FBXW7

Summary

FBXW7 (F-box and WD repeat domain containing 7, HGNC:16712) is a protein-coding gene on chromosome 4q31.3, encoding F-box/WD repeat-containing protein 7 (Q969H0). Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. In precision oncology, FBXW7 Mutation confers sensitivity to MTOR Inhibitor in Cancer (CIViC Level B); 3 further curated variant–drug associations are listed below.

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Mutations in this gene are detected in ovarian and breast cancer cell lines, implicating the gene’s potential role in the pathogenesis of human cancers. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 55294 — RefSeq curated summary.

At a glance

• Gene–disease (curated): developmental delay, hypotonia, and impaired language (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 298 total — 14 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 23
• Precision-oncology evidence (CIViC): 4 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 22 cancer types
• MANE Select transcript: NM_001349798

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16712
Approved symbol	FBXW7
Name	F-box and WD repeat domain containing 7
Location	4q31.3
Locus type	gene with protein product
Status	Approved
Aliases	AGO, FLJ11071, SEL-10, SEL10, FBW7, FBX30, CDC4, FBXW6
Ensembl gene	ENSG00000109670
Ensembl biotype	protein_coding
OMIM	606278
Entrez	55294

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 14 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000281708, ENST00000296555, ENST00000393956, ENST00000603548, ENST00000603821, ENST00000603841, ENST00000604069, ENST00000604095, ENST00000604316, ENST00000604822, ENST00000604872, ENST00000605042, ENST00000642901, ENST00000643834, ENST00000647166, ENST00000647183, ENST00000703551, ENST00000703552, ENST00000703553, ENST00000703554, ENST00000703555, ENST00000865658, ENST00000937353

RefSeq mRNA: 5 — MANE Select: NM_001349798 NM_001013415, NM_001257069, NM_001349798, NM_018315, NM_033632

CCDS: CCDS34078, CCDS3777, CCDS3778, CCDS64082

Canonical transcript exons

ENST00000281708 — 14 exons

Exon	Start	End
ENSE00000740036	152346930	152347071
ENSE00000821072	152324184	152324394
ENSE00000821073	152326006	152326231
ENSE00000821077	152332596	152332719
ENSE00001002596	152337802	152337936
ENSE00001200526	152411303	152411872
ENSE00001480632	152534941	152535033
ENSE00003478818	152328208	152328389
ENSE00003495121	152330732	152330868
ENSE00003504561	152412480	152412529
ENSE00003539732	152320544	152323149
ENSE00003629197	152329672	152329785
ENSE00003667952	152350042	152350124
ENSE00003817109	152535127	152536092

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.2659 / max 1650.6656, expressed in 1809 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54387	15.4897	1786
54371	6.0968	816
54372	1.7082	177
54370	1.0539	354
54368	0.8164	234
54369	0.7904	286
54379	0.7520	343
54373	0.6735	94
54377	0.3295	69
54386	0.1474	84

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.03	gold quality
calcaneal tendon	UBERON:0003701	98.78	gold quality
colonic epithelium	UBERON:0000397	98.77	gold quality
middle temporal gyrus	UBERON:0002771	98.74	gold quality
superior frontal gyrus	UBERON:0002661	98.53	gold quality
occipital lobe	UBERON:0002021	98.17	gold quality
pons	UBERON:0000988	98.15	gold quality
parietal lobe	UBERON:0001872	98.10	gold quality
primary visual cortex	UBERON:0002436	97.99	gold quality
postcentral gyrus	UBERON:0002581	97.88	gold quality
sural nerve	UBERON:0015488	97.84	gold quality
nipple	UBERON:0002030	97.76	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.09	gold quality
endothelial cell	CL:0000115	96.94	gold quality
entorhinal cortex	UBERON:0002728	96.94	gold quality
cerebellar vermis	UBERON:0004720	96.89	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.68	gold quality
left ventricle myocardium	UBERON:0006566	96.57	gold quality
tendon	UBERON:0000043	96.40	gold quality
frontal cortex	UBERON:0001870	96.29	gold quality
frontal lobe	UBERON:0016525	96.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.11	gold quality
neocortex	UBERON:0001950	95.96	gold quality
prefrontal cortex	UBERON:0000451	95.86	gold quality
upper leg skin	UBERON:0004262	95.81	gold quality
cortical plate	UBERON:0005343	95.79	gold quality
cerebral cortex	UBERON:0000956	95.39	gold quality
right frontal lobe	UBERON:0002810	95.38	gold quality
bone marrow cell	CL:0002092	95.34	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-76312	yes	1328.29
E-HCAD-25	yes	83.92
E-ANND-3	yes	22.73
E-CURD-88	yes	14.31
E-GEOD-93593	yes	10.23

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
SREBF1	Repression
SREBF2	Repression

Upstream regulators (CollecTRI, top): JUN, MYC, NRF1, TAL1, TP53, ZNF143

miRNA regulators (miRDB)

204 targeting FBXW7, 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-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939

Literature-anchored findings (GeneRIF, showing 40)

• associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro (PMID:11533444)
• Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend the potential options for therapeutic targeting of kinases in the treatment of phenotypically distinct pancreatic adenocarcinoma subsets. (PMID:14507635)
• antagonizes the apoptotic c-Jun-dependent effector arm of JNK signaling, allowing neurons to tolerate potentially neurotoxic JNK activity (PMID:14739463)
• hCdc4 function is a prerequisite for cell cycle regulation of cyclin E levels, and loss of hCdc4 function is sufficient to deregulate cyclin E in cancer. (PMID:14871801)
• genetic inactivation of hCDC4, by means of targeted disruption of the gene in karyotypically stable colorectal cancer cells, results in a striking phenotype associated with micronuclei and chromosomal instability (PMID:14999283)
• Results show that the F-box protein Fbw7 interacts with and destabilizes c-Myc in a manner dependent on phosphorylation of its MB1 domain. (PMID:15103331)
• Because Fbw7 mediates the degradation of cyclin E, Notch, and c-Jun, as well as c-Myc, the loss of Fbw7 is likely to elicit profound effects on cell proliferation during tumorigenesis. (PMID:15150404)
• The observed cyclin E deregulation is attributed to the downregulation of Fbxw7, which encodes the Fbw7 receptor subunit of the SCF(FBW7) ubiquitin ligase (E3) responsible for targeting cyclin E for proteolysis. (PMID:15467469)
• Fbw7gamma regulates c-Myc’s growth-promoting function in the nucleolus. (PMID:15498494)
• SV40 large T antigen competes with cellular proteins for Fbw7 binding in a substrate-like fashion (PMID:15611062)
• The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4 (PMID:15611062)
• Fbw7 may be a major regulator of lipid metabolism through control of the phosphorylation-dependent degradation of the sterol regulatory element binding protein family of transcription factors. (PMID:16054087)
• These results identify glycogen synthase kinase 3beta and FBW7 as potential cancer therapeutic targets and MYC as a critical substrate in the GSK3beta survival-signaling pathway. (PMID:16210249)
• Fbxw7 seems to regulate the levels of multiple targets to suppress cancer development. (PMID:16863506)
• We conclude that somatic hCDC4 mutations are infrequent in osteosarcoma, and are unlikely to play an important role in aneuploidy of this tumor. (PMID:16938571)
• highly suppressed mRNA expression of the FBXW7 beta-form was found in all the human glioma cell lines analyzed; enhanced expressions of CCNE1, MYC, and AURKA were observed in these cells. (PMID:17274947)
• mutations were present in only five (11.4%) of cases of primary ovarian cancer; low frequency of these mutations suggests that they are unlikely to play an important role in human ovarian tumorigenesis (PMID:17320938)
• FBXW7 deficiency is unlikely to contribute to the extensive copy number aberrations associated with breast and possibly other tumor types (PMID:17588203)
• FBW7 is a novel tumor suppressor in T cell leukemia, and its loss may be a potential mechanism of drug resistance in T-ALL (PMID:17646408)
• FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors (PMID:17646409)
• Usp28 dissociates from Fbw7alpha in response to UV irradiation, providing a mechanism how Fbw7-mediated degradation of Myc is enhanced upon DNA damage. (PMID:17873522)
• FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of approximately 6%. (PMID:17909001)
• There were no mutations in exons 8 or 9 in 160 acute leukemia samples from Korea, in contrast to earlier reports suggesting a role in T-ALL. (PMID:17992009)
• FBW7 has a role in the development of cancer (PMID:18094723)
• Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy. (PMID:18391985)
• Both SCF(Cdc4alpha) and SCF(Cdc4gamma) are required for cyclin E turnover in cell lines that do not overexpress cyclin E. (PMID:18414042)
• could not confirm that hCDC4 is frequently mutated in colon cancers. (PMID:18428053)
• FBXW7 mutation is associated with adult T-cell and B-cell acute lymphocytic leukemias (PMID:18485478)
• summarize what is known about Fbxw7/hCdc4-mediated degradation in the regulation of cellular proliferation and discuss how alteration of its function contributes to human tumorigenesis (PMID:18541364)
• These data suggest that oscillations in cyclin E-CDK2-specific activity during the cell cycle regulate the timing of cyclin E degradation. (PMID:18559665)
• NPM regulates turnover of the c-Myc oncoprotein by acting on the F-box protein Fbw7gamma, a component of the E3 ligase complex involved in the ubiquitination and proteasome degradation of c-Myc.[Fbw7gamma] (PMID:18625840)
• Fbxw7, the F-box protein of an SCF complex, targets c-Myb for degradation in a Wnt-1- and NLK-dependent manner. (PMID:18765672)
• p18-Cyclin E by the Skp1-Cul1-Fbw7 (SCF) complex and its interaction with the Fbw7 protein isoforms can take place independently of phosphorylation of p18-Cyclin E at a C-terminal phosphodegron. (PMID:18784078)
• findings show mTOR is targeted for ubiquitination & degradation by binding to FBXW7; breast cancer cell lines & primary tumors showed a reciprocal relation between loss of FBXW7 & deletion or mutation of PTEN, which also activates mTOR (PMID:18787170)
• The inactivation of the FBXW7 beta-form plays an important role in the pathogenesis of gliomas;an unknown mechanism(s) other than mutation and methylation is the major cause of the suppression of the FBXW7 beta-form in gliomas. (PMID:18931460)
• A significantly high frequency of methylation in the FBXW7 beta-form promoter was observed in types B1 or higher human thymomas. (PMID:18938137)
• Since SCF(Fbxw7/hCdc4) is functionally inactivated in several cancer types, alteration of this molecular pathway could contribute to the deregulation of cyclin E2 in tumorigenesis. (PMID:19084516)
• demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-cell acute lymphoblastic leukemia (PMID:19109228)
• In T-ALL, FBW7 mutations in addition to prior Notch1 mutations further augmented reporter gene activity & increased median transcripts for NOTCH1 target genes (HES1, DELTEX1 and cMYC) and downstream chemotherapy-related genes. (PMID:19340001)
• Gastric cancer patients who had low FBXW7 expression levels and p53 mutation had a distinctively poor prognosis in comparison with other subgroups (PMID:19366810)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxw7	ENSDARG00000060994
mus_musculus	Fbxw7	ENSMUSG00000028086
rattus_norvegicus	Fbxw7	ENSRNOG00000010889
drosophila_melanogaster	ago	FBGN0041171

Paralogs (14): WDR54 (ENSG00000005448), FBXW11 (ENSG00000072803), TRAF7 (ENSG00000131653), FBXW9 (ENSG00000132004), FBXO36 (ENSG00000153832), WDR64 (ENSG00000162843), FBXW12 (ENSG00000164049), BTRC (ENSG00000166167), WDR49 (ENSG00000174776), FBXW8 (ENSG00000174989), PAAF1 (ENSG00000175575), WDR86 (ENSG00000187260), FBXO16 (ENSG00000214050), EFCAB8 (ENSG00000215529)

Protein

Protein identifiers

F-box/WD repeat-containing protein 7 — Q969H0 (reviewed: Q969H0)

Alternative names: Archipelago homolog, F-box and WD-40 domain-containing protein 7, F-box protein FBX30, SEL-10, hCdc4

All UniProt accessions (9): Q969H0, A0A994J3P3, A0A994J3V4, A0A994J497, A0A994J6F2, A0A994J6T8, G0Z2K0, S4R3N3, S4R3U4

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter brings them to the SCF complex for ubiquitination. Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, MLST8, RICTOR, and probably PSEN1. Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation. Involved in bone homeostasis and negative regulation of osteoclast differentiation. Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination. Also able to promote ‘Lys-63’-linked ubiquitination in response to DNA damage. The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and ‘Lys-63’-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining.

Subunit / interactions. Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation. Component of the SCF(FBXW7) complex consisting of CUL1, RBX1, SKP1 and FBXW7. Interacts (via F-box domain) with SKP1. Interacts (via F-box domain) with pseudophosphatase STYX; the interaction is direct and prevents FBXW7 interaction with SKP1. Interacts with cyclin-E (CCNE1 or CCNE2). Interacts with PSEN1. Forms a trimeric complex with NOTCH1 and SGK1. Interacts with NOTCH1 intracellular domain/NICD and NOTCH4 intracellular domain/NICD. Interacts with NOTCH2 intracellular domain (N2ICD). Interacts with MYC (when phosphorylated). Interacts with USP28, counteracting ubiquitination of MYC. Interacts with JUN. Found in a complex with JUN and PRR7. Interacts with JUN and PRR7; the interaction inhibits ubiquitination-mediated JUN degradation, promoting its phosphorylation and transcriptional activity. Interacts (when phosphorylated at Thr-205) with PIN1, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation. Interacts with UBE2QL1. Interacts with FAM83D; promotes FBXW7 degradation. Interacts with MYCN; FBXW7 competes with AURKA for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN. Interacts with STOML1. Interacts with NFE2L1. Interacts with USP36, counteracting ubiquitination of MYC. Interacts with NR1D1. Interacts with RICTOR; mediates RICTOR ubiquitination and degradation. Interacts with USP38, counteracting ubiquitination of MYC. (Microbial infection) Interacts (via WD repeats) with SV40 large T antigen (via CPD region).

Subcellular location. Nucleus. Nucleoplasm. Chromosome Cytoplasm Nucleus. Nucleolus.

Tissue specificity. Widely expressed. Expressed in brain.

Post-translational modifications. Phosphorylation at Thr-205 promotes interaction with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation. Phosphorylated by ATM at Ser-26 in response to DNA damage, promoting recruitment to DNA damage sites and ‘Lys-63’-linked ubiquitination of phosphorylated XRCC4. Ubiquitinated: autoubiquitinates following phosphorylation at Thr-205 and subsequent interaction with PIN1. Ubiquitination leads to its proteasomal degradation.

Disease relevance. Developmental delay, hypotonia, and impaired language (DEDHIL) [MIM:620012] An autosomal dominant neurodevelopmental disorder characterized by global developmental delay, borderline to severe intellectual disability, language difficulties, hypotonia, and gastrointestinal problems. Brain imaging shows variable structural abnormalities affecting the cerebellum, corpus collosum, and white matter. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The WD repeats mediate interaction with substrates of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. The F-box domain mediates interaction with SKP1.

Pathway. Protein modification; protein ubiquitination.

Isoforms (3)

UniProt ID	Names	Canonical?
Q969H0-1	1, Archipelago alpha, FBW7alpha, 110K, common	yes
Q969H0-2	2, Archipelago beta, FBW7beta, 69K
Q969H0-4	3, Archipelago gamma, FBW7gamma, Hippocampal

RefSeq proteins (5): NP_001013433, NP_001243998, NP_001336727, NP_060785, NP_361014 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR001810	F-box_dom	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR020472	WD40_PAC1	Repeat
IPR036047	F-box-like_dom_sf	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Pfam: PF00400, PF12937

UniProt features (111 total): strand 33, sequence variant 30, helix 8, turn 7, repeat 7, mutagenesis site 7, sequence conflict 5, compositionally biased region 4, splice variant 4, modified residue 3, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2OVR	X-RAY DIFFRACTION	2.5
5IBK	X-RAY DIFFRACTION	2.5
7T1Y	X-RAY DIFFRACTION	2.55
2OVQ	X-RAY DIFFRACTION	2.6
5V4B	X-RAY DIFFRACTION	2.6
7T1Z	X-RAY DIFFRACTION	2.77
2OVP	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969H0-F1	77.16	0.60

Functional residue map

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

Post-translational modifications (3): 26, 205, 227

Mutagenesis-validated functional residues (7):

Position	Phenotype
26	abolished phosphorylation by atm.
72	does not affect phosphorylation by atm.
159	does not affect interaction with pin1.
205	impaired interaction with pin1.
252–257	prevents homodimerization.
349	does not affect interaction with pin1.
372	does not affect interaction with pin1.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-390471	Association of TriC/CCT with target proteins during biosynthesis
R-HSA-8951664	Neddylation
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2644607	Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-9604323	Negative regulation of NOTCH4 signaling

MSigDB gene sets: 594 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_CIRCADIAN_RHYTHM, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_SIGNALING_BY_NOTCH, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_LIPID_STORAGE, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, FREAC2_01, MODY_HIPPOCAMPUS_POSTNATAL

GO Biological Process (36): vasculature development (GO:0001944), DNA repair (GO:0006281), DNA damage response (GO:0006974), sister chromatid cohesion (GO:0007062), negative regulation of gene expression (GO:0010629), negative regulation of triglyceride biosynthetic process (GO:0010868), regulation of lipid storage (GO:0010883), ubiquitin recycling (GO:0010992), protein ubiquitination (GO:0016567), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), positive regulation of protein ubiquitination (GO:0031398), regulation of protein localization (GO:0032880), cellular response to UV (GO:0034644), regulation of circadian rhythm (GO:0042752), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742), negative regulation of Notch signaling pathway (GO:0045746), rhythmic process (GO:0048511), protein stabilization (GO:0050821), lipid homeostasis (GO:0055088), positive regulation of ERK1 and ERK2 cascade (GO:0070374), regulation of mitophagy (GO:1901524), positive regulation of proteasomal protein catabolic process (GO:1901800), regulation of cell cycle G1/S phase transition (GO:1902806), positive regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway (GO:1903378), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), negative regulation of hepatocyte proliferation (GO:2000346), negative regulation of SREBP signaling pathway (GO:2000639), negative regulation of osteoclast development (GO:2001205), G1/S transition of mitotic cell cycle (GO:0000082), regulation of mitotic cell cycle (GO:0007346), regulation of protein stability (GO:0031647), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of ubiquitin-dependent protein catabolic process (GO:2000059)

GO Molecular Function (9): cyclin binding (GO:0030332), protein-macromolecule adaptor activity (GO:0030674), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), ubiquitin binding (GO:0043130), phosphothreonine residue binding (GO:0050816), ubiquitin-protein transferase activator activity (GO:0097027), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), protein-containing complex (GO:0032991), Parkin-FBXW7-Cul1 ubiquitin ligase complex (GO:1990452), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Chaperonin-mediated protein folding	1
Post-translational protein modification	1
Class I MHC mediated antigen processing & presentation	1
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
FBXW7 Mutants and NOTCH1 in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH4	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	3
nuclear lumen	2
intracellular membraneless organelle	2
system development	1
circulatory system development	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
cell cycle process	1
chromosome organization	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
regulation of triglyceride biosynthetic process	1
triglyceride biosynthetic process	1
negative regulation of lipid biosynthetic process	1
negative regulation of triglyceride metabolic process	1
lipid storage	1
regulation of cellular process	1
cellular homeostasis	1
protein modification by small protein conjugation	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
intracellular protein localization	1
regulation of localization	1
response to UV	1
cellular response to light stimulus	1
circadian rhythm	1
regulation of biological process	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
positive regulation of ERBB signaling pathway	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1

Protein interactions and networks

STRING

4684 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXW7	SKP1	P34991	997
FBXW7	CUL1	Q13616	997
FBXW7	FLI1	Q01543	995
FBXW7	RBX1	P62877	994
FBXW7	JUN	P05412	982
FBXW7	USP28	Q96RU2	952
FBXW7	MYC	P01106	935
FBXW7	SKP2	Q13309	915
FBXW7	CDC34	P49427	908
FBXW7	CTNNB1	P35222	898
FBXW7	NOTCH1	P46531	885
FBXW7	PIK3CA	P42336	845
FBXW7	TP53	P04637	842
FBXW7	PTEN	P60484	830
FBXW7	BTRC	Q9Y297	792

IntAct

1426 interactions, top by confidence:

A	B	Type	Score
MYC	MAX	psi-mi:“MI:0914”(association)	0.980
FBXW7	CUL1	psi-mi:“MI:0915”(physical association)	0.920
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
FBXW7	NOTCH1	psi-mi:“MI:0914”(association)	0.880
FBXW7	NOTCH1	psi-mi:“MI:0407”(direct interaction)	0.880
FBXW7	NOTCH1	psi-mi:“MI:0915”(physical association)	0.880
NOTCH1	FBXW7	psi-mi:“MI:0915”(physical association)	0.880
FBXW7	MYC	psi-mi:“MI:0915”(physical association)	0.870
FBXW7	MYC	psi-mi:“MI:0914”(association)	0.870
FBXW7	SKP1	psi-mi:“MI:0914”(association)	0.860
FBXW7	SKP1	psi-mi:“MI:0915”(physical association)	0.860
FBXW7	SKP1	psi-mi:“MI:0407”(direct interaction)	0.860
STYX	FBXW7	psi-mi:“MI:0915”(physical association)	0.760
STYX	FBXW7	psi-mi:“MI:0407”(direct interaction)	0.760
TRAF2	HTRA2	psi-mi:“MI:0914”(association)	0.750
MED28	MED19	psi-mi:“MI:0914”(association)	0.730
FBXW7	CCNE1	psi-mi:“MI:2364”(proximity)	0.680
RELB	NFKBIE	psi-mi:“MI:0914”(association)	0.670

BioGRID (1846): CUL1 (Affinity Capture-Western), FBXW7 (Biochemical Activity), CCNE1 (Biochemical Activity), FBXW7 (Reconstituted Complex), FBXW7 (Biochemical Activity), MCL1 (Biochemical Activity), FBXW7 (Affinity Capture-RNA), FBXW7 (Affinity Capture-RNA), CCNE1 (Reconstituted Complex), USP36 (Affinity Capture-Western), FBXW7 (Affinity Capture-Western), SNCA (Affinity Capture-Western), NOTCH1 (Affinity Capture-Western), MED13 (Affinity Capture-Western), MED13 (Affinity Capture-MS)

ESM2 similar proteins: A5E2R6, A8PWQ8, A9VDW7, B3NXQ7, B4GXH4, B4JWS7, B4PYR0, C4YBE4, C5DF48, D3Z902, F1MNN4, O17468, O62305, O94394, P0C1J0, P0CS38, P0CS39, P26309, P39706, P53621, P87053, P87314, Q09589, Q10990, Q15291, Q24371, Q27954, Q39190, Q3UMY5, Q4P5F5, Q52T38, Q5XUX1, Q61FW2, Q652L2, Q6CXX3, Q6NL34, Q74ZN0, Q75E60, Q8BX09, Q8CIE6

Diamond homologs: A1C7E4, A1CF18, A1CUD6, A1DP19, A2QP30, A4R3M4, A7EKM8, A7S338, A8NEG8, A8XZJ9, A9V790, B0LSW3, B0XM00, B2AEZ5, B2B766, B2VWG7, B3MEY6, B3NPW0, B3S4I5, B4GAJ1, B4HSL3, B4JWA1, B4KT48, B4LQ21, B4MY65, B4P6P9, B4QHG6, B5X3C4, B5X3Z6, B6GZD3, B6HP56, B6QC06, B6QC56, B7FNU7, B7PS00, B8M0Q1, B8N9H4, B8NGT5, B8P4B0, B8PD53

SIGNOR signaling

32 interactions.

A	Effect	B	Mechanism
FBXW7	down-regulates	NOTCH4	ubiquitination
FBXW7	“down-regulates quantity by destabilization”	NOTCH1	ubiquitination
SGK1	up-regulates	FBXW7	phosphorylation
PLK2	down-regulates	FBXW7	phosphorylation
FBXW7	down-regulates	CCDC6	binding
FBXW7	“down-regulates quantity”	MYC	ubiquitination
FBXW7	“form complex”	SCF-FBW7	binding
FBXW7	“down-regulates quantity by destabilization”	MYC	ubiquitination
STYX	“down-regulates activity”	FBXW7	binding
FBXW7	“down-regulates quantity by destabilization”	NOTCH	ubiquitination
FBXW7	“down-regulates quantity by destabilization”	DAB2IP	ubiquitination
FBXW7	“down-regulates quantity by destabilization”	GATA2	ubiquitination
ATM	“up-regulates activity”	FBXW7	phosphorylation
FBXW7	“down-regulates quantity by destabilization”	EGLN2	ubiquitination
FBXW7	“down-regulates quantity by destabilization”	ZNF322	ubiquitination
FBXW7	“down-regulates quantity by destabilization”	MED13L	ubiquitination
FBXW7	“down-regulates quantity by destabilization”	MED13	ubiquitination
FBXW7	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding
FBXW7	“down-regulates quantity by destabilization”	CCNE2	binding
FBXW7	“down-regulates quantity by destabilization”	CCNE1	binding
FBXW7	“down-regulates quantity by destabilization”	PSEN1	binding
FBXW7	“down-regulates quantity by destabilization”	JUN	binding
AKT1	“up-regulates activity”	FBXW7	phosphorylation
FBXW7	“down-regulates quantity by destabilization”	GATA3	ubiquitination
PRKCA	“down-regulates activity”	FBXW7	phosphorylation
PRKCI	“down-regulates activity”	FBXW7	phosphorylation
TRIM25	“down-regulates activity”	FBXW7	ubiquitination
NPM1	“up-regulates quantity”	FBXW7	binding
FBXW7	“down-regulates quantity by destabilization”	NFKB2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 175 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
Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)	9	36.4×	2e-10
TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest	6	27.3×	4e-06
G1 Phase	9	22.6×	2e-08
Signaling by ERBB2 ECD mutants	5	21.4×	8e-05
Signaling by ERBB2 TMD/JMD mutants	7	21.2×	2e-06
Transcription of E2F targets under negative control by DREAM complex	6	20.8×	1e-05
Cyclin A:Cdk2-associated events at S phase entry	12	20.3×	1e-10
GRB2 events in ERBB2 signaling	5	20.2×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
embryonic placenta development	6	27.0×	7e-06
negative regulation of stem cell differentiation	5	24.8×	1e-04
positive regulation of peptidyl-serine phosphorylation	5	22.5×	1e-04
positive regulation of erythrocyte differentiation	7	21.0×	4e-06
positive regulation of G1/S transition of mitotic cell cycle	8	18.9×	1e-06
mitotic G2 DNA damage checkpoint signaling	7	18.3×	9e-06
G1/S transition of mitotic cell cycle	15	17.7×	3e-12
cellular response to gamma radiation	5	17.7×	4e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 22 cancer types — ANSC, BLCA, BRCA, CEAD, CESC, CHOL, CLLSLL, COAD, COADREAD, ESCA, HNSC, LUAD…(+10 more).

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	17
Uncertain significance	134
Likely benign	55
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
155492	GRCh38/hg38 4q28.3-35.2(chr4:134935616-190036318)x3	Pathogenic
1684078	NM_001349798.2(FBXW7):c.1177C>T (p.Arg393Ter)	Pathogenic
1702997	NM_001349798.2(FBXW7):c.1713_1714del (p.Asn572fs)	Pathogenic
1702998	NM_001349798.2(FBXW7):c.1267G>A (p.Gly423Arg)	Pathogenic
1702999	NM_001349798.2(FBXW7):c.2066G>A (p.Arg689Gln)	Pathogenic
1703001	NM_001349798.2(FBXW7):c.2020C>T (p.Arg674Trp)	Pathogenic
1722937	NM_001349798.2(FBXW7):c.670C>T (p.Arg224Ter)	Pathogenic
2584429	NM_001349798.2(FBXW7):c.1855+1G>C	Pathogenic
2681279	NM_001349798.2(FBXW7):c.803T>A (p.Met268Lys)	Pathogenic
3377097	NM_001349798.2(FBXW7):c.1331_1332del (p.Lys444fs)	Pathogenic
3630384	NM_001349798.2(FBXW7):c.981_985del (p.Glu328fs)	Pathogenic
3722731	NM_001349798.2(FBXW7):c.802_803del (p.Met268fs)	Pathogenic
376414	NM_001349798.2(FBXW7):c.1393C>T (p.Arg465Cys)	Pathogenic
998140	NM_001349798.2(FBXW7):c.256del (p.Ser86fs)	Pathogenic
1698991	NM_001349798.2(FBXW7):c.1877C>T (p.Ala626Val)	Likely pathogenic
1701892	NM_001349798.2(FBXW7):c.832C>T (p.Arg278Ter)	Likely pathogenic
1701898	NM_001349798.2(FBXW7):c.1939A>T (p.Lys647Ter)	Likely pathogenic
1703000	NM_001349798.2(FBXW7):c.1439A>G (p.Asp480Gly)	Likely pathogenic
1800495	NM_001349798.2(FBXW7):c.1259A>T (p.His420Leu)	Likely pathogenic
2626983	NM_001349798.2(FBXW7):c.1315A>G (p.Thr439Ala)	Likely pathogenic
2632735	NM_001349798.2(FBXW7):c.1793A>T (p.Asn598Ile)	Likely pathogenic
3061317	NM_001349798.2(FBXW7):c.1044_1045del (p.His348fs)	Likely pathogenic
3068110	NM_001349798.2(FBXW7):c.471_472insCTCC (p.Ser158fs)	Likely pathogenic
3093874	NM_001349798.2(FBXW7):c.1433C>T (p.Ser478Phe)	Likely pathogenic
3235824	NM_001349798.2(FBXW7):c.915_918dup (p.Thr307fs)	Likely pathogenic
3255132	NM_001349798.2(FBXW7):c.1919del (p.Ser640fs)	Likely pathogenic
3337271	NM_001349798.2(FBXW7):c.1944_1945del (p.Trp649fs)	Likely pathogenic
3384084	NM_001349798.2(FBXW7):c.1989_1990del (p.Ser665fs)	Likely pathogenic
4293972	NM_001349798.2(FBXW7):c.1149_1152dup (p.Thr385fs)	Likely pathogenic
4755465	NM_001349798.2(FBXW7):c.502-2450C>T	Likely pathogenic

SpliceAI

3519 predictions. Top by Δscore:

Variant	Effect	Δscore
4:152323148:ACCTA:A	acceptor_loss	1.0000
4:152323149:CCT:C	acceptor_loss	1.0000
4:152323150:C:CC	acceptor_gain	1.0000
4:152324390:TCAAA:T	acceptor_gain	1.0000
4:152324391:CAAA:C	acceptor_gain	1.0000
4:152324391:CAAAC:C	acceptor_gain	1.0000
4:152324395:C:CC	acceptor_gain	1.0000
4:152328202:CCTTA:C	donor_loss	1.0000
4:152328204:TTACC:T	donor_loss	1.0000
4:152328205:TA:T	donor_loss	1.0000
4:152328206:A:C	donor_loss	1.0000
4:152328207:C:A	donor_loss	1.0000
4:152328388:CA:C	acceptor_gain	1.0000
4:152328390:C:CC	acceptor_gain	1.0000
4:152329665:AACTT:A	donor_loss	1.0000
4:152329666:ACTTA:A	donor_loss	1.0000
4:152329667:CTTAC:C	donor_loss	1.0000
4:152329668:TTACT:T	donor_loss	1.0000
4:152329669:TA:T	donor_loss	1.0000
4:152329670:A:AC	donor_gain	1.0000
4:152329670:ACTT:A	donor_loss	1.0000
4:152329671:C:CT	donor_gain	1.0000
4:152329671:CTTTG:C	donor_gain	1.0000
4:152329783:CAC:C	acceptor_gain	1.0000
4:152329786:C:CC	acceptor_gain	1.0000
4:152329786:CTATA:C	acceptor_loss	1.0000
4:152332590:CCTTA:C	donor_loss	1.0000
4:152332591:CTTA:C	donor_loss	1.0000
4:152332592:TTAC:T	donor_loss	1.0000
4:152332593:TAC:T	donor_loss	1.0000

AlphaMissense

4666 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:152322899:A:C	F702L	1.000
4:152322899:A:T	F702L	1.000
4:152322900:A:G	F702S	1.000
4:152322901:A:G	F702L	1.000
4:152322906:A:G	L700P	1.000
4:152322912:A:G	L698P	1.000
4:152322915:A:C	L697R	1.000
4:152322915:A:G	L697P	1.000
4:152322915:A:T	L697Q	1.000
4:152322921:G:A	T695I	1.000
4:152322926:T:A	E693D	1.000
4:152322926:T:G	E693D	1.000
4:152322933:C:T	G691E	1.000
4:152322934:C:A	G691W	1.000
4:152322935:A:C	N690K	1.000
4:152322935:A:T	N690K	1.000
4:152322939:C:G	R689P	1.000
4:152322940:G:C	R689G	1.000
4:152322941:A:C	S688R	1.000
4:152322941:A:T	S688R	1.000
4:152322942:C:A	S688I	1.000
4:152322943:T:G	S688R	1.000
4:152322945:C:A	G687V	1.000
4:152322945:C:T	G687E	1.000
4:152322946:C:A	G687W	1.000
4:152322946:C:G	G687R	1.000
4:152322946:C:T	G687R	1.000
4:152322948:A:T	V686D	1.000
4:152322951:G:T	A685E	1.000
4:152322952:C:G	A685P	1.000

dbSNP variants (sampled 300 via entrez): RS1000003948 (4:152422904 C>G), RS1000046286 (4:152385477 C>A), RS1000047645 (4:152338075 T>G), RS1000050928 (4:152464513 G>C), RS1000056442 (4:152507653 G>A,C), RS1000061034 (4:152514385 A>G), RS1000070722 (4:152514091 A>G), RS1000104480 (4:152495385 G>A), RS1000142655 (4:152397025 G>A), RS1000159863 (4:152344268 T>A,C), RS1000163673 (4:152410665 T>C,G), RS1000214561 (4:152494013 G>C), RS1000229746 (4:152344995 C>T), RS1000233466 (4:152490275 T>C,G), RS1000252667 (4:152447008 A>C,T)

Disease associations

OMIM: gene MIM:606278 | disease phenotypes: MIM:620012, MIM:114500

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental delay, hypotonia, and impaired language	Strong	Autosomal dominant

Mondo (4): developmental delay, hypotonia, and impaired language (MONDO:0859280), neurodevelopmental disorder (MONDO:0700092), pervasive developmental disorder (MONDO:0000594), colorectal cancer (MONDO:0005575)

Orphanet (2): Rare pervasive developmental disorder (Orphanet:168778), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000410	Mixed hearing impairment
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001875	Decreased total neutrophil count
HP:0002019	Constipation
HP:0002020	Gastroesophageal reflux
HP:0002376	Developmental regression
HP:0006532	Recurrent pneumonia
HP:0008751	Laryngeal cleft
HP:0011968	Feeding difficulties
HP:0012443	Abnormal brain morphology
HP:0100704	Cerebral visual impairment

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002381_212	Eosinophil count	4.000000e-19
GCST90002382_103	Eosinophil percentage of white cells	1.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002659	Child Development Disorders, Pervasive	F03.625.164
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 4 predictive associations from 4 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
FBXW7 Mutation	MTOR Inhibitor	Cancer	Sensitivity/Response	CIViC B	EID1631
FBXW7 Mutation	Panitumumab + Cetuximab	Colorectal Cancer	Resistance	CIViC B	EID718
FBXW7 Loss-of-function	Sirolimus	Cancer	Sensitivity/Response	CIViC D	EID1632
FBXW7 Loss-of-function	Everolimus	Renal Cell Carcinoma	Sensitivity/Response	CIViC E	EID1628

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
Aflatoxin B1	affects expression, decreases methylation, increases expression, increases methylation	4
Arsenic Trioxide	affects binding, affects reaction, decreases expression, increases reaction, increases expression	3
Formaldehyde	decreases expression, increases expression	2
Ozone	increases abundance, increases expression, increases oxidation, affects expression	2
Tobacco Smoke Pollution	increases expression	2
Tretinoin	decreases expression, increases reaction, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
trichostatin A	affects expression	1
dimethylselenide	increases expression, increases oxidation	1
arsenite	increases expression, increases cleavage, increases reaction, increases response to substance	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	increases abundance, increases expression	1
periodate-oxidized adenosine	affects expression	1
nickel sulfate	affects reaction, increases degradation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
1,25-dihydroxyvitamin D	increases degradation, affects reaction, decreases degradation, increases expression, decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
SB 216763	decreases reaction, increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
MRK 003	decreases response to substance	1
jinfukang	decreases expression	1
MT19c compound	increases expression	1

Cellosaurus cell lines

672 cell lines: 671 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0065	Jurkat	Cancer cell line	Male
CVCL_0138	ACH-2	Cancer cell line	Female
CVCL_0207	CCRF-CEM	Cancer cell line	Female
CVCL_0289	HCA7	Cancer cell line	Female
CVCL_0354	J.CaM1.6	Cancer cell line	Male
CVCL_0367	Jurkat E6.1	Cancer cell line	Male
CVCL_0399	LoVo	Cancer cell line	Male
CVCL_0420	MDAH 2774	Cancer cell line	Female
CVCL_0532	SK-OV-3	Cancer cell line	Female
CVCL_0584	Jurkat Wurzburg	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
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