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[PMID]: 28859055 [Au] Autor: Gurvits N; Löyttyniemi E; Nykänen M; Kuopio T; Kronqvist P; Talvinen K [Ad] Endereço: Institute of Biomedicine, Department of Pathology and Forensic Medicine, University of Turku and Turku University Hospital, Turku 20510, Finland. [Ti] Título: Separase is a marker for prognosis and mitotic activity in breast cancer. [So] Source: Br J Cancer;117(9):1383-1391, 2017 Oct 24. [Is] ISSN: 1532-1827 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Cancer cell proliferation is a critical feature in classifying and predicting the outcome of breast carcinoma. Separase has a central role in cell cycle progression in unleashing sister-chromatids at anaphase onset. Abnormally functioning separase is known to lead to chromosomal instability. METHODS: The study comprises 349 breast carcinoma patients treated in Central Hospital of Central Finland. The prognostic value, role as a proliferation marker and regulatory interactions of separase are evaluated by immunohistochemical and double- and triple-immunofluorescence (IF) detections based on complete clinical data and >22-year follow-up of the patient material. RESULTS: In our material, abnormal separase expression predicted doubled risk of breast cancer death (P<0.001). Up to 11.3-year survival difference was observed when comparing patients with and without separase expressing cancer cell mitoses. Particularly, abnormal separase expression predicted impaired survival for luminal breast carcinoma (P<0.001, respectively). In multivariate analyses, abnormal separase expression showed independent prognostic value. The complex inhibitory interactions involving securin and cyclin B1 were investigated in double- and triple-IFs and revealed patient subgroups with aberrant regulation and expression patterns of separase. CONCLUSIONS: In our experience, separase is a promising and clinically applicable proliferation marker. Separase expression shows strong and independent prognostic value and could be developed into a biomarker for treatment decisions in breast carcinoma, particularly defining prognostic subgroups among luminal carcinomas. [Mh] Termos MeSH primário: Biomarcadores Tumorais/metabolismo Neoplasias da Mama/patologia Mitose/fisiologia Securina/metabolismo Separase/metabolismo [Mh] Termos MeSH secundário: Neoplasias da Mama/metabolismo Neoplasias da Mama/terapia Feminino Seres Humanos Estadiamento de Neoplasias Prognóstico Taxa de Sobrevida [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers, Tumor); 0 (Securin); EC 3.4.22.49 (Separase) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171110 [Lr] Data última revisão: 171110 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170901 [St] Status: MEDLINE [do] DOI: 10.1038/bjc.2017.301

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[PMID]: 28504713 [Au] Autor: Read ML; Fong JC; Modasia B; Fletcher A; Imruetaicharoenchoke W; Thompson RJ; Nieto H; Reynolds JJ; Bacon A; Mallick U; Hackshaw A; Watkinson JC; Boelaert K; Turnell AS; Smith VE; McCabe CJ [Ad] Endereço: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK. [Ti] Título: Elevated PTTG and PBF predicts poor patient outcome and modulates DNA damage response genes in thyroid cancer. [So] Source: Oncogene;36(37):5296-5308, 2017 Sep 14. [Is] ISSN: 1476-5594 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression. Irradiation exposure to amplify p53 levels further induced significant repression of DDR genes in Bi-Tg thyrocytes (P=2.4 × 10 ) compared with either PBF- (P=1.5 × 10 ) or PTTG-expressing thyrocytes (P=NS). Consistent with this, genetic instability was greatest in Bi-Tg thyrocytes with a mean genetic instability (GI) index of 35.8±2.6%, as well as significant induction of gross chromosomal aberrations in thyroidal TPC-1 cells following overexpression of PBF and PTTG. We extended our findings to human thyroid cancer using TCGA data sets (n=322) and found striking correlations with PBF and PTTG expression in well-characterised DDR gene panel RNA-seq data. In addition, genetic associations and transient transfection identified PBF as a downstream target of the receptor tyrosine kinase-BRAF signalling pathway, emphasising a role for PBF as a novel component in a pathway well described to drive neoplastic growth. We also showed that overall survival (P=1.91 × 10 ) and disease-free survival (P=4.9 × 10 ) was poorer for TCGA patients with elevated tumoural PBF/PTTG expression and mutationally activated BRAF. Together our findings indicate that PBF and PTTG have a critical role in promoting thyroid cancer that is predictive of poorer patient outcome. [Mh] Termos MeSH primário: Dano ao DNA Proteínas de Membrana/metabolismo Securina/metabolismo Neoplasias da Glândula Tireoide/genética Neoplasias da Glândula Tireoide/metabolismo [Mh] Termos MeSH secundário: Animais Modelos Animais de Doenças Feminino Seres Humanos Masculino Proteínas de Membrana/genética Camundongos Camundongos Transgênicos Prognóstico Securina/genética Taxa de Sobrevida Neoplasias da Glândula Tireoide/patologia Transfecção Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Membrane Proteins); 0 (PTTG1IP protein, human); 0 (Securin); 0 (pituitary tumor-transforming protein 1, human) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171115 [Lr] Data última revisão: 171115 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170516 [St] Status: MEDLINE [do] DOI: 10.1038/onc.2017.154

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[PMID]: 28384135 [Au] Autor: Singleton MR; Uhlmann F [Ad] Endereço: Structural Biology of Chromosome Segregation Laboratory, The Francis Crick Institute, London, UK. [Ti] Título: Separase-securin complex: a cunning way to control chromosome segregation. [So] Source: Nat Struct Mol Biol;24(4):337-339, 2017 04 06. [Is] ISSN: 1545-9985 [Cp] País de publicação: United States [La] Idioma: eng [Mh] Termos MeSH primário: Segregação de Cromossomos Securina/química Securina/metabolismo Separase/química Separase/metabolismo [Mh] Termos MeSH secundário: Animais Cristalografia por Raios X Seres Humanos Modelos Moleculares Ligação Proteica Conformação Proteica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Securin); EC 3.4.22.49 (Separase) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170814 [Lr] Data última revisão: 170814 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170407 [St] Status: MEDLINE [do] DOI: 10.1038/nsmb.3393

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[PMID]: 28263324 [Au] Autor: Boland A; Martin TG; Zhang Z; Yang J; Bai XC; Chang L; Scheres SH; Barford D [Ad] Endereço: MRC Laboratory of Molecular Biology, Cambridge, UK. [Ti] Título: Cryo-EM structure of a metazoan separase-securin complex at near-atomic resolution. [So] Source: Nat Struct Mol Biol;24(4):414-418, 2017 Apr. [Is] ISSN: 1545-9985 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Separase is a caspase-family protease that initiates chromatid segregation by cleaving the kleisin subunits (Scc1 and Rec8) of cohesin, and regulates centrosome duplication and mitotic spindle function through cleavage of kendrin and Slk19. To understand the mechanisms of securin regulation of separase, we used single-particle cryo-electron microscopy (cryo-EM) to determine a near-atomic-resolution structure of the Caenorhabditis elegans separase-securin complex. Separase adopts a triangular-shaped bilobal architecture comprising an N-terminal tetratricopeptide repeat (TPR)-like α-solenoid domain docked onto the conserved C-terminal protease domain. Securin engages separase in an extended antiparallel conformation, interacting with both lobes. It inhibits separase by interacting with the catalytic site through a pseudosubstrate mechanism, thus revealing that in the inhibited separase-securin complex, the catalytic site adopts a conformation compatible with substrate binding. Securin is protected from cleavage because an aliphatic side chain at the P1 position represses protease activity by disrupting the organization of catalytic site residues. [Mh] Termos MeSH primário: Microscopia Crioeletrônica Securina/ultraestrutura Separase/ultraestrutura [Mh] Termos MeSH secundário: Motivos de Aminoácidos Animais Caenorhabditis elegans Seres Humanos Modelos Moleculares Ligação Proteica Domínios Proteicos Estabilidade Proteica Estrutura Secundária de Proteína Securina/química Separase/química Especificidade por Substrato [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Securin); EC 3.4.22.49 (Separase) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170307 [St] Status: MEDLINE [do] DOI: 10.1038/nsmb.3386

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[PMID]: 28146474 [Au] Autor: Luo S; Tong L [Ad] Endereço: Department of Biological Sciences, Columbia University, New York, New York 10027, USA. [Ti] Título: Molecular mechanism for the regulation of yeast separase by securin. [So] Source: Nature;542(7640):255-259, 2017 02 09. [Is] ISSN: 1476-4687 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Separase is a cysteine protease with a crucial role in the dissolution of cohesion among sister chromatids during chromosome segregation. In human tumours separase is overexpressed, making it a potential target for drug discovery. The protease activity of separase is strictly regulated by the inhibitor securin, which forms a tight complex with separase and may also stabilize this enzyme. Separases are large, 140-250-kilodalton enzymes, with an amino-terminal α-helical region and a carboxy-terminal caspase-like catalytic domain. Although crystal structures of the C-terminal two domains of separase and low-resolution electron microscopy reconstructions of the separase-securin complex have been reported, the atomic structures of full-length separase and especially the complex with securin are unknown. Here we report crystal structures at up to 2.6 Å resolution of the yeast Saccharomyces cerevisiae separase-securin complex. The α-helical region of separase (also known as Esp1) contains four domains (I-IV), and a substrate-binding domain immediately precedes the catalytic domain and has tight associations with it. The separase-securin complex assumes a highly elongated structure. Residues 258-373 of securin (Pds1), named the separase interaction segment, are primarily in an extended conformation and traverse the entire length of separase, interacting with all of its domains. Most importantly, residues 258-269 of securin are located in the separase active site, illuminating the mechanism of inhibition. Biochemical studies confirm the structural observations and indicate that contacts outside the separase active site are crucial for stabilizing the complex, thereby defining an important function for the helical region of separase. [Mh] Termos MeSH primário: Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores Proteínas de Saccharomyces cerevisiae/química Proteínas de Saccharomyces cerevisiae/metabolismo Saccharomyces cerevisiae/química Saccharomyces cerevisiae/enzimologia Securina/química Securina/metabolismo Separase/antagonistas & inibidores Separase/química [Mh] Termos MeSH secundário: Domínio Catalítico Cristalografia por Raios X Estabilidade Enzimática Modelos Moleculares Ligação Proteica Domínios Proteicos Domínios e Motivos de Interação entre Proteínas Separase/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S. [Nm] Nome de substância: 0 (PDS1 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (Securin); EC 3.4.22.49 (ESP1 protein, S cerevisiae); EC 3.4.22.49 (Separase) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 171121 [Lr] Data última revisão: 171121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170202 [St] Status: MEDLINE [do] DOI: 10.1038/nature21061

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[PMID]: 27991932 [Au] Autor: Wang SA; Wang YC; Chuang YP; Huang YH; Su WC; Chang WC; Hung JJ [Ad] Endereço: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan. [Ti] Título: EGF-mediated inhibition of ubiquitin-specific peptidase 24 expression has a crucial role in tumorigenesis. [So] Source: Oncogene;36(21):2930-2945, 2017 May 25. [Is] ISSN: 1476-5594 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: In this study, several cancer-related proteins (Bax, p300, E2F4 and securin) have been proven to be substrates of ubiquitin-specific peptidase 24 (USP24), and relevance has been shown between USP24 and its substrates in samples from clinical lung cancer patients. Silencing USP24 increases the cancer formation by inhibiting cellular apoptosis and increasing cellular proliferation. Epidermal growth factor (EGF) treatment, and the Kras and EGFR mutations decrease USP24 protein stability via EGF- or CDK1-mediated phosphorylation at Ser1616, Ser2047 and Ser2604. Knockdown of USP24 decreases Bax and p300 levels, and reduces Ku70 acetylation, thereby preventing cancer cell apoptosis. In addition, knockdown of USP24 increases cell cycle progression by enhancing the G1-S transition and metaphase-anaphase transition. The molecular mechanism involves a decrease in the USP24 level, which reduces the expression of E2F4 and its partner TFDP1, and thus increases the G1/S transition. In conclusion, the USP24 level was decreased during the early stage of cancer and the mitotic stage of the cell cycle to regulate its substrates p300, Bax, E2F4 and securin, resulting in decreased cell apoptosis and increased cell cycle progression and, thus, cancer formation. [Mh] Termos MeSH primário: Carcinogênese/efeitos dos fármacos Carcinogênese/genética Fator de Crescimento Epidérmico/farmacologia Ubiquitina Tiolesterase/genética [Mh] Termos MeSH secundário: Células A549 Animais Ciclo Celular/genética Linhagem Celular Tumoral Proteína p300 Associada a E1A/genética Fator de Transcrição E2F4/genética Fator de Crescimento Epidérmico/fisiologia Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos Regulação Neoplásica da Expressão Gênica Células HeLa Seres Humanos Camundongos Camundongos Transgênicos Securina/genética Proteína X Associada a bcl-2/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (BAX protein, human); 0 (E2F4 Transcription Factor); 0 (E2F4 protein, human); 0 (Securin); 0 (bcl-2-Associated X Protein); 0 (pituitary tumor-transforming protein 1, human); 62229-50-9 (Epidermal Growth Factor); EC 2.3.1.48 (E1A-Associated p300 Protein); EC 2.3.1.48 (EP300 protein, human); EC 3.1.2.15 (USP24 protein, human); EC 3.4.19.12 (Ubiquitin Thiolesterase) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161220 [St] Status: MEDLINE [do] DOI: 10.1038/onc.2016.445

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[PMID]: 27787230 [Au] Autor: Li Y; Li M; Min W; Han G; Wang L; Chen C; Li Z; Zhang Y; Li J; Yue Z [Ad] Endereço: Department of Neurosurgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. lij_liu@163.com. [Ti] Título: Integrated in silico-in vitro characterization, identification and disruption of the intermolecular interaction between SH3 domain-containing protein kinases and human pituitary tumor-transforming gene 1. [So] Source: Gen Physiol Biophys;36(1):91-98, 2017 Jan. [Is] ISSN: 0231-5882 [Cp] País de publicação: Slovakia [La] Idioma: eng [Ab] Resumo: The human pituitary tumor-transforming gene-1 (hPTTG1) has been found to be overexpressed in various cancers. Accumulated evidences implicate that some of protein kinases can specifically recognize two PXXP motifs at hPTTG1 C-terminus through their Src homology (SH3) domain and then phosphorylate the protein by their catalytic domain. Here, we integrate in silico analysis and in vitro assay to characterize the intermolecular interaction between the two hPTTG1 motif peptides 161LGPPSPVK168 (M1P) and 168KMPSPPWE175 (M2P) and the SH3 domains of Ser/Thr-specific protein kinases MAP3K and PI3K. It is identified that the two peptides bind to MAP3K SH3 domain with a moderate affinity, but cannot form stable complexes with PI3K SH3 domain. Long time scale molecular dynamics (MD) simulations reveal that the M1P peptide can fold into a standard poly-proline II helix that is bound in the peptide-binding pocket of MAP3K SH3 domain, while the M2P peptide gradually moves out of the pocket during the simulations and finally forms a weak, transient encounter complex with the domain. All these suggest that the MAP3K M1P site is a potential interacting partner of MAP3K SH3 domain, which may mediate the intermolecular recognition between hPTTG1 and MAP3K. [Mh] Termos MeSH primário: MAP Quinase Quinase Quinases/química MAP Quinase Quinase Quinases/ultraestrutura Fosfatidilinositol 3-Quinases/química Fosfatidilinositol 3-Quinases/ultraestrutura Securina/química Securina/ultraestrutura [Mh] Termos MeSH secundário: Sítios de Ligação Ativação Enzimática Seres Humanos Modelos Químicos Simulação de Acoplamento Molecular Ligação Proteica Conformação Proteica Relação Estrutura-Atividade Especificidade por Substrato Domínios de Homologia de src [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Securin); 0 (pituitary tumor-transforming protein 1, human); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinases) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170616 [Lr] Data última revisão: 170616 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161028 [St] Status: MEDLINE [do] DOI: 10.4149/gpb_2016035

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[PMID]: 27756608 [Au] Autor: Zhang Z; Jin B; Jin Y; Huang S; Niu X; Mao Z; Xin D [Ad] Endereço: Department of Urology, First Hospital, Peking University & Institute of Urology, Peking University, Beijing 100034, China. [Ti] Título: PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion. [So] Source: Exp Cell Res;350(1):1-8, 2017 Jan 01. [Is] ISSN: 1090-2422 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the -851 to -836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. [Mh] Termos MeSH primário: Proliferação Celular Regulação Neoplásica da Expressão Gênica Próstata/metabolismo Neoplasias da Próstata/genética Receptores Androgênicos/metabolismo Securina/genética [Mh] Termos MeSH secundário: Animais Linhagem Celular Tumoral Proliferação Celular/genética Seres Humanos Masculino Neoplasias da Próstata/metabolismo Neoplasias da Próstata/patologia Receptores Androgênicos/genética Securina/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (AR protein, human); 0 (Receptors, Androgen); 0 (Securin); 0 (pituitary tumor-transforming protein 1, human) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170601 [Lr] Data última revisão: 170601 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161021 [St] Status: MEDLINE

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[PMID]: 27524416 [Au] Autor: Chen R; Duan J; Li L; Ma Q; Sun Q; Ma J; Li C; Zhou X; Chen H; Jing Y; Zhao S; Wu X; Zhang H [Ad] Endereço: State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. [Ti] Título: mTOR promotes pituitary tumor development through activation of PTTG1. [So] Source: Oncogene;36(7):979-988, 2017 Feb 16. [Is] ISSN: 1476-5594 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: As one of the most common intracranial tumors, pituitary tumor is associated with high morbidity. Effective therapy is currently not available for some pituitary tumors due to the largely undefined pathological processes of pituitary tumorigenesis. In this study, hyperactivation of mammalian/mechanistic target of rapamycin (mTOR) signaling was observed in estrogen-induced rat pituitary tumor and mTOR inhibitor rapamycin blocked the tumor development. Pituitary knockout of either mTOR signaling pathway negative regulator Tsc1 or Pten caused mouse pituitary prolactinoma, which was abolished by rapamycin treatment. Mechanistically, the expression of pituitary tumor transforming gene 1 (PTTG1) was upregulated in an mTOR complex 1-dependent manner. Overexpressed PTTG1 was crucial in hyperactive mTOR-mediated tumorigenesis. mTOR-PTTG1 signaling axis may be targeted for the treatment of tumors with mTOR hyperactivation. [Mh] Termos MeSH primário: Proliferação Celular Transformação Celular Neoplásica/patologia Neoplasias Hipofisárias/patologia Securina/metabolismo Serina-Treonina Quinases TOR/metabolismo [Mh] Termos MeSH secundário: Animais Apoptose Transformação Celular Neoplásica/genética Transformação Celular Neoplásica/metabolismo Células Cultivadas Feminino Seres Humanos Masculino Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout PTEN Fosfo-Hidrolase/fisiologia Neoplasias Hipofisárias/genética Neoplasias Hipofisárias/metabolismo Ratos Ratos Endogâmicos F344 Securina/genética Transdução de Sinais Serina-Treonina Quinases TOR/genética Proteínas Supressoras de Tumor/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (PTTG1 protein, mouse); 0 (Securin); 0 (Tumor Suppressor Proteins); 0 (tuberous sclerosis complex 1 protein); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (Pten protein, mouse) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170912 [Lr] Data última revisão: 170912 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160816 [St] Status: MEDLINE [do] DOI: 10.1038/onc.2016.264

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[PMID]: 27488803 [Au] Autor: Palou R; Palou G; Quintana DG [Ad] Endereço: Biophysics Unit, School of Medicine, and Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, 08193, Catalonia, Spain. [Ti] Título: A role for the spindle assembly checkpoint in the DNA damage response. [So] Source: Curr Genet;63(2):275-280, 2017 May. [Is] ISSN: 1432-0983 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Spontaneous DNA damage poses a continuous threat to genomic integrity. If unchecked, genotoxic insults result in genomic instability, a hallmark of cancer cells. In eukaryotic cells a DNA Damage Response (DDR) detects and responds to genotoxic stress, acting as an anti-cancer barrier in humans. Among other actions, the DDR blocks the segregation of incompletely replicated or damaged chromosomes, thus preventing aneuploidy. In a work aimed at better understanding such S-M control, we recently showed that cells block anaphase through different control pathways. The S phase checkpoint kinase Mec1/ATR inhibits mitotic Cyclin Dependent Kinase activity through effector kinases Swe1/Wee1 and Rad53/Chk2. Cells also stabilize the levels of Pds1/securin to block sister chromatid segregation in response to DNA damage. We show here that Pds1/securin abundance is still secured when the S phase checkpoint response is fully abrogated in mec1/ATR tel1/ATM double null mutants. When such cells are exposed to genotoxic stress, Pds1/securin is stabilized in a spindle assembly checkpoint (SAC) dependent manner. Disruption of the SAC and the S phase checkpoint together, allows chromosome segregation in the presence of DNA damage or replication stress. Our results place the SAC as a part of the DDR, which appears to count on different, independent control layers to preserve genomic integrity when chromosome replication is challenged. [Mh] Termos MeSH primário: Dano ao DNA Proteínas de Saccharomyces cerevisiae/genética Saccharomyces cerevisiae/genética Fuso Acromático/genética [Mh] Termos MeSH secundário: Anáfase/genética Proteína Quinase CDC2/genética Proteína Quinase CDC2/metabolismo Proteínas de Ciclo Celular/genética Proteínas de Ciclo Celular/metabolismo Quinase do Ponto de Checagem 2/genética Quinase do Ponto de Checagem 2/metabolismo Segregação de Cromossomos/genética DNA Fúngico/genética DNA Fúngico/metabolismo Seres Humanos Peptídeos e Proteínas de Sinalização Intracelular/genética Peptídeos e Proteínas de Sinalização Intracelular/metabolismo Modelos Genéticos Mutação Proteínas Serina-Treonina Quinases/genética Proteínas Serina-Treonina Quinases/metabolismo Pontos de Checagem da Fase S do Ciclo Celular/genética Saccharomyces cerevisiae/metabolismo Proteínas de Saccharomyces cerevisiae/metabolismo Securina/genética Securina/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cell Cycle Proteins); 0 (DNA, Fungal); 0 (Intracellular Signaling Peptides and Proteins); 0 (PDS1 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (Securin); EC 2.7.1.11 (Checkpoint Kinase 2); EC 2.7.11.1 (MEC1 protein, S cerevisiae); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (TEL1 protein, S cerevisiae); EC 2.7.11.22 (CDC2 Protein Kinase); EC 2.7.12.1 (RAD53 protein, S cerevisiae) [Em] Mês de entrada: 1705 [Cu] Atualização por classe: 170504 [Lr] Data última revisão: 170504 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160805 [St] Status: MEDLINE [do] DOI: 10.1007/s00294-016-0634-y

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1			PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2
2	and or and not		PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2
3	and or and not		PalavrasDescritor de assuntoDescritor de assunto primárioLimitesAutorPalavras do títuloPalavras do resumoIdiomaPaís de publicaçãoNome de substânciaNome de pessoa como assuntoRevistaAssunto de RevistaISSNTipo de publicaçãoIdentificador únicoMês de entradaAno de publicaçãoTexto completoAtualização por classeCategoria DeCSCategoria DeCS explodidaCategoria CID-10SubSetsPais de AfiliaçãoAfiliaçãoAfiliação 2

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