APR_HUMAN
ID APR_HUMAN Reviewed; 54 AA.
AC Q13794; B2R4T7; Q8N589;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=Phorbol-12-myristate-13-acetate-induced protein 1;
DE Short=PMA-induced protein 1;
DE AltName: Full=Immediate-early-response protein APR;
DE AltName: Full=Protein Noxa;
GN Name=PMAIP1; Synonyms=NOXA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2398525; DOI=10.1128/jvi.64.10.4632-4639.1990;
RA Hijikata M., Kato N., Sato T., Kagami Y., Shimotohno K.;
RT "Molecular cloning and characterization of a cDNA for a novel phorbol-12-
RT myristate-13-acetate-responsive gene that is highly expressed in an adult
RT T-cell leukemia cell line.";
RL J. Virol. 64:4632-4639(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16177791; DOI=10.1038/nature03983;
RA Nusbaum C., Zody M.C., Borowsky M.L., Kamal M., Kodira C.D., Taylor T.D.,
RA Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Abouelleil A., Allen N.R., Anderson S., Bloom T., Bugalter B., Butler J.,
RA Cook A., DeCaprio D., Engels R., Garber M., Gnirke A., Hafez N., Hall J.L.,
RA Norman C.H., Itoh T., Jaffe D.B., Kuroki Y., Lehoczky J., Lui A.,
RA Macdonald P., Mauceli E., Mikkelsen T.S., Naylor J.W., Nicol R., Nguyen C.,
RA Noguchi H., O'Leary S.B., Piqani B., Smith C.L., Talamas J.A., Topham K.,
RA Totoki Y., Toyoda A., Wain H.M., Young S.K., Zeng Q., Zimmer A.R.,
RA Fujiyama A., Hattori M., Birren B.W., Sakaki Y., Lander E.S.;
RT "DNA sequence and analysis of human chromosome 18.";
RL Nature 437:551-555(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Ovary, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, AND INDUCTION.
RX PubMed=10807576; DOI=10.1126/science.288.5468.1053;
RA Oda E., Ohki R., Murasawa H., Nemoto J., Shibue T., Yamashita T.,
RA Tokino T., Taniguchi T., Tanaka N.;
RT "Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-
RT induced apoptosis.";
RL Science 288:1053-1058(2000).
RN [6]
RP FUNCTION, INDUCTION, SUBCELLULAR LOCATION, INTERACTION WITH BAX, AND
RP MUTAGENESIS OF LEU-29.
RX PubMed=15705586; DOI=10.1074/jbc.m412630200;
RA Sun Y., Leaman D.W.;
RT "Involvement of Noxa in cellular apoptotic responses to interferon, double-
RT stranded RNA, and virus infection.";
RL J. Biol. Chem. 280:15561-15568(2005).
RN [7]
RP FUNCTION, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF PHE-32 AND
RP LYS-35, AND INTERACTION WITH MCL1.
RX PubMed=15694340; DOI=10.1016/j.molcel.2004.12.030;
RA Chen L., Willis S.N., Wei A., Smith B.J., Fletcher J.I., Hinds M.G.,
RA Colman P.M., Day C.L., Adams J.M., Huang D.C.S.;
RT "Differential targeting of prosurvival Bcl-2 proteins by their BH3-only
RT ligands allows complementary apoptotic function.";
RL Mol. Cell 17:393-403(2005).
RN [8]
RP FUNCTION, INTERACTION WITH MCL1, INDUCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17374615; DOI=10.1074/jbc.m611186200;
RA Han J., Goldstein L.A., Hou W., Rabinowich H.;
RT "Functional linkage between NOXA and Bim in mitochondrial apoptotic
RT events.";
RL J. Biol. Chem. 282:16223-16231(2007).
RN [9]
RP FUNCTION, MUTAGENESIS OF LEU-29; PHE-32 AND LEU-36, AND INTERACTION WITH
RP MCL1.
RX PubMed=17389404; DOI=10.1073/pnas.0701297104;
RA Czabotar P.E., Lee E.F., van Delft M.F., Day C.L., Smith B.J.,
RA Huang D.C.S., Fairlie W.D., Hinds M.G., Colman P.M.;
RT "Structural insights into the degradation of Mcl-1 induced by BH3
RT domains.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:6217-6222(2007).
RN [10]
RP INTERACTION WITH BCL2L10.
RX PubMed=23563182; DOI=10.1038/onc.2013.99;
RA van de Kooij B., Rooswinkel R.W., Kok F., Herrebout M., de Vries E.,
RA Paauwe M., Janssen G.M., van Veelen P.A., Borst J.;
RT "Polyubiquitination and proteasomal turnover controls the anti-apoptotic
RT activity of Bcl-B.";
RL Oncogene 32:5439-5448(2013).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.24 ANGSTROMS) OF 19-43 IN COMPLEX WITH BCL2A1.
RG Northeast structural genomics consortium (NESG);
RT "Crystal structure of human BFL-1 in complex with NOXA BH3 peptide.";
RL Submitted (JUL-2010) to the PDB data bank.
CC -!- FUNCTION: Promotes activation of caspases and apoptosis. Promotes
CC mitochondrial membrane changes and efflux of apoptogenic proteins from
CC the mitochondria. Contributes to p53/TP53-dependent apoptosis after
CC radiation exposure. Promotes proteasomal degradation of MCL1. Competes
CC with BAK1 for binding to MCL1 and can displace BAK1 from its binding
CC site on MCL1 (By similarity). Competes with BIM/BCL2L11 for binding to
CC MCL1 and can displace BIM/BCL2L11 from its binding site on MCL1.
CC {ECO:0000250, ECO:0000269|PubMed:10807576, ECO:0000269|PubMed:15694340,
CC ECO:0000269|PubMed:15705586, ECO:0000269|PubMed:17374615,
CC ECO:0000269|PubMed:17389404}.
CC -!- SUBUNIT: Interacts with MCL1 (PubMed:15694340, PubMed:17374615,
CC PubMed:17389404). Interacts with BCL2A1 (Ref.11). Interacts with BAX
CC (PubMed:15705586). Interacts with BCL2L10 (PubMed:23563182).
CC {ECO:0000269|PubMed:15694340, ECO:0000269|PubMed:15705586,
CC ECO:0000269|PubMed:17374615, ECO:0000269|PubMed:17389404,
CC ECO:0000269|PubMed:23563182, ECO:0000269|Ref.11}.
CC -!- INTERACTION:
CC Q13794; P10415: BCL2; NbExp=3; IntAct=EBI-707392, EBI-77694;
CC Q13794; P10415-1: BCL2; NbExp=3; IntAct=EBI-707392, EBI-4370304;
CC Q13794; Q07820: MCL1; NbExp=5; IntAct=EBI-707392, EBI-1003422;
CC Q13794-2; P61019: RAB2A; NbExp=3; IntAct=EBI-12170575, EBI-752037;
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:15705586,
CC ECO:0000269|PubMed:17374615}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13794-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13794-2; Sequence=VSP_056247;
CC -!- TISSUE SPECIFICITY: Highly expressed in adult T-cell leukemia cell
CC line.
CC -!- INDUCTION: Up-regulated by p53/TP53, phorbol esters, double-stranded
CC RNA, IFNB1/IFN-beta and viruses. {ECO:0000269|PubMed:10807576,
CC ECO:0000269|PubMed:15705586, ECO:0000269|PubMed:17374615}.
CC -!- DOMAIN: The BH3 motif is essential for pro-apoptotic activity.
CC -!- SIMILARITY: Belongs to the PMAIP1 family. {ECO:0000305}.
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DR EMBL; D90070; BAA14111.1; -; mRNA.
DR EMBL; AK311943; BAG34884.1; -; mRNA.
DR EMBL; AC107990; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013120; AAH13120.1; -; mRNA.
DR EMBL; BC032663; AAH32663.1; -; mRNA.
DR CCDS; CCDS11975.1; -. [Q13794-1]
DR PIR; I37018; I37018.
DR RefSeq; NP_066950.1; NM_021127.2. [Q13794-1]
DR PDB; 3MQP; X-ray; 2.24 A; B=19-43.
DR PDBsum; 3MQP; -.
DR AlphaFoldDB; Q13794; -.
DR SMR; Q13794; -.
DR BioGRID; 111379; 175.
DR ComplexPortal; CPX-304; MCL1:PMAIP1 complex.
DR IntAct; Q13794; 12.
DR MINT; Q13794; -.
DR STRING; 9606.ENSP00000326119; -.
DR iPTMnet; Q13794; -.
DR PhosphoSitePlus; Q13794; -.
DR BioMuta; PMAIP1; -.
DR EPD; Q13794; -.
DR jPOST; Q13794; -.
DR MassIVE; Q13794; -.
DR MaxQB; Q13794; -.
DR PaxDb; Q13794; -.
DR PeptideAtlas; Q13794; -.
DR PRIDE; Q13794; -.
DR ProteomicsDB; 59684; -. [Q13794-1]
DR ProteomicsDB; 72022; -.
DR Antibodypedia; 9901; 476 antibodies from 41 providers.
DR DNASU; 5366; -.
DR Ensembl; ENST00000269518.9; ENSP00000269518.9; ENSG00000141682.12. [Q13794-2]
DR Ensembl; ENST00000316660.7; ENSP00000326119.7; ENSG00000141682.12. [Q13794-1]
DR GeneID; 5366; -.
DR KEGG; hsa:5366; -.
DR MANE-Select; ENST00000316660.7; ENSP00000326119.7; NM_021127.3; NP_066950.1.
DR UCSC; uc002lic.3; human. [Q13794-1]
DR CTD; 5366; -.
DR DisGeNET; 5366; -.
DR GeneCards; PMAIP1; -.
DR HGNC; HGNC:9108; PMAIP1.
DR HPA; ENSG00000141682; Tissue enriched (bone).
DR MIM; 604959; gene.
DR neXtProt; NX_Q13794; -.
DR OpenTargets; ENSG00000141682; -.
DR PharmGKB; PA33434; -.
DR VEuPathDB; HostDB:ENSG00000141682; -.
DR eggNOG; ENOG502SEAE; Eukaryota.
DR GeneTree; ENSGT00530000065105; -.
DR HOGENOM; CLU_3049644_0_0_1; -.
DR InParanoid; Q13794; -.
DR OMA; LITKLFC; -.
DR PhylomeDB; Q13794; -.
DR PathwayCommons; Q13794; -.
DR Reactome; R-HSA-111448; Activation of NOXA and translocation to mitochondria.
DR Reactome; R-HSA-111453; BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members.
DR Reactome; R-HSA-6803204; TP53 Regulates Transcription of Genes Involved in Cytochrome C Release.
DR SignaLink; Q13794; -.
DR SIGNOR; Q13794; -.
DR BioGRID-ORCS; 5366; 28 hits in 1091 CRISPR screens.
DR EvolutionaryTrace; Q13794; -.
DR GeneWiki; Phorbol-12-myristate-13-acetate-induced_protein_1; -.
DR GenomeRNAi; 5366; -.
DR Pharos; Q13794; Tbio.
DR PRO; PR:Q13794; -.
DR Proteomes; UP000005640; Chromosome 18.
DR RNAct; Q13794; protein.
DR Bgee; ENSG00000141682; Expressed in buccal mucosa cell and 171 other tissues.
DR ExpressionAtlas; Q13794; baseline and differential.
DR Genevisible; Q13794; HS.
DR GO; GO:0097136; C:Bcl-2 family protein complex; IPI:ComplexPortal.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; IMP:MGI.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:InterPro.
DR GO; GO:0042149; P:cellular response to glucose starvation; IMP:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IDA:BHF-UCL.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; IMP:UniProtKB.
DR GO; GO:0010917; P:negative regulation of mitochondrial membrane potential; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0043517; P:positive regulation of DNA damage response, signal transduction by p53 class mediator; IMP:UniProtKB.
DR GO; GO:1902237; P:positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; TAS:ParkinsonsUK-UCL.
DR GO; GO:1902043; P:positive regulation of extrinsic apoptotic signaling pathway via death domain receptors; IDA:BHF-UCL.
DR GO; GO:0010907; P:positive regulation of glucose metabolic process; IDA:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0090200; P:positive regulation of release of cytochrome c from mitochondria; IDA:UniProtKB.
DR GO; GO:0010498; P:proteasomal protein catabolic process; IDA:UniProtKB.
DR GO; GO:0072593; P:reactive oxygen species metabolic process; IDA:UniProtKB.
DR GO; GO:0046902; P:regulation of mitochondrial membrane permeability; IDA:UniProtKB.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IEA:InterPro.
DR GO; GO:0043331; P:response to dsRNA; IDA:HGNC-UCL.
DR GO; GO:0043029; P:T cell homeostasis; ISS:UniProtKB.
DR InterPro; IPR024140; Noxa.
DR PANTHER; PTHR14299; PTHR14299; 1.
DR Pfam; PF15150; PMAIP1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Mitochondrion;
KW Reference proteome.
FT CHAIN 1..54
FT /note="Phorbol-12-myristate-13-acetate-induced protein 1"
FT /id="PRO_0000064644"
FT REGION 41..50
FT /note="Required for mitochondrial location"
FT MOTIF 29..37
FT /note="BH3"
FT VAR_SEQ 20..54
FT /note="ELEVECATQLRRFGDKLNFRQKLLNLISKLFCSGT -> GPAGTAGTARDQA
FT GFAIGMQLRFTRGKKLLSSSLSSSPLALPRGHEEQVQVAGSRVCYSTQEIWRQTELPAE
FT TSESDIQTLLLRNLTASKTCMRGLLQKSFLRRCTFHQFEERLHCN (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_056247"
FT MUTAGEN 29
FT /note="L->A: Reduced interaction with BAX."
FT /evidence="ECO:0000269|PubMed:15705586,
FT ECO:0000269|PubMed:17389404"
FT MUTAGEN 29
FT /note="L->E: Loss of interaction with MCL1 and of increased
FT MCL1 degradation; when associated with E-32 and E-32."
FT /evidence="ECO:0000269|PubMed:15705586,
FT ECO:0000269|PubMed:17389404"
FT MUTAGEN 32
FT /note="F->E: Loss of interaction with MCL1 and of increased
FT MCL1 degradation; when associated with E-29 and E-36."
FT /evidence="ECO:0000269|PubMed:15694340,
FT ECO:0000269|PubMed:17389404"
FT MUTAGEN 32
FT /note="F->I: Alters specificity of protein interaction and
FT enhances pro-apoptotic activity; when associated with E-
FT 35."
FT /evidence="ECO:0000269|PubMed:15694340,
FT ECO:0000269|PubMed:17389404"
FT MUTAGEN 35
FT /note="K->E: Alters specificity of protein interaction and
FT enhances pro-apoptotic activity; when associated with I-
FT 32."
FT /evidence="ECO:0000269|PubMed:15694340"
FT MUTAGEN 36
FT /note="L->E: Loss of interaction with MCL1 and of increased
FT MCL1 degradation; when associated with E-29 and E-32."
FT /evidence="ECO:0000269|PubMed:17389404"
FT HELIX 21..40
FT /evidence="ECO:0007829|PDB:3MQP"
SQ SEQUENCE 54 AA; 6030 MW; 291A142B27167E70 CRC64;
MPGKKARKNA QPSPARAPAE LEVECATQLR RFGDKLNFRQ KLLNLISKLF CSGT
