ID PTTG1_HUMAN Reviewed; 202 AA. AC O95997; DT 25-MAR-2003, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1999, sequence version 1. DT 11-NOV-2015, entry version 126. DE RecName: Full=Securin; DE AltName: Full=Esp1-associated protein; DE AltName: Full=Pituitary tumor-transforming gene 1 protein; DE Short=Tumor-transforming protein 1; DE Short=hPTTG; GN Name=PTTG1; Synonyms=EAP1, PTTG, TUTR1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Thymus; RX PubMed=9811450; DOI=10.1038/sj.onc.1202140; RA Dominguez A., Ramos-Morales F., Romero F., Rios R.M., Dreyfus F., RA Tortolero M., Pintor-Toro J.A.; RT "hPTTG, a human homologue of rat PTTG, is overexpressed in RT hematopoietic neoplasms. Evidence for a transcriptional activation RT function of hPTTG."; RL Oncogene 17:2187-2193(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Pituitary adenoma; RA Mu Y.; RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND DISEASE. RC TISSUE=Testis; RX PubMed=10393434; RA Kakar S.S., Jennes L.; RT "Molecular cloning and characterization of the tumor transforming gene RT (TUTR1): a novel gene in human tumorigenesis."; RL Cytogenet. Cell Genet. 84:211-216(1999). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10580151; DOI=10.1016/S0378-1119(99)00446-1; RA Kakar S.S.; RT "Molecular cloning, genomic organization, and identification of the RT promoter for the human pituitary tumor transforming gene (PTTG)."; RL Gene 240:317-324(1999). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA], DISEASE, AND MUTAGENESIS OF PRO-163 AND RP 170-PRO--PRO-173. RC TISSUE=Fetal liver; RX PubMed=9892021; DOI=10.1210/mend.13.1.0225; RA Zhang X., Horwitz G.A., Prezant T.R., Valentini A., Nakashima M., RA Bronstein M.D., Melmed S.; RT "Structure, expression, and function of human pituitary tumor- RT transforming gene (PTTG)."; RL Mol. Endocrinol. 13:156-166(1999). RN [6] RP DISEASE. RX PubMed=10022450; DOI=10.1210/jcem.84.2.5432; RA Zhang X., Horwitz G.A., Heaney A.P., Nakashima M., Prezant T.R., RA Bronstein M.D., Melmed S.; RT "Pituitary tumor transforming gene (PTTG) expression in pituitary RT adenomas."; RL J. Clin. Endocrinol. Metab. 84:761-767(1999). RN [7] RP FUNCTION, INTERACTION WITH ESPL1, UBIQUITINATION, AND MUTAGENESIS OF RP ARG-61 AND LEU-64. RX PubMed=10411507; DOI=10.1126/science.285.5426.418; RA Zou H., McGarry T.J., Bernal T., Kirschner M.W.; RT "Identification of a vertebrate sister-chromatid separation inhibitor RT involved in transformation and tumorigenesis."; RL Science 285:418-422(1999). RN [8] RP INTERACTION WITH PTTG1IP. RX PubMed=10781616; DOI=10.1074/jbc.M910105199; RA Chien W., Pei L.; RT "A novel binding factor facilitates nuclear translocation and RT transcriptional activation function of the pituitary tumor- RT transforming gene product."; RL J. Biol. Chem. 275:19422-19427(2000). RN [9] RP FUNCTION, AND INTERACTION WITH KU. RX PubMed=11238996; DOI=10.1093/nar/29.6.1300; RA Romero F., Multon M.C., Ramos-Morales F., Dominguez A., Bernal J.A., RA Pintor-Toro J.A., Tortolero M.; RT "Human securin, hPTTG, is associated with Ku heterodimer, the RT regulatory subunit of the DNA-dependent protein kinase."; RL Nucleic Acids Res. 29:1300-1307(2001). RN [10] RP FUNCTION. RX PubMed=11371342; DOI=10.1016/S0092-8674(01)00340-3; RA Jallepalli P.V., Waizenegger I.C., Bunz F., Langer S., Speicher M.R., RA Peters J.-M., Kinzler K.W., Vogelstein B., Lengauer C.; RT "Securin is required for chromosomal stability in human cells."; RL Cell 105:445-457(2001). RN [11] RP DISEASE. RX PubMed=11158059; DOI=10.1210/jcem.86.2.7184; RA Ishikawa H., Heaney A.P., Yu R., Horwitz G.A., Melmed S.; RT "Human pituitary tumor-transforming gene induces angiogenesis."; RL J. Clin. Endocrinol. Metab. 86:867-874(2001). RN [12] RP INTERACTION WITH TP53, AND FUNCTION IN TP53 PATHWAY. RX PubMed=12355087; DOI=10.1038/ng997; RA Bernal J.A., Luna R., Espina A., Lazaro I., Ramos-Morales F., RA Romero F., Arias C., Silva A., Tortolero M., Pintor-Toro J.A.; RT "Human securin interacts with p53 and modulates p53-mediated RT transcriptional activity and apoptosis."; RL Nat. Genet. 32:306-311(2002). RN [13] RP PHOSPHORYLATION AT SER-165, AND MUTAGENESIS OF SER-165. RX PubMed=10656688; DOI=10.1038/sj.onc.1203320; RA Ramos-Morales F., Dominguez A., Romero F., Luna R., Multon M.-C., RA Pintor-Toro J.A., Tortolero M.; RT "Cell cycle regulated expression and phosphorylation of hpttg proto- RT oncogene product."; RL Oncogene 19:403-409(2000). RN [14] RP UBIQUITINATION, AND DOMAIN TEK-BOX. RX PubMed=18485873; DOI=10.1016/j.cell.2008.04.012; RA Jin L., Williamson A., Banerjee S., Philipp I., Rape M.; RT "Mechanism of ubiquitin-chain formation by the human anaphase- RT promoting complex."; RL Cell 133:653-665(2008). RN [15] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., RA Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N- RT terminal acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). CC -!- FUNCTION: Regulatory protein, which plays a central role in CC chromosome stability, in the p53/TP53 pathway, and DNA repair. CC Probably acts by blocking the action of key proteins. During the CC mitosis, it blocks Separase/ESPL1 function, preventing the CC proteolysis of the cohesin complex and the subsequent segregation CC of the chromosomes. At the onset of anaphase, it is ubiquitinated, CC conducting to its destruction and to the liberation of ESPL1. Its CC function is however not limited to a blocking activity, since it CC is required to activate ESPL1. Negatively regulates the CC transcriptional activity and related apoptosis activity of TP53. CC The negative regulation of TP53 may explain the strong CC transforming capability of the protein when it is overexpressed. CC May also play a role in DNA repair via its interaction with Ku, CC possibly by connecting DNA damage-response pathways with sister CC chromatid separation. {ECO:0000269|PubMed:10411507, CC ECO:0000269|PubMed:11238996, ECO:0000269|PubMed:11371342, CC ECO:0000269|PubMed:12355087}. CC -!- SUBUNIT: Interacts with RPS10 and DNAJA1 (By similarity). CC Interacts with the caspase-like ESPL1, and prevents its protease CC activity probably by covering its active site. Interacts with TP53 CC and blocks its activity probably by blocking its binding to DNA. CC Interacts with the Ku 70 kDa subunit of ds-DNA kinase. Interacts CC with PTTG1IP. {ECO:0000250, ECO:0000269|PubMed:10411507, CC ECO:0000269|PubMed:10781616, ECO:0000269|PubMed:11238996, CC ECO:0000269|PubMed:12355087}. CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. CC -!- TISSUE SPECIFICITY: Expressed at low level in most tissues, except CC in adult testis, where it is highly expressed. Overexpressed in CC many patients suffering from pituitary adenomas, primary CC epithelial neoplasias, and esophageal cancer. CC {ECO:0000269|PubMed:9811450}. CC -!- DEVELOPMENTAL STAGE: Low level during G1 and S phases. Peaks at M CC phase. During anaphase, it is degraded. CC -!- DOMAIN: The N-terminal destruction box (D-box) acts as a CC recognition signal for degradation via the ubiquitin-proteasome CC pathway. {ECO:0000250}. CC -!- DOMAIN: The TEK-boxes are required for 'Lys-11'-linked CC ubiquitination and facilitate the transfer of the first ubiquitin CC and ubiquitin chain nucleation. TEK-boxes may direct a CC catalytically competent orientation of the UBE2C/UBCH10-ubiquitin CC thioester with the acceptor lysine residue. CC {ECO:0000269|PubMed:18485873}. CC -!- PTM: Phosphorylated at Ser-165 by CDK1 during mitosis. CC {ECO:0000269|PubMed:10656688}. CC -!- PTM: Phosphorylated in vitro by ds-DNA kinase. CC {ECO:0000269|PubMed:10656688}. CC -!- PTM: Ubiquitinated through 'Lys-11' linkage of ubiquitin moieties CC by the anaphase promoting complex (APC) at the onset of anaphase, CC conducting to its degradation. 'Lys-11'-linked ubiquitination is CC mediated by the E2 ligase UBE2C/UBCH10. CC {ECO:0000269|PubMed:10411507, ECO:0000269|PubMed:18485873}. CC -!- SIMILARITY: Belongs to the securin family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/PTTG1ID41943ch5q35.html"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AJ223953; CAA11683.1; -; mRNA. DR EMBL; AF095287; AAC64409.1; -; mRNA. DR EMBL; AF075242; AAD19335.1; -; mRNA. DR EMBL; AF167564; AAF06995.1; -; Genomic_DNA. DR EMBL; AF167560; AAF06995.1; JOINED; Genomic_DNA. DR EMBL; AF167561; AAF06995.1; JOINED; Genomic_DNA. DR EMBL; AF167562; AAF06995.1; JOINED; Genomic_DNA. DR EMBL; AF167563; AAF06995.1; JOINED; Genomic_DNA. DR CCDS; CCDS4353.1; -. DR RefSeq; NP_001269311.1; NM_001282382.1. DR RefSeq; NP_001269312.1; NM_001282383.1. DR RefSeq; NP_004210.1; NM_004219.3. DR UniGene; Hs.350966; -. DR DisProt; DP00521; -. DR ProteinModelPortal; O95997; -. DR BioGrid; 114663; 25. DR DIP; DIP-56460N; -. DR IntAct; O95997; 5. DR STRING; 9606.ENSP00000344936; -. DR PhosphoSite; O95997; -. DR MaxQB; O95997; -. DR PaxDb; O95997; -. DR PRIDE; O95997; -. DR DNASU; 9232; -. DR Ensembl; ENST00000352433; ENSP00000344936; ENSG00000164611. DR Ensembl; ENST00000393964; ENSP00000377536; ENSG00000164611. DR Ensembl; ENST00000520452; ENSP00000430642; ENSG00000164611. DR GeneID; 9232; -. DR KEGG; hsa:9232; -. DR UCSC; uc003lyj.3; human. DR CTD; 9232; -. DR GeneCards; PTTG1; -. DR H-InvDB; HIX0034255; -. DR HGNC; HGNC:9690; PTTG1. DR HPA; CAB008373; -. DR HPA; HPA008890; -. DR HPA; HPA045034; -. DR MIM; 604147; gene. DR neXtProt; NX_O95997; -. DR PharmGKB; PA34033; -. DR eggNOG; ENOG410IVQH; Eukaryota. DR eggNOG; ENOG410Z8MR; LUCA. DR HOGENOM; HOG000035097; -. DR HOVERGEN; HBG053264; -. DR InParanoid; O95997; -. DR KO; K06635; -. DR OMA; FSAKKVT; -. DR OrthoDB; EOG7MPRH0; -. DR PhylomeDB; O95997; -. DR TreeFam; TF330797; -. DR Reactome; R-HSA-174154; APC/C:Cdc20 mediated degradation of Securin. DR Reactome; R-HSA-174178; APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1. DR Reactome; R-HSA-2467813; Separation of Sister Chromatids. DR GeneWiki; PTTG1; -. DR GenomeRNAi; 9232; -. DR NextBio; 34605; -. DR PRO; PR:O95997; -. DR Proteomes; UP000005640; Chromosome 5. DR Bgee; O95997; -. DR CleanEx; HS_PTTG1; -. DR ExpressionAtlas; O95997; baseline and differential. DR Genevisible; O95997; HS. DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005634; C:nucleus; TAS:ProtInc. DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; NAS:UniProtKB. DR GO; GO:0030414; F:peptidase inhibitor activity; IBA:GO_Central. DR GO; GO:0003700; F:transcription factor activity, sequence-specific DNA binding; TAS:ProtInc. DR GO; GO:0031145; P:anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process; TAS:Reactome. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:0051276; P:chromosome organization; IEA:InterPro. DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW. DR GO; GO:0045143; P:homologous chromosome segregation; IBA:GO_Central. DR GO; GO:0000278; P:mitotic cell cycle; TAS:Reactome. DR GO; GO:0007067; P:mitotic nuclear division; IEA:UniProtKB-KW. DR GO; GO:0010951; P:negative regulation of endopeptidase activity; NAS:GOC. DR GO; GO:2000816; P:negative regulation of mitotic sister chromatid separation; IBA:GO_Central. DR GO; GO:0010466; P:negative regulation of peptidase activity; IBA:GO_Central. DR GO; GO:0006355; P:regulation of transcription, DNA-templated; TAS:GOC. DR GO; GO:0007283; P:spermatogenesis; TAS:ProtInc. DR GO; GO:0006366; P:transcription from RNA polymerase II promoter; TAS:ProtInc. DR InterPro; IPR018008; Securin_separation-inh_met. DR InterPro; IPR006940; Securin_separation_inhibitor. DR PANTHER; PTHR10418; PTHR10418; 1. DR Pfam; PF04856; Securin; 1. PE 1: Evidence at protein level; KW Acetylation; Cell cycle; Cell division; Chromosome partition; KW Complete proteome; Cytoplasm; DNA damage; DNA repair; Mitosis; KW Nucleus; Phosphoprotein; Proto-oncogene; Reference proteome; Repeat; KW SH3-binding; Ubl conjugation. FT INIT_MET 1 1 Removed. {ECO:0000244|PubMed:22814378}. FT CHAIN 2 202 Securin. FT /FTId=PRO_0000206361. FT MOTIF 61 64 D-box. FT MOTIF 71 73 TEK-box 1. FT MOTIF 94 96 TEK-box 2. FT MOTIF 163 173 SH3-binding. FT MOD_RES 2 2 N-acetylalanine. FT {ECO:0000244|PubMed:22814378}. FT MOD_RES 165 165 Phosphoserine; by CDK1. FT {ECO:0000269|PubMed:10656688}. FT MUTAGEN 61 61 R->A: Abolishes ubiquitination and FT subsequent degradation; when associated FT with A-64. {ECO:0000269|PubMed:10411507}. FT MUTAGEN 64 64 L->A: Abolishes ubiquitination and FT subsequent degradation; when associated FT with A-61. {ECO:0000269|PubMed:10411507}. FT MUTAGEN 163 163 P->A: Strongly reduces transforming FT capability; when associated with L-170; FT A-172 and L-173. FT {ECO:0000269|PubMed:9892021}. FT MUTAGEN 165 165 S->A: Abolishes phosphorylation. FT {ECO:0000269|PubMed:10656688}. FT MUTAGEN 170 173 PSPP->LSAL: Strongly reduces transforming FT capability; when associated with A-163. FT {ECO:0000269|PubMed:9892021}. SQ SEQUENCE 202 AA; 22024 MW; 5F4740619AB8856F CRC64; MATLIYVDKE NGEPGTRVVA KDGLKLGSGP SIKALDGRSQ VSTPRFGKTF DAPPALPKAT RKALGTVNRA TEKSVKTKGP LKQKQPSFSA KKMTEKTVKA KSSVPASDDA YPEIEKFFPF NPLDFESFDL PEEHQIAHLP LSGVPLMILD EERELEKLFQ LGPPSPVKMP SPPWESNLLQ SPSSILSTLD VELPPVCCDI DI //