JNK pathways. (PMID:12631284)
• activating transcription factor 1(AP-1) motif is important in determining the up-regulatory effects induced by leptin on aromatase expression in MCF-7 breast cancer cells (PMID:12734209)
• transcriptional activation of the interleukin-8 promoter by bradykinin involves the prostanoid-independent activation of nuclear factor-kappaB, and prostanoid-dependent activation of activating protein-1 and nuclear factor-interleukin-6 (PMID:12748173)
• Blockade of AP-1 activation by the recombinant adenovirus containing a dominant negative c-Jun markedly reduced the IL-1beta-and TGF-beta1-induced IL-11 mRNA expression. (PMID:12760902)
• The role of activator protein-1 in regulating the promoter of IFGBP4 was studied in CaCo-2 cells. (PMID:14767471)
• some protease inhibitors might act as stress and induced TF expression with direct phosphorylation of JNK and p38, followed by phosphorylation and activation of AP-1 in monocytic cells (PMID:15041276)
• Simultaneous expression of the EWSR1-ATF1 and MITF-M transcripts in clear cell carcinoma has led to the proposal that the MITF-M promoter is transactivated by EWSR1-ATF1. (PMID:15884099)
• CREB/ATF1 and c-Jun were shown to bind to an oligonucleotide encompassing a distal, conserved CREB/AP1 site in the 5’-flanking region of the MUC2 gene, and this cis element was shown to mediate promoter reporter activation by VIP (PMID:16227528)
• There was evidence of ATF1 oncogene protein fusion in this sarcoma. (PMID:16327442)
• The cytokines TNFalpha and GM-CSF activate CAEV transcription, and this effect occurs independently of AP-1. (PMID:16716376)
• PIAS3 is a new regulator of ATF1 that regulates the ARE-mediated transcription of the ferritin H gene (PMID:17565989)
• CDK3 phosphorylates activating transcription factor 1 (ATF1)and enhances the transactivation and transcriptional activities of ATF1. (PMID:18794154)
• Thirteen of 15 cases of clear cell sarcoma harbored a type 1 chimeric transcript (EWSR1 exon 8/ATF1 exon 4) (PMID:19561568)
• DNA cytosine methylation in the bovine leukemia virus promoter has a role in direct inhibition of cAMP-responsive element (CRE)-binding protein/CRE modulator/activation transcription factor binding (PMID:20413592)
• An increase in phosphorylation of CREB/ATF-1 in human dental pulp cells was noted after exposure to PGF2alpha for 1-20 min,with a maximal induction at 10 min. (PMID:20536573)
• Differential expression of CREB/ATF transcription factors could be observed on neurogenic induction, pointing to a decisive role of the cAMP-CREB/ATF system. (PMID:20945072)
• Hyalinizing clear-cell carcinoma is a unique low-grade salivary carcinoma that consistently harbors EWSR1-ATF1 fusion. (PMID:21484932)
• ATF-1 mediates HO-1 induction by heme and drives macrophage adaptation to intraplaque hemorrhage. (PMID:22052915)
• Review: discuss clinicopathologic and molecular features of group of neoplasms unified by the presence of EWSR1-CREB1 and EWSR1-ATF1 genetic fusions. (PMID:22510762)
• ATF1 protein expression was significantly lower in colorectal cancer tissues than corresponding normal tissues; patients with higher ATF1 expression levels have a significantly higher survival rate than those with lower expression (PMID:22631637)
• Heme activates the ATF1 pathway in human macrophages via AMPK, and that a similar response occurs after treatment of cells with metformin. (PMID:24051143)
• EWSR1-ATF1 fusion gene was found in hyalinizing clear cell carcinoma (PMID:25359601)
• genetic association studies in a population in China: Data suggest that an SNP in ATF1 (rs11169571) is associated with essential hypertension in the population studied; altered binding of microRNA-1283 appears to be involved. (PMID:26149214)
• Case Reports: maxillary sinus clear cell carcinomas with EWSR1-ATF1 gene fusion. (PMID:27916624)
• Report a distinct group of myxoid mesenchymal neoplasms occurring in children or young adults with a predilection for intracranial locations with EWSR1-AFT1/CREB1/CREM fusions. (PMID:28009602)
• Pin1 is a novel regulator of ATF1 at Thr184. (PMID:28032861)
• our results demonstrated that miR-30a may modulate the radiosensitivity of non-small cell lung cancer (NSCLC) through reducing the function of ATF1 in phosphorylation of ATM and have potential therapeutic value. (PMID:28259977)
• Results expand the spectrum of tumor types harboring EWSR1/FUS-ATF1 gene fusions to include a subgroup of conventional epithelioid malignant mesothelioma. (PMID:28505004)
• a breakpoint in the EWSR1-ATF1 fusion to be the same as that reported in HCCC. Established CCOC-T cells grew extremely slowly, but the cells showed highly invasive activity (PMID:28559020)
• LncRNA GHET1 was intimately involved in the occurrence and development of HCC through regulating ATF1. (PMID:28772210)
• Knockdown of ATF1 effectively reduced cell proliferation, induced S phase cell cycle arrest, and inhibited cell migration and invasion. (PMID:28912415)
• Exome-wide association analysis identifies a rare missense variant in TCF7L2 and a common regulatory variant in ATF1 as susceptibility factors of colorectal cancer. (PMID:30026326)
• carcinogenic role of lncRNA RP11-552M11.4 in CC was mediated through miR-3941/ATF1 axis (PMID:30790638)
• The human ATF1 rs11169571 polymorphism is associated with risk of nasopharyngeal carcinoma in Southern Chinese populations. (PMID:30905073)
• Promoter-enhancer interaction module between the ATF1 regulatory elements dbSNP: rs61926301 and dbSNP: rs7959129 are the molecular drivers of Colorectal Cancer. (PMID:31204011)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Atf1	ENSMUSG00000023027
rattus_norvegicus	Atf1	ENSRNOG00000061088
drosophila_melanogaster	CrebA	FBGN0004396
drosophila_melanogaster	Atf6	FBGN0033010
drosophila_melanogaster	CrebB	FBGN0265784
caenorhabditis_elegans		WBGENE00000222
caenorhabditis_elegans		WBGENE00000793
caenorhabditis_elegans		WBGENE00016162

Paralogs (9): CREB3L3 (ENSG00000060566), CREM (ENSG00000095794), CREB3 (ENSG00000107175), ATF6 (ENSG00000118217), CREB1 (ENSG00000118260), CREB3L4 (ENSG00000143578), CREB3L1 (ENSG00000157613), CREB3L2 (ENSG00000182158), ATF6B (ENSG00000213676)

Protein

Protein identifiers

Cyclic AMP-dependent transcription factor ATF-1 — P18846 (reviewed: P18846)

Alternative names: Activating transcription factor 1, Protein TREB36

All UniProt accessions (5): P18846, F8VRN2, F8VS03, F8VYE5, F8VYN3

UniProt curated annotations — full annotation on UniProt →

Function. This protein binds the cAMP response element (CRE) (consensus: 5’-GTGACGT[AC][AG]-3’), a sequence present in many viral and cellular promoters. Binds to the Tax-responsive element (TRE) of HTLV-I. Mediates PKA-induced stimulation of CRE-reporter genes. Represses the expression of FTH1 and other antioxidant detoxification genes. Triggers cell proliferation and transformation.

Subunit / interactions. Binds DNA as a dimer. Interacts with HIPK2 and CDK3. Interacts with MOTS-c, a peptide produced by the mitochondrially encoded 12S rRNA MT-RNR1; the interaction occurs in the nucleus following metabolic stress.

Subcellular location. Nucleus.

Post-translational modifications. Phosphorylated at Ser-198 by HIPK2 in response to genotoxic stress. This phosphorylation promotes transcription repression of FTH1 and other antioxidant detoxification genes. The CDK3-mediated phosphorylation at Ser-63 promotes its transactivation and transcriptional activities. Phosphorylated at Ser-63 by RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli.

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. Chromosomal aberrations involving ATF1 are found in patients with angiomatoid fibrous histiocytoma. Translocation t(12;16)(q13;p11.2) with FUS generates a chimeric ATF1/FUS protein. Translocation t(12;22)(q13;q12) with EWSR1 generates a chimeric ATF1/EWSR1 protein.

Similarity. Belongs to the bZIP family. ATF subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P18846-1	1	yes
P18846-2	2

RefSeq proteins (25): NP_001399889, NP_001399890, NP_001399891, NP_001399892, NP_001399893, NP_001399894, NP_001399895, NP_001399896, NP_001399897, NP_001399898, NP_001399899, NP_001399900, NP_001399901, NP_001399902, NP_001399903, NP_001399904, NP_001399905, NP_001399906, NP_001399907, NP_001399908, NP_001399909, NP_001399910, NP_001399911, NP_001399912, NP_005162* (*=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 (17 total): region of interest 3, domain 2, cross-link 2, sequence conflict 2, site 2, modified residue 2, chain 1, splice variant 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P18846-F1	66.41	0.23

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 (2): 110 (breakpoint for translocation to form chimeric ewsr1/atf1 protein); 112 (breakpoint for translocation to form chimeric fus/atf1 protein)

Post-translational modifications (4): 208, 215, 63, 198

Mutagenesis-validated functional residues (1):

Position	Phenotype
63	impaired cdk3-mediated phosphorylation and altered transactivation and transcriptional activities.

Function

Pathways and Gene Ontology

Reactome pathways

30 pathways

ID	Pathway
R-HSA-199920	CREB phosphorylation
R-HSA-9031628	NGF-stimulated transcription
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-166520	Signaling by NTRKs
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-198725	Nuclear Events (kinase and transcription factor activation)
R-HSA-448424	Interleukin-17 signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-450282	MAPK targets/ Nuclear events mediated by MAP kinases
R-HSA-450294	MAP kinase activation
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-975155	MyD88 dependent cascade initiated on endosome
R-HSA-975871	MyD88 cascade initiated on plasma membrane

MSigDB gene sets: 235 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_UP, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, HOFMANN_CELL_LYMPHOMA_UP, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, RIZ_ERYTHROID_DIFFERENTIATION_CCNE1, GOBP_NEUROGENESIS, YY1_Q6, GOBP_RESPONSE_TO_METAL_ION, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, MARTINEZ_RB1_TARGETS_DN

GO Biological Process (9): regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of neuron projection development (GO:0010976), response to purine-containing compound (GO:0014074), response to cobalt ion (GO:0032025), positive regulation of DNA replication (GO:0045740), positive regulation of transcription by RNA polymerase II (GO:0045944), protein-containing complex assembly (GO:0065003), cAMP/PKA signal transduction (GO:0141156), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (10): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), RNA polymerase II transcription regulator complex (GO:0090575), ATF4-CREB1 transcription factor complex (GO:1990589), ATF1-ATF4 transcription factor complex (GO:1990590), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Toll-like Receptor Cascades	7
Nuclear Events (kinase and transcription factor activation)	2
Immune System	2
Toll Like Receptor 4 (TLR4) Cascade	2
Toll Like Receptor 2 (TLR2) Cascade	2
MAPK targets/ Nuclear events mediated by MAP kinases	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Signaling by Receptor Tyrosine Kinases	1
Innate Immune System	1
Signaling by NTRKs	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
transcription cis-regulatory region binding	2
binding	2
cellular anatomical structure	2
RNA polymerase II transcription regulator complex	2
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
response to nitrogen compound	1
response to metal ion	1
DNA replication	1
regulation of DNA replication	1
positive regulation of DNA metabolic process	1
positive regulation of DNA-templated transcription	1
cellular component assembly	1
protein-containing complex organization	1
intracellular signaling cassette	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	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
protein binding	1
nucleic acid binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
transcription regulator complex	1
nuclear protein-containing complex	1
protein-containing complex	1

Protein interactions and networks

STRING

1126 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATF1	EWSR1	Q01844	874
ATF1	FUS	P35637	829
ATF1	RPS6KA5	O75582	783
ATF1	A0A087WTZ4	A0A087WTZ4	716
ATF1	CREB3L2	Q70SY1	645
ATF1	CREBBP	Q92793	630
ATF1	MAPKAPK2	P49137	611
ATF1	FOS	P01100	600
ATF1	MAPK13	O15264	541
ATF1	MAPKAPK3	Q16644	536
ATF1	MAPK11	Q15759	516
ATF1	HNF1A	P20823	495
ATF1	RPS6KA1	Q15418	492
ATF1	TARDBP	Q13148	469
ATF1	EP300	Q09472	455

IntAct

75 interactions, top by confidence:

A	B	Type	Score
ATF1	CREB1	psi-mi:“MI:0915”(physical association)	0.760
CREB1	ATF1	psi-mi:“MI:0915”(physical association)	0.760
CREB1	ATF1	psi-mi:“MI:0407”(direct interaction)	0.760
ATF1	CREB1	psi-mi:“MI:0407”(direct interaction)	0.760
HSPA8	GAK	psi-mi:“MI:0914”(association)	0.760
CCDC97	SF3B1	psi-mi:“MI:0914”(association)	0.730
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
ATF1	ATF1	psi-mi:“MI:0407”(direct interaction)	0.620
ATF1	NFIL3	psi-mi:“MI:0407”(direct interaction)	0.590
NFIL3	ATF1	psi-mi:“MI:0407”(direct interaction)	0.590
ATF1	ESR1	psi-mi:“MI:0407”(direct interaction)	0.590
ATF1	NFATC1	psi-mi:“MI:0915”(physical association)	0.580
CACNG2	CCNT1	psi-mi:“MI:0914”(association)	0.530
MIA2	RGPD3	psi-mi:“MI:0914”(association)	0.530
ARIH1	SPOP	psi-mi:“MI:0914”(association)	0.530
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
TRPV5	ATF1	psi-mi:“MI:0914”(association)	0.530
	ATF1	psi-mi:“MI:0915”(physical association)	0.520
ATF1		psi-mi:“MI:0915”(physical association)	0.520
JUN	ATF1	psi-mi:“MI:0915”(physical association)	0.500
ATF1	HBZ	psi-mi:“MI:0407”(direct interaction)	0.440
MDV005	ATF1	psi-mi:“MI:0407”(direct interaction)	0.440
BACH1	ATF1	psi-mi:“MI:0407”(direct interaction)	0.440
HBZ	ATF1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (77): ATF1 (Affinity Capture-MS), ATF1 (Affinity Capture-MS), ATF1 (Affinity Capture-MS), ATF1 (Co-fractionation), JUNB (Co-fractionation), ATF1 (Affinity Capture-MS), ATF1 (Affinity Capture-MS), ATF1 (Reconstituted Complex), ATF1 (Biochemical Activity), ATF1 (Biochemical Activity), ATF1 (Biochemical Activity), ATF1 (Affinity Capture-MS), ATF1 (Affinity Capture-MS), ATF1 (Affinity Capture-MS), ATF1 (Affinity Capture-MS)

ESM2 similar proteins: A6QQW0, B4F7E9, O15391, O43167, O62836, O70230, O70494, P08048, P15337, P17010, P17012, P18846, P20385, P25490, P27699, P36508, P52747, P79145, P81069, P81269, Q00420, Q00899, Q01147, Q01611, Q02447, Q03060, Q03061, Q06547, Q08DA8, Q0V8G2, Q1LYE3, Q1LZH5, Q1RMI3, Q4V8R6, Q52KB5, Q52V16, Q58DZ6, Q5XIU2, Q66K89, Q6B4Z5

Diamond homologs: P15337, P16220, P18846, P27699, P27925, P51984, P51985, P79145, P81269, Q01147, Q03060, Q03061, Q08DA8, Q1LZH5, Q66HA2, Q96BA8, Q9U2I0, Q9VWW0, Q9Z125

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
RPS6KA4	up-regulates	ATF1	phosphorylation
CSNK2A1	down-regulates	ATF1	phosphorylation
PPP2R5C	up-regulates	ATF1	dephosphorylation
CDK3	up-regulates	ATF1	phosphorylation
HNF1B	“up-regulates activity”	ATF1	binding
ATF1	“down-regulates quantity by repression”	FTH1	“transcriptional regulation”
ATF1	“up-regulates quantity by expression”	PCSK1	“transcriptional regulation”
ATF1	“up-regulates quantity by expression”	IL10	“transcriptional regulation”
ATM	“up-regulates activity”	ATF1	phosphorylation
RPS6KA3	“up-regulates activity”	ATF1	phosphorylation
CSNK2A1	up-regulates	ATF1	phosphorylation
RPS6KA5	“up-regulates activity”	ATF1	phosphorylation
RPS6KA4	“up-regulates activity”	ATF1	phosphorylation
PRKACA	“up-regulates activity”	ATF1	phosphorylation
CAMK1	“up-regulates activity”	ATF1	phosphorylation
CAMK2G	“up-regulates activity”	ATF1	phosphorylation
ATF1	“up-regulates quantity by expression”	EGR1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 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.

GO biological processes:

GO term	Partners	Fold	FDR
chromatin remodeling	8	9.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1728 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:50814416:A:C	R216S	1.000
12:50814416:A:T	R216S	1.000
12:50814424:G:C	R219T	1.000
12:50814424:G:T	R219M	1.000
12:50814425:G:C	R219S	1.000
12:50814425:G:T	R219S	1.000
12:50814427:T:C	L220S	1.000
12:50814432:A:G	K222E	1.000
12:50814433:A:T	K222I	1.000
12:50814434:A:C	K222N	1.000
12:50814434:A:T	K222N	1.000
12:50814435:A:G	N223D	1.000
12:50814436:A:T	N223I	1.000
12:50814437:C:A	N223K	1.000
12:50814437:C:G	N223K	1.000
12:50814439:G:C	R224T	1.000
12:50814439:G:T	R224I	1.000
12:50819635:A:C	R224S	1.000
12:50819635:A:T	R224S	1.000
12:50819639:G:C	A226P	1.000
12:50819640:C:A	A226D	1.000
12:50819642:G:C	A227P	1.000
12:50819643:C:A	A227D	1.000
12:50819643:C:T	A227V	1.000
12:50819646:G:C	R228P	1.000
12:50819651:T:C	C230R	1.000
12:50819654:C:A	R231S	1.000
12:50819654:C:G	R231G	1.000
12:50819654:C:T	R231C	1.000
12:50819660:A:G	K233E	1.000

dbSNP variants (sampled 300 via entrez): RS1000027016 (12:50773535 C>T), RS1000058315 (12:50773119 A>G), RS1000105244 (12:50795295 G>A), RS1000136423 (12:50794943 TAAA>T,TAA,TAAAA), RS1000141638 (12:50779458 T>C), RS1000159130 (12:50820108 TA>T,TAA), RS1000166928 (12:50810612 T>A), RS1000190607 (12:50767248 T>G), RS1000202665 (12:50778386 G>A,C), RS1000211153 (12:50819827 G>A), RS1000223484 (12:50775661 G>A), RS1000269354 (12:50812927 GA>G,GAA), RS1000269766 (12:50787750 A>C), RS1000283595 (12:50781931 A>C), RS1000289806 (12:50773820 C>G)

Disease associations

OMIM: gene MIM:123803 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

28 associations (top):

Study	Trait	p-value
GCST000843_4	Colorectal cancer	2.000000e-10
GCST001099_29	Sudden cardiac arrest	3.000000e-07
GCST002411_2	Colorectal cancer	3.000000e-08
GCST002919_13	Colorectal cancer	4.000000e-08
GCST003983_33	Male-pattern baldness	2.000000e-09
GCST006231_51	Mean arterial pressure	5.000000e-06
GCST007267_312	Systolic blood pressure	1.000000e-14
GCST007293_76	Body fat distribution (arm fat ratio)	4.000000e-07
GCST007294_123	Body fat distribution (trunk fat ratio)	2.000000e-09
GCST007294_2	Body fat distribution (trunk fat ratio)	1.000000e-18
GCST007295_152	Body fat distribution (leg fat ratio)	4.000000e-13
GCST007856_42	Colorectal cancer or advanced adenoma	2.000000e-23
GCST008058_19	Estimated glomerular filtration rate	2.000000e-09
GCST008059_255	Estimated glomerular filtration rate	3.000000e-10
GCST009597_267	Multiple sclerosis	9.000000e-06
GCST010241_371	Apolipoprotein A1 levels	3.000000e-10
GCST010242_373	HDL cholesterol levels	2.000000e-10
GCST010703_176	Brain morphology (MOSTest)	5.000000e-11
GCST010796_5316	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_5317	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_5318	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_5319	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_5320	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_5321	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_5322	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST90011898_16	Alanine aminotransferase levels	1.000000e-10
GCST90013405_40	Liver enzyme levels (alanine transaminase)	8.000000e-13
GCST90016667_30	Spleen volume	9.000000e-10

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004278	sudden cardiac arrest
EFO:0006340	mean arterial pressure
EFO:0006335	systolic blood pressure
EFO:0004341	body fat distribution
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3255 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

18 potent at pChembl≥5 of 18 total, top 18 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.30	IC50	50	nM	CHEMBL336546
6.92	IC50	120	nM	CHEMBL131636
6.82	IC50	150	nM	CHEMBL134490
6.31	IC50	490	nM	CHEMBL135133
6.30	IC50	500	nM	CHEMBL336099
6.30	IC50	500	nM	CHEMBL334485
6.18	IC50	660	nM	CHEMBL423153
6.05	IC50	900	nM	CHEMBL134603
5.92	IC50	1200	nM	CHEMBL337482
5.92	IC50	1200	nM	CHEMBL133940
5.80	IC50	1600	nM	CHEMBL131789
5.57	IC50	2700	nM	CHEMBL131622
5.55	IC50	2800	nM	CHEMBL134990
5.52	IC50	3000	nM	CHEMBL337695
5.52	IC50	3000	nM	CHEMBL131976
5.52	IC50	3000	nM	CHEMBL337516
5.42	IC50	3800	nM	CHEMBL335697
5.40	IC50	4000	nM	CHEMBL335655

PubChem BioAssay actives

18 with measured affinity, of 31 total; 18 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[3,5-bis(trifluoromethyl)phenyl]-2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	0.0500	uM
butyl 3-[[2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl]amino]-5-(trifluoromethyl)benzoate	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	0.1200	uM
ethyl 3-[[2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl]amino]-5-(trifluoromethyl)benzoate	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	0.1500	uM
2-chloro-4-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	0.4900	uM
2-chloro-N-(2,6-dichloropyrimidin-4-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	0.5000	uM
2-chloro-N-(3,5-dichlorophenyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	0.5000	uM
hexyl 3-[[2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl]amino]-5-(trifluoromethyl)benzoate	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	0.6600	uM
2-chloro-N-(3,4,5-trichlorophenyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	0.9000	uM
cyclohexyl 3-[[2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl]amino]-5-(trifluoromethyl)benzoate	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	1.2000	uM
octyl 3-[[2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl]amino]-5-(trifluoromethyl)benzoate	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	1.2000	uM
2-chloro-N-(3,5-dimethoxyphenyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	1.6000	uM
N-benzyl-2-chloro-N-(3,5-dichlorophenyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	2.7000	uM
2-chloro-N-(5-methylthiophen-2-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	2.8000	uM
2-chloro-N-(3,5-dichlorophenyl)-N-methyl-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	3.0000	uM
N-[3-carbamoyl-5-(trifluoromethyl)phenyl]-2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	3.0000	uM
diethoxyphosphorylmethyl 3-[[2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl]amino]-5-(trifluoromethyl)benzoate	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	3.0000	uM
2-chloro-N-(3-methyl-1,2-oxazol-5-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	3.8000	uM
N-(3,5-dichlorophenyl)-2-piperidin-1-yl-4-(trifluoromethyl)pyrimidine-5-carboxamide	30748: In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	ic50	4.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	6
sodium arsenite	affects methylation, decreases expression, increases phosphorylation	5
trichostatin A	affects cotreatment, decreases expression	3
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases reaction, increases phosphorylation, affects cotreatment	3
Cadmium Chloride	decreases reaction, increases phosphorylation, decreases expression	3
(+)-JQ1 compound	decreases expression	2
Resveratrol	increases expression, increases phosphorylation, decreases reaction	2
Hydrogen Peroxide	decreases expression, increases phosphorylation, decreases reaction	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Dinoprostone	decreases reaction, increases phosphorylation, affects cotreatment, affects binding, increases reaction	2
dicrotophos	decreases expression	1
deoxynivalenol	increases expression	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases phosphorylation, decreases reaction	1
gossypin	decreases phosphorylation	1
manganese chloride	increases abundance, increases expression	1
cupric oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
SB 203580	affects cotreatment, decreases reaction, increases phosphorylation	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	affects cotreatment, decreases reaction, increases phosphorylation	1
RTKI cpd	decreases reaction, increases phosphorylation	1
EKB 569	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
quinocetone	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
3,5-bis(2-fluorobenzylidene)piperidin-4-one	decreases reaction, increases expression	1
BIX 02189	decreases reaction, increases phosphorylation	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL640575	Binding	In vitro inhibitory activity against human Jurkat T-Cells stably transfected with activating transcription factor 1	2-Chloro-4-(trifluoromethyl)pyrimidine-5-N-(3’,5’- bis(trifluoromethyl)phenyl)-carboxamide: a potent inhibitor of NF-kappa B- and AP-1-mediated gene expression identified using solution-phase combinatorial chemistry. — J Med Chem

Cellosaurus cell lines

26 cell lines: 23 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0J30	CCS292	Cancer cell line	Sex unspecified
CVCL_0J31	DTC1	Cancer cell line	Sex unspecified
CVCL_0J32	Hewga-CCS	Cancer cell line	Female
CVCL_0J33	MP-CCS-SY	Cancer cell line	Female
CVCL_0J34	MST-1	Cancer cell line	Female
CVCL_0J35	MST-2	Cancer cell line	Male
CVCL_0J36	MST-3	Cancer cell line	Male
CVCL_0J37	UM-CCS-1	Cancer cell line	Female
CVCL_9707	GG-62	Cancer cell line	Female
CVCL_A0D9	SEES3-1V human ATF1, clone1	Embryonic stem cell	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.