PMAIP1

Summary

PMAIP1 (phorbol-12-myristate-13-acetate-induced protein 1, HGNC:9108) is a protein-coding gene on chromosome 18q21.32, encoding Phorbol-12-myristate-13-acetate-induced protein 1 (Q13794). Promotes activation of caspases and apoptosis.

This gene belongs to a pro-apoptotic subfamily within the BCL-2 protein family, referred to as the BCL-2 homology domain 3 (BH3)-only subfamily, which determine whether a cell commits to apoptosis. In response to death-inducing stimuli, BH3-only members inhibit the anti-apoptotic BCL-2 family members, which under steady-state conditions keep the multi-BH domain proteins BAX and BAK, in an inactive state.

Source: NCBI Gene 5366 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 5 total
• Druggable target: yes
• MANE Select transcript: NM_021127

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9108
Approved symbol	PMAIP1
Name	phorbol-12-myristate-13-acetate-induced protein 1
Location	18q21.32
Locus type	gene with protein product
Status	Approved
Aliases	APR, NOXA
Ensembl gene	ENSG00000141682
Ensembl biotype	protein_coding
OMIM	604959
Entrez	5366

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000269518, ENST00000316660, ENST00000590596, ENST00000919087

RefSeq mRNA: 6 — MANE Select: NM_021127 NM_001382615, NM_001382616, NM_001382617, NM_001382618, NM_001382623, NM_021127

CCDS: CCDS11975, CCDS92468

Canonical transcript exons

ENST00000316660 — 2 exons

Exon	Start	End
ENSE00001558981	59899996	59900235
ENSE00001711735	59902647	59904305

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 94.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.8111 / max 3751.5799, expressed in 1750 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
170478	60.8111	1750

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	94.29	gold quality
cartilage tissue	UBERON:0002418	93.85	gold quality
oral cavity	UBERON:0000167	93.76	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.50	gold quality
cervix squamous epithelium	UBERON:0006922	93.25	gold quality
monocyte	CL:0000576	93.01	gold quality
mononuclear cell	CL:0000842	92.47	gold quality
cervix epithelium	UBERON:0004801	92.19	gold quality
upper leg skin	UBERON:0004262	91.94	gold quality
leukocyte	CL:0000738	91.86	gold quality
nipple	UBERON:0002030	91.22	gold quality
esophagus squamous epithelium	UBERON:0006920	90.96	gold quality
squamous epithelium	UBERON:0006914	89.99	gold quality
oviduct epithelium	UBERON:0004804	89.18	gold quality
penis	UBERON:0000989	88.72	gold quality
bone marrow	UBERON:0002371	88.48	gold quality
epithelium of esophagus	UBERON:0001976	87.87	gold quality
palpebral conjunctiva	UBERON:0001812	87.35	gold quality
mucosa of paranasal sinus	UBERON:0005030	86.51	gold quality
pharyngeal mucosa	UBERON:0000355	86.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.39	gold quality
bone marrow cell	CL:0002092	86.17	gold quality
skin of abdomen	UBERON:0001416	86.04	gold quality
amniotic fluid	UBERON:0000173	85.97	gold quality
gingiva	UBERON:0001828	85.18	gold quality
lower esophagus mucosa	UBERON:0035834	84.78	gold quality
esophagus mucosa	UBERON:0002469	83.70	gold quality
stromal cell of endometrium	CL:0002255	83.27	gold quality
gingival epithelium	UBERON:0001949	83.07	gold quality
tongue squamous epithelium	UBERON:0006919	83.07	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-7606	yes	2338.78
E-GEOD-106540	yes	1959.61
E-MTAB-8142	yes	1784.14
E-GEOD-111727	yes	1108.01
E-MTAB-9388	yes	662.00
E-MTAB-8530	yes	654.37
E-HCAD-4	yes	48.26
E-CURD-120	yes	43.62
E-MTAB-8410	yes	22.58
E-CURD-46	yes	16.09
E-HCAD-10	yes	13.51
E-MTAB-8498	yes	9.19
E-CURD-89	no	3259.87
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ATF3, ATF4, ATM, BAX, E2F1, ESR1, FOXC1, FOXO1, FUBP1, HIF1A, IRF1, IRF3, IRF4, IRF7, KLF6, KLF9, MYC, MYCN, NFKB, NR3C1, POU4F1, POU4F2, PRDM1, SP1, TP53, TP63, TP73, ZNF331

miRNA regulators (miRDB)

80 targeting PMAIP1, 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-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-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-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-8076	99.78	68.52	1170

Literature-anchored findings (GeneRIF, showing 40)

• Noxa may not be of importance in the development of colorectal cancer (PMID:12879012)
• Noxa-induced mitochondrial dysfunction has a role in p53-mediated cell death (PMID:14500711)
• Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1alpha. (PMID:14699081)
• BOK and NOXA are essential mediators of p53-dependent apoptosis (PMID:15102863)
• p53 activation is not necessary for up-regulation of NOXA in melanoma cells (PMID:15299072)
• E1A activation of p73 and the p53 apoptotic target Noxa can occur in the absence of a functional p53 (PMID:15572378)
• component of the innate immune response of cells to viral infection, leading to enhanced cellular apoptosis (PMID:15705586)
• Noxa/Mcl-1 axis is an apoptosis rheostat in dividing cells, in a selective pathway that functions to restrain lymphocyte expansion and can be triggered by glucose deprivation (PMID:16782027)
• We conclude that Noxa and Bim establish a connection between FKHRL1 and mitochondria, and that both BH3-only proteins are critically involved in FKHRL1-induced apoptosis in neuroblastoma. (PMID:16888645)
• functional eIF2alpha played an essential role in PS-341-induced Noxa expression (PMID:16928686)
• suppression of Noxa in the lymph node environment contributes to the persistence of B-CLL at these sites and suggest that therapeutic targeting of Noxa might be beneficial (PMID:17038534)
• These data demonstrate the importance of Noxa induction in determining the apoptotic response to fenretinide and emphasise the role of Noxa in p53-independent apoptosis. (PMID:17216584)
• GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. (PMID:17227835)
• Interferon gamma induces XAF1 and Noxa expression and potentiates apoptosis by STAT3 activation (PMID:18192275)
• PMAIP1 may play an important role in the progression of pancreatic cancer. (PMID:18231856)
• Noxa expression was enhanced by GSH depletion and inhibited by increasing GSH levels in the multiple myeloma cells (PMID:18354037)
• At higher concentrations of bortezomib, however, Noxa was also upregulated in resistant cells and this effect was sufficient to induce apoptosis. (PMID:18398749)
• the involvement of multiple pathways in Noxa-induced apoptosis that are triggered at mitochondria and the endoplasmic reticulum (PMID:18408751)
• Two splicing variants of the human Noxa geneare identified, which consists of three exons and two introns. Alternative splicing of exon 2 yields three transcripts. Transcript-1 joins exons 1 and 3 to encode Noxa of 54 amino acids. (PMID:18630524)
• hMTH1 plays an important role in protecting cells against H(2)O(2)-induced apoptosis via a Noxa- and caspase-3/7-mediated signaling pathway, thus conferring a survival advantage through the inhibition of oxidative-stress-induced DNA damage (PMID:18708163)
• In 12 CLL patients, the ratio of Noxa/actin band intensities increased from 2.9-fold to 40.3-fold after hyperforin treatment, compared to untreated controls, whereas this ratio did not change upon flavopiridol exposure. (PMID:18784742)
• Depletion of Noxa by short hairpin RNA protected cells from hyperthermia by preventing Mcl-1 degradation. (PMID:19148187)
• ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells (PMID:19164757)
• expression is regulated via binding with Bmi1; involved in Th2 memory cell survival (PMID:19269851)
• Therapeutic potential of proapoptotic molecule NOXA in the selective elimination of tumor cells is reported. (PMID:19298224)
• Increased Noxa Expression Results in Increased Sensitivity to ABT-737 in small cell lung cancer. (PMID:19372561)
• T(reg) cells in CLL may accumulate both by increased formation, facilitated by CD27-CD70 interaction in the lymph node proliferation centres, and decreased sensitivity to apoptosis because of a shifted Noxa-Bcl-2 balance (PMID:19452318)
• PAS may represent a novel class of drug that induces apoptosis in CLL cells independently of p53 status by a mechanism involving Noxa up-regulation. (PMID:19515722)
• Results provide novel insight into the role of Noxa in mitochondrial dynamics and cell death. (PMID:19540835)
• Data show that both Akt inhibitors decreased MCL-1 protein level, increased PUMA and NOXA protein levels, and induced apoptosis irrespective of TP53 status. (PMID:19815839)
• Data suggest that MCL1 steady-state expression levels do not affect sensitivity to proteasome-inhibitor treatment in neuronal tumor cells, and that both the repression of Bcl-xL and the activation of Noxa are necessary for bortezomib-induced cell death. (PMID:20051518)
• Data show H2O2-induced caspase-dependent apoptosis was strongly suppressed by silencing of Noxa, indicating that Noxa plays a crucial role in this form of apoptosis. (PMID:20085765)
• Glucocorticoid Response Elements (GREs) within the promoter regulatory regions of the Bcl-2 family members NOXA and Mcl-1 were identified, indicating that they are direct GR transcriptional targets. (PMID:20156337)
• results suggest that the loss/inactivation of Mcl-1 in conjunction with an induced Noxa/Bcl-xL interaction may serve as a trigger for mitochondrial dysfunction during DNA damage-induced apoptosis (PMID:20223826)
• the pro-apoptotic mechanisms orchestrated by p38(MAPK) in human keratinocytes in response to ultraviolet rays B involve an HIF-1/Noxa axis (PMID:20393480)
• These observations reveal a novel ERK-regulated route to Noxa expression that is important for the cell killing activity of platinum-based chemotherapeutic drugs. (PMID:20802529)
• Noxa RNA-interference markedly decreased sensitivity to CDDP/F-ara-A, supporting a key role for Noxa as mediator between ROS signaling and apoptosis induction. (PMID:20935673)
• Noxa participates in triggering mitochondrial dysfunction in multiple apoptotic pathways through distinct mechanisms (PMID:21113147)
• The proapoptotic function of Noxa in human leukemia cells is regulated by the kinase Cdk5 and by glucose (PMID:21145489)
• Expression of p53-inducible BH3-only apoptotic proteins Puma and Noxa was elevated and large activation of executive caspases was observed. (PMID:21153863)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pmaip1	ENSMUSG00000024521
rattus_norvegicus	Pmaip1	ENSRNOG00000018770

Protein

Protein identifiers

Phorbol-12-myristate-13-acetate-induced protein 1 — Q13794 (reviewed: Q13794)

Alternative names: Immediate-early-response protein APR, Protein Noxa

All UniProt accessions (3): A0A0S2Z490, A0A0S2Z4V2, Q13794

UniProt curated annotations — full annotation on UniProt →

Function. Promotes activation of caspases and apoptosis. Promotes mitochondrial membrane changes and efflux of apoptogenic proteins from the mitochondria. Contributes to p53/TP53-dependent apoptosis after radiation exposure. Promotes proteasomal degradation of MCL1. Competes with BAK1 for binding to MCL1 and can displace BAK1 from its binding site on MCL1. Competes with BIM/BCL2L11 for binding to MCL1 and can displace BIM/BCL2L11 from its binding site on MCL1.

Subunit / interactions. Interacts with MCL1. Interacts with BCL2A1 (Ref.11). Interacts with BAX. Interacts with BCL2L10.

Subcellular location. Mitochondrion.

Tissue specificity. Highly expressed in adult T-cell leukemia cell line.

Domain organisation. The BH3 motif is essential for pro-apoptotic activity.

Induction. Up-regulated by p53/TP53, phorbol esters, double-stranded RNA, IFNB1/IFN-beta and viruses.

Similarity. Belongs to the PMAIP1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13794-1	1	yes
Q13794-2	2

RefSeq proteins (6): NP_001369544, NP_001369545, NP_001369546, NP_001369547, NP_001369552, NP_066950* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024140	Noxa	Family

Pfam: PF15150

UniProt features (11 total): mutagenesis site 6, chain 1, region of interest 1, helix 1, short sequence motif 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3MQP	X-RAY DIFFRACTION	2.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13794-F1	82.84	0.56

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
29	reduced interaction with bax.
29	loss of interaction with mcl1 and of increased mcl1 degradation; when associated with e-32 and e-32.
32	loss of interaction with mcl1 and of increased mcl1 degradation; when associated with e-29 and e-36.
32	alters specificity of protein interaction and enhances pro-apoptotic activity; when associated with e-35.
35	alters specificity of protein interaction and enhances pro-apoptotic activity; when associated with i-32.
36	loss of interaction with mcl1 and of increased mcl1 degradation; when associated with e-29 and e-32.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-111448	Activation of NOXA and translocation to mitochondria
R-HSA-111453	BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members
R-HSA-6803204	TP53 Regulates Transcription of Genes Involved in Cytochrome C Release
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-114452	Activation of BH3-only proteins
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5357801	Programmed Cell Death
R-HSA-5633008	TP53 Regulates Transcription of Cell Death Genes
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 473 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, BROWNE_HCMV_INFECTION_4HR_UP, MODULE_97, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, YAGI_AML_WITH_INV_16_TRANSLOCATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, LU_IL4_SIGNALING, AMIT_EGF_RESPONSE_60_HELA, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_T_CELL_HOMEOSTASIS, GOBP_LYMPHOCYTE_HOMEOSTASIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (21): release of cytochrome c from mitochondria (GO:0001836), apoptotic process (GO:0006915), DNA damage response (GO:0006974), proteasomal protein catabolic process (GO:0010498), positive regulation of glucose metabolic process (GO:0010907), negative regulation of mitochondrial membrane potential (GO:0010917), cellular response to glucose starvation (GO:0042149), T cell homeostasis (GO:0043029), positive regulation of apoptotic process (GO:0043065), response to dsRNA (GO:0043331), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), regulation of mitochondrial membrane permeability (GO:0046902), defense response to virus (GO:0051607), cellular response to hypoxia (GO:0071456), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), reactive oxygen species metabolic process (GO:0072593), positive regulation of release of cytochrome c from mitochondria (GO:0090200), intrinsic apoptotic signaling pathway (GO:0097193), positive regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902043), positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902237), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), Bcl-2 family protein complex (GO:0097136)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Intrinsic Pathway for Apoptosis	2
Activation of BH3-only proteins	1
TP53 Regulates Transcription of Cell Death Genes	1
Programmed Cell Death	1
Apoptosis	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Transcriptional Regulation by TP53	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic signaling pathway	3
cellular response to stress	2
intracellular membrane-bounded organelle	2
cytoplasm	2
apoptotic mitochondrial changes	1
programmed cell death	1
execution phase of apoptosis	1
protein catabolic process	1
glucose metabolic process	1
regulation of glucose metabolic process	1
positive regulation of carbohydrate metabolic process	1
positive regulation of small molecule metabolic process	1
negative regulation of membrane potential	1
regulation of mitochondrial membrane potential	1
cellular response to starvation	1
lymphocyte homeostasis	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
response to nitrogen compound	1
DNA damage response, signal transduction by p53 class mediator	1
regulation of DNA damage response, signal transduction by p53 class mediator	1
positive regulation of signal transduction by p53 class mediator	1
regulation of membrane permeability	1
defense response	1
response to virus	1
response to hypoxia	1
cellular response to decreased oxygen levels	1
signal transduction by p53 class mediator	1
intrinsic apoptotic signaling pathway	1
metabolic process	1
release of cytochrome c from mitochondria	1
positive regulation of organelle organization	1
regulation of release of cytochrome c from mitochondria	1
intracellular signal transduction	1
extrinsic apoptotic signaling pathway via death domain receptors	1
regulation of extrinsic apoptotic signaling pathway via death domain receptors	1
positive regulation of extrinsic apoptotic signaling pathway	1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1
regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	1

Protein interactions and networks

STRING

1670 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PMAIP1	MCL1	Q07820	999
PMAIP1	BCL2L1	Q07817	998
PMAIP1	BCL2	P10415	997
PMAIP1	BCL2L2-PABPN1	Q92843	996
PMAIP1	BCL2A1	Q16548	995
PMAIP1	BCL2L11	O43521	948
PMAIP1	HRK	O00198	883
PMAIP1	TP53	P04637	880
PMAIP1	BBC3	Q96PG8	875
PMAIP1	CYCS	P00001	855
PMAIP1	BMF	Q96LC9	855
PMAIP1	BIK	Q13323	853
PMAIP1	RTL10	Q7L3V2	840
PMAIP1	BCL2L10	Q9HD36	777
PMAIP1	CASP3	P42574	721

IntAct

26 interactions, top by confidence:

A	B	Type	Score
MCL1	BCL2L11	psi-mi:“MI:0914”(association)	0.950
BCL2L11	BAX	psi-mi:“MI:0915”(physical association)	0.940
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MCL1	PMAIP1	psi-mi:“MI:0407”(direct interaction)	0.850
MCL1	PMAIP1	psi-mi:“MI:0915”(physical association)	0.850
BCL2L1	PMAIP1	psi-mi:“MI:0407”(direct interaction)	0.680
PMAIP1	BCL2L1	psi-mi:“MI:0407”(direct interaction)	0.680
BCL2L2	PMAIP1	psi-mi:“MI:0407”(direct interaction)	0.560
BCL2	PMAIP1	psi-mi:“MI:0407”(direct interaction)	0.540
PMAIP1	BCL2	psi-mi:“MI:0915”(physical association)	0.540
MCL1	PRKAG1	psi-mi:“MI:0914”(association)	0.530
PMAIP1	BCL2	psi-mi:“MI:0915”(physical association)	0.520
PMAIP1	Mcl1	psi-mi:“MI:0407”(direct interaction)	0.440
Bcl2a1	PMAIP1	psi-mi:“MI:0407”(direct interaction)	0.440
PMAIP1	OPG045	psi-mi:“MI:0915”(physical association)	0.400
GSK3B	PMAIP1	psi-mi:“MI:0915”(physical association)	0.370
PMAIP1	ZBTB16	psi-mi:“MI:0915”(physical association)	0.000
PMAIP1	PPBP	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (213): PMAIP1 (Protein-peptide), PMAIP1 (Protein-peptide), PMAIP1 (Protein-peptide), PMAIP1 (Affinity Capture-MS), PMAIP1 (Affinity Capture-Western), MCL1 (Affinity Capture-Western), PMAIP1 (Affinity Capture-Western), PMAIP1 (Biochemical Activity), BAX (Affinity Capture-Western), PMAIP1 (Protein-peptide), PMAIP1 (Protein-peptide), PMAIP1 (Protein-peptide), MCL1 (Affinity Capture-Western), MCL1 (Affinity Capture-Western), PMAIP1 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GVM5, A0A1D8PSK2, A2BYT2, A8MQ11, G3UWD5, J3QM76, O66096, P03085, P0CT62, P0CT63, P0CU23, P11794, P14063, P14998, P26874, P27070, P27975, P34539, P49689, P50892, P60096, P60097, P64570, P64571, P68191, P68192, P68193, Q09020, Q09557, Q0ABH1, Q0THU0, Q12ZJ3, Q13794, Q16048, Q1RBT8, Q2N9B5, Q320R9, Q3MFB7, Q3Z1M3, Q46FA3

Diamond homologs: Q13794, Q1PCT2, Q5U777, Q9JM54

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
TP53	“up-regulates quantity by expression”	PMAIP1	“transcriptional regulation”
CDK5	down-regulates	PMAIP1	phosphorylation
TP73	“up-regulates quantity by expression”	PMAIP1	“transcriptional regulation”
FUBP1	“down-regulates quantity by repression”	PMAIP1	“transcriptional regulation”
RNF7	“down-regulates activity”	PMAIP1	ubiquitination
PMAIP1	“up-regulates activity”	GNA15	phosphorylation
MARCHF5	“down-regulates quantity”	PMAIP1	ubiquitination
hsa-mir-200b-3p	“down-regulates quantity by destabilization”	PMAIP1	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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
release of cytochrome c from mitochondria	5	292.6×	3e-10
extrinsic apoptotic signaling pathway in absence of ligand	7	273.1×	3e-14
intrinsic apoptotic signaling pathway in response to DNA damage	6	162.0×	1e-10
positive regulation of apoptotic process	7	33.1×	3e-08
negative regulation of apoptotic process	5	14.5×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	2
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

271 predictions. Top by Δscore:

Variant	Effect	Δscore
18:59902645:A:AG	acceptor_gain	1.0000
18:59902646:G:GG	acceptor_gain	1.0000
18:59900231:AGCAG:A	donor_loss	0.9900
18:59900232:GCAG:G	donor_gain	0.9900
18:59900233:CAGGT:C	donor_loss	0.9900
18:59900234:AGGTA:A	donor_loss	0.9900
18:59900235:GGTA:G	donor_loss	0.9900
18:59900236:G:T	donor_loss	0.9900
18:59900237:T:A	donor_loss	0.9900
18:59902632:T:TA	acceptor_gain	0.9900
18:59902644:CAGAG:C	acceptor_loss	0.9900
18:59902646:G:GC	acceptor_loss	0.9900
18:59902646:GA:G	acceptor_gain	0.9900
18:59902646:GAGC:G	acceptor_gain	0.9900
18:59902646:GAGCT:G	acceptor_gain	0.9900
18:59900233:C:T	donor_gain	0.9800
18:59900487:C:G	donor_gain	0.9800
18:59900502:G:T	donor_gain	0.9800
18:59900152:C:G	donor_gain	0.9700
18:59900504:C:T	donor_gain	0.9700
18:59900116:GCTCC:G	donor_gain	0.9600
18:59900577:GT:G	donor_gain	0.9600
18:59900699:GAGCC:G	donor_gain	0.9600
18:59902643:TCAG:T	acceptor_gain	0.9600
18:59902646:G:C	acceptor_gain	0.9600
18:59902642:CTCAG:C	acceptor_gain	0.9500
18:59902644:CAG:C	acceptor_gain	0.9500
18:59902645:AG:A	acceptor_gain	0.9500
18:59900572:TGC:T	donor_gain	0.9400
18:59901191:G:GT	donor_gain	0.9100

AlphaMissense

340 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:59902732:A:C	K48N	0.874
18:59902732:A:T	K48N	0.874
18:59902686:G:A	G33E	0.872
18:59902686:G:T	G33V	0.870
18:59902722:T:C	L45P	0.870
18:59902711:A:C	K41N	0.813
18:59902711:A:T	K41N	0.813
18:59902685:G:A	G33R	0.805
18:59902685:G:C	G33R	0.805
18:59902689:A:T	D34V	0.785
18:59902709:A:G	K41E	0.774
18:59902730:A:G	K48E	0.763
18:59902731:A:T	K48I	0.760
18:59902678:G:C	R30S	0.745
18:59902678:G:T	R30S	0.745
18:59902725:T:A	I46K	0.744
18:59902674:T:C	L29P	0.736
18:59902688:G:C	D34H	0.734
18:59902689:A:C	D34A	0.731
18:59902713:T:C	L42P	0.723
18:59902708:G:C	Q40H	0.710
18:59902708:G:T	Q40H	0.710
18:59902707:A:C	Q40P	0.706
18:59902674:T:A	L29H	0.699
18:59902661:T:C	C25R	0.696
18:59902710:A:T	K41I	0.692
18:59902734:T:C	L49P	0.689
18:59902713:T:A	L42H	0.671
18:59902725:T:G	I46R	0.671
18:59902674:T:G	L29R	0.651

dbSNP variants (sampled 300 via entrez): RS1000374717 (18:59900674 G>A), RS1001089796 (18:59899834 T>G), RS1001376120 (18:59902085 G>A), RS1002191572 (18:59904464 A>G), RS1002371860 (18:59898612 C>A,G), RS1002629518 (18:59898164 T>C), RS1002998693 (18:59900855 C>A,T), RS1003227227 (18:59899657 T>A,C), RS1003669240 (18:59899293 C>T), RS1005276893 (18:59900114 G>A), RS1005749042 (18:59900292 C>A,T), RS1006216276 (18:59900385 C>A,G,T), RS1006340954 (18:59901412 A>G), RS1006679210 (18:59901178 T>C), RS1006982890 (18:59899184 T>C)

Disease associations

OMIM: gene MIM:604959 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST000753_12	Metabolic syndrome	7.000000e-06
GCST000882_1	Response to bleomycin (chromatid breaks)	3.000000e-08
GCST002021_12	Body mass index	4.000000e-17
GCST002073_8	Chronic lymphocytic leukemia	3.000000e-08
GCST003116_6	Coronary artery disease	3.000000e-08
GCST003468_18	Chronic lymphocytic leukemia	8.000000e-07
GCST004904_100	Body mass index	8.000000e-37
GCST004904_199	Body mass index	2.000000e-84
GCST005950_3	Body mass index x sex x age interaction (4df test)	9.000000e-60
GCST005951_194	Body mass index	2.000000e-58
GCST005952_3	Body mass index (age>50)	2.000000e-23
GCST005954_2	Body mass index x age interaction	7.000000e-07
GCST006921_9	Regular attendance at a pub or social club	4.000000e-09
GCST008070_31	HDL cholesterol levels	1.000000e-09
GCST008074_79	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-08
GCST008075_174	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-11
GCST008075_69	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-09
GCST008083_132	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	8.000000e-08
GCST008084_193	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-15
GCST008084_78	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	8.000000e-11
GCST008085_168	HDL cholesterol levels in current drinkers	3.000000e-08
GCST008087_34	Triglyceride levels in current drinkers	5.000000e-07
GCST008839_124	Height	6.000000e-17
GCST009391_1099	Metabolite levels	2.000000e-06
GCST009391_1810	Metabolite levels	9.000000e-06
GCST009391_2133	Metabolite levels	7.000000e-06
GCST010241_139	Apolipoprotein A1 levels	4.000000e-22
GCST010242_288	HDL cholesterol levels	1.000000e-26
GCST010866_160	Coronary artery disease	4.000000e-09
GCST011995_5	Restless legs syndrome	6.000000e-07

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0000195	metabolic syndrome
EFO:0007593	chromatid break measurement
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009592	social interaction measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004329	alcohol drinking
EFO:0010447	3-hydroxyanthranilic acid measurement
EFO:0010403	triacylglycerol 48:0 measurement
EFO:0010383	phosphatidylcholine 36:5 measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0005091	monocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066576 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

77 potent at pChembl≥5 of 77 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.51	IC50	0.31	nM	CHEMBL5744397
9.47	IC50	0.34	nM	CHEMBL5941324
9.47	IC50	0.34	nM	CHEMBL5818075
9.40	IC50	0.4	nM	CHEMBL5863023
9.32	IC50	0.48	nM	CHEMBL5886592
9.28	IC50	0.52	nM	CHEMBL5986470
9.23	IC50	0.59	nM	CHEMBL5818075
9.22	IC50	0.6	nM	CHEMBL5768345
9.19	IC50	0.64	nM	CHEMBL5771735
9.13	IC50	0.74	nM	CHEMBL5940404
9.10	IC50	0.8	nM	CHEMBL5984018
9.10	IC50	0.8	nM	CHEMBL5757332
9.05	IC50	0.89	nM	CHEMBL5909453
9.03	IC50	0.93	nM	CHEMBL5863023
9.03	IC50	0.94	nM	CHEMBL5763676
9.03	IC50	0.94	nM	CHEMBL5863023
9.02	IC50	0.96	nM	CHEMBL5940404
8.96	IC50	1.1	nM	CHEMBL5763676
8.96	IC50	1.1	nM	CHEMBL5818075
8.92	IC50	1.2	nM	CHEMBL5986470
8.89	IC50	1.3	nM	CHEMBL5766468
8.89	IC50	1.3	nM	CHEMBL6026365
8.82	IC50	1.5	nM	CHEMBL5944041
8.82	IC50	1.5	nM	CHEMBL5757332
8.77	IC50	1.7	nM	CHEMBL5766468
8.77	IC50	1.7	nM	CHEMBL6010486
8.77	IC50	1.7	nM	CHEMBL5909453
8.77	IC50	1.7	nM	CHEMBL5771735
8.74	IC50	1.8	nM	CHEMBL5768345
8.72	IC50	1.9	nM	CHEMBL5763676
8.72	IC50	1.9	nM	CHEMBL5768345
8.68	IC50	2.1	nM	CHEMBL5887574
8.68	IC50	2.1	nM	CHEMBL5919839
8.68	IC50	2.1	nM	CHEMBL5886592
8.66	IC50	2.2	nM	CHEMBL5928847
8.62	IC50	2.4	nM	CHEMBL5763676
8.57	IC50	2.7	nM	CHEMBL5921517
8.52	IC50	3	nM	CHEMBL5744397
8.51	IC50	3.1	nM	CHEMBL5877719
8.51	IC50	3.1	nM	CHEMBL6012035
8.49	IC50	3.2	nM	CHEMBL5937754
8.49	IC50	3.2	nM	CHEMBL5858946
8.48	IC50	3.3	nM	CHEMBL6003893
8.47	IC50	3.4	nM	CHEMBL5942676
8.47	IC50	3.4	nM	CHEMBL5985258
8.46	IC50	3.5	nM	CHEMBL6015561
8.44	IC50	3.6	nM	CHEMBL5897906
8.44	IC50	3.6	nM	CHEMBL5824431
8.40	IC50	4	nM	CHEMBL6037308
8.38	IC50	4.2	nM	CHEMBL5830746

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	decreases reaction, affects cotreatment, increases phosphorylation, affects binding, decreases expression (+5 more)	18
Bortezomib	affects cotreatment, increases expression, decreases reaction, decreases expression, increases reaction (+3 more)	13
Benzo(a)pyrene	decreases reaction, increases activity, affects expression, decreases methylation, increases expression	11
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression, increases reaction	8
Arsenic Trioxide	affects cotreatment, decreases expression, increases expression, increases reaction, increases activity	7
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	6
Valproic Acid	decreases expression, decreases methylation, increases expression, affects expression	6
Cyclosporine	increases expression	6
Cadmium Chloride	increases expression, decreases reaction, increases abundance	6
nutlin 3	affects cotreatment, increases expression	5
Cadmium	increases abundance, increases expression, decreases reaction	5
Doxorubicin	affects reaction, increases response to substance, increases reaction, affects cotreatment, increases expression (+1 more)	5
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	5
Aflatoxin B1	affects expression, increases expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
sodium arsenite	decreases expression, increases expression	4
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases expression	4
Benzene	decreases expression, decreases reaction, increases expression	4
Formaldehyde	increases expression	4
Particulate Matter	increases reaction, increases abundance, increases expression, decreases expression, affects expression	4
nickel chloride	increases expression	3
pifithrin	decreases activity, decreases reaction, increases expression, decreases expression	3
venetoclax	affects response to substance, affects cotreatment, decreases reaction, increases expression, affects reaction (+1 more)	3
Resveratrol	affects cotreatment, increases expression	3
Temozolomide	decreases response to substance, increases expression, increases reaction, affects cotreatment, decreases expression	3
Vorinostat	affects cotreatment, increases expression, increases activity, increases reaction	3
Acetaminophen	increases expression	3
Cannabidiol	affects cotreatment, increases expression	3
Methotrexate	decreases reaction, increases expression	3
Thapsigargin	increases expression, increases reaction, decreases reaction, affects binding	3

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5738290	Binding	Protein-Protein Interaction Assay: MCL-1/Noxa BH3 Peptide (MCL-1 Assay): From there, 50 nl were transferred in a dark test plate (Greiner Bio-One, Frickenhausen, Germany). The assay was initiated by addition of 2 μl of a 2.5-fold concentrat	Macrocyclic indole derivatives

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1H1	Abcam A-549 PMAIP1 KO 1	Cancer cell line	Male
CVCL_B2PK	Abcam A-549 PMAIP1 KO 2	Cancer cell line	Male
CVCL_TE72	HAP1 PMAIP1 (-) 1	Cancer cell line	Male
CVCL_XR65	HAP1 PMAIP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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