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  1 / 8439 MEDLINE  
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[PMID]:29390348
[Au] Autor:Eso Y; Uza N; Yamagishi H; Imada K; Kimura Y; Masui T; Kodama Y; Seno H
[Ad] Endereço:Department of Gastroenterology and Hepatology.
[Ti] Título:Utility of KRAS mutational analysis in the preoperative diagnosis of synchronous pancreatic cancer and intrahepatic cholangiocarcinoma: A case report.
[So] Source:Medicine (Baltimore);96(50):e9217, 2017 Dec.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: It is often challenging to discriminate between intrahepatic cholangiocarcinoma (ICC) and metastatic liver tumors, especially when the hepatic tumor is small and of a mass-forming type. PATIENT CONCERNS: We report a 69-year-old woman presented at our hospital with a small solid tumor in the head of the pancreas that was previously discovered during a medical checkup. DIAGNOSES: The patient was diagnosed with synchronous pancreatic cancer and ICC. INTERVENTIONS: The patient underwent clinical, histological, immunohistological, and KRAS mutational analysis. OUTCOMES: Computed tomography revealed poorly enhanced small nodules in both the pancreatic head and liver. Biopsies of both nodules revealed adenocarcinoma; however, it was unclear whether the hepatic lesion was a metastasis of the pancreatic tumor or primary ICC. KRAS mutational analysis from FFPE biopsy samples revealed a discordance of mutation status between the tumors. Therefore, the patient was diagnosed with synchronous pancreatic cancer and ICC, whereupon she underwent hepatopancreatoduodenectomy. LESSONS: KRAS mutational analysis of FFPE biopsy samples can be utilized for differentiating between ICC and metastatic liver tumor.
[Mh] Termos MeSH primário: Neoplasias dos Ductos Biliares/diagnóstico
Neoplasias dos Ductos Biliares/genética
Colangiocarcinoma/diagnóstico
Colangiocarcinoma/genética
Neoplasias Primárias Múltiplas/diagnóstico
Neoplasias Primárias Múltiplas/genética
Neoplasias Pancreáticas/diagnóstico
Neoplasias Pancreáticas/genética
Proteínas Proto-Oncogênicas p21(ras)/genética
[Mh] Termos MeSH secundário: Idoso
Neoplasias dos Ductos Biliares/cirurgia
Colangiocarcinoma/cirurgia
Análise Mutacional de DNA
Diagnóstico Diferencial
Feminino
Seres Humanos
Neoplasias Primárias Múltiplas/cirurgia
Neoplasias Pancreáticas/cirurgia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KRAS protein, human); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000009217


  2 / 8439 MEDLINE  
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[PMID]:29324343
[Au] Autor:Capilla AS; Soucek R; Grau L; Romero M; Rubio-Martínez J; Caignard DH; Pujol MD
[Ad] Endereço:Laboratori de Química Farmacèutica (Unitat associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Spain.
[Ti] Título:Substituted tetrahydroisoquinolines: synthesis, characterization, antitumor activity and other biological properties.
[So] Source:Eur J Med Chem;145:51-63, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:This work deals with the molecular design, synthesis and biological activity of a series of tetrahydro[1,4]dioxanisoquinolines and dimethoxyisoquinoline analogues. This study describes the synthesis strategy of these potential antitumor compounds, their multi-step synthesis and their optimization. A series of tetrahydroisoquinolines was synthesized and their cytotoxicity evaluated. Some of these tetrahydroisoquinolines showed promising KRas inhibition, antiangiogenesis activity and antiosteoporosis properties. Molecular modeling studies showed that compound 12 bind in the p1 pocket of the KRas protein making interactions with the hydrophobic residues Leu56, Tyr64, Tyr71 and Thr74 and hydrogen bonds with residues Glu37 and Asp38.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/farmacologia
Antineoplásicos/farmacologia
Osteoporose/tratamento farmacológico
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores
Tetra-Hidroisoquinolinas/farmacologia
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/síntese química
Inibidores da Angiogênese/química
Animais
Antineoplásicos/síntese química
Antineoplásicos/química
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Camundongos
Modelos Moleculares
Estrutura Molecular
Inibidores de Proteínas Quinases/síntese química
Inibidores de Proteínas Quinases/química
Proteínas Proto-Oncogênicas p21(ras)/metabolismo
Relação Estrutura-Atividade
Tetra-Hidroisoquinolinas/síntese química
Tetra-Hidroisoquinolinas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Antineoplastic Agents); 0 (KRAS protein, human); 0 (Protein Kinase Inhibitors); 0 (Tetrahydroisoquinolines); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE


  3 / 8439 MEDLINE  
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[PMID]:28451792
[Au] Autor:Chen N; Fang W; Lin Z; Peng P; Wang J; Zhan J; Hong S; Huang J; Liu L; Sheng J; Zhou T; Chen Y; Zhang H; Zhang L
[Ad] Endereço:State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, People's Republic of China.
[Ti] Título:KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma.
[So] Source:Cancer Immunol Immunother;66(9):1175-1187, 2017 Sep.
[Is] ISSN:1432-0851
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:It was reported that PD-L1 expression was correlated with genetic alterations. Whether PD-L1 was regulated by mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) in non-small-cell lung cancer (NSCLC) and the underlying molecular mechanism were largely unknown. In this study, we investigated the correlation between PD-L1 expression and KRAS mutation and the functional significance of PD-1/PD-L1 blockade in KRAS-mutant lung adenocarcinoma. We found that PD-L1 expression was associated with KRAS mutation both in the human lung adenocarcinoma cell lines and tissues. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling. We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by anti-PD-1 antibody (Pembrolizumab) or ERK inhibitor. PD-1 blocker or ERK inhibitor could recover the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, Pembrolizumab combined with ERK inhibitor did not show synergistic effect on killing tumor cells in co-culture system. Our study demonstrated that KRAS mutation could induce PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Blockade of PD-1/PD-L1 pathway may be a promising therapeutic strategy for human KRAS-mutant lung adenocarcinoma.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Antígeno B7-H1/metabolismo
Neoplasias Pulmonares/genética
Proteínas Proto-Oncogênicas p21(ras)/genética
Evasão Tumoral
[Mh] Termos MeSH secundário: Adenocarcinoma/patologia
Antígeno B7-H1/genética
Linhagem Celular Tumoral
Seres Humanos
Neoplasias Pulmonares/patologia
Meia-Idade
Mutação
Estudos Prospectivos
Transdução de Sinais
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (CD274 protein, human); 0 (KRAS protein, human); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1007/s00262-017-2005-z


  4 / 8439 MEDLINE  
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[PMID]:27779106
[Au] Autor:Bobrov E; Skobeleva N; Restifo D; Beglyarova N; Cai KQ; Handorf E; Campbell K; Proia DA; Khazak V; Golemis EA; Astsaturov I
[Ad] Endereço:Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
[Ti] Título:Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models.
[So] Source:Oncotarget;8(3):4399-4409, 2017 Jan 17.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The lack of effective treatment modalities is a major problem in pancreatic cancer (PCa), a devastating malignancy that is nearly universally driven by the "undruggable" KRAS and TP53 cancer genes. Poor tumor tissue penetration is the major source of resistance in pancreatic cancer where chemotherapy is the mainstay of treatment. In this study we exploited the selective tumor-targeting properties of the heat shock 90 protein inhibitors as the vehicle for drug delivery to pancreatic tumor tissues. STA-12-8666 is a novel esterase-cleavable conjugate of an HSP90i and a topoisomerase I inhibitor, SN-38. STA-12-8666 selectively binds activated HSP90 and releases its cytotoxic payload resulting in drug accumulation in pancreatic cancer cells in vivo. We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer.Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced stages of pancreatic tumors doubled their survival (49 days vs. 74 days, p=0.008). STA-12-8666 also demonstrated dramatically superior activity in comparison to equimolar doses of irinotecan against 5 patient-derived pancreatic adenocarcinoma xenografts with prolonged remissions in some tumors. Analysis of activity of STA-12-8666 against tumor tissues and matched cell lines demonstrated prolonged accumulation and release of cytotoxic payload in the tumor leading to DNA damage response and cell cycle arrest.Our results provide a proof-of-principle validation that HSP90i-based drug conjugates can overcome the notorious treatment resistance by utilizing the inherently high affinity of pancreatic cancer cells to HSP90 antagonists.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Camptotecina/análogos & derivados
Carcinoma Ductal Pancreático/tratamento farmacológico
Neoplasias Pancreáticas/tratamento farmacológico
Resorcinóis/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Camptotecina/administração & dosagem
Camptotecina/farmacologia
Carcinoma Ductal Pancreático/genética
Carcinoma Ductal Pancreático/metabolismo
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Dano ao DNA
Seres Humanos
Camundongos
Terapia de Alvo Molecular
Neoplasias Pancreáticas/genética
Neoplasias Pancreáticas/metabolismo
Proteínas Proto-Oncogênicas p21(ras)/genética
Resorcinóis/farmacologia
Proteína Supressora de Tumor p53/genética
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Resorcinols); 0 (STA-12-8666); 0 (Tumor Suppressor Protein p53); EC 3.6.5.2 (Kras2 protein, mouse); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.12642


  5 / 8439 MEDLINE  
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[PMID]:28468669
[Au] Autor:Kondo Y; Hayashi K; Kawakami K; Miwa Y; Hayashi H; Yamamoto M
[Ad] Endereço:Department of Chemotherapy and Palliative Care, Tokyo Women's Medical University, 8-1 Kawada-chyo, Shinjuku-ku, Tokyo, 162-8666, Japan. kondo.yurin@twmu.ac.jp.
[Ti] Título:KRAS mutation analysis of single circulating tumor cells from patients with metastatic colorectal cancer.
[So] Source:BMC Cancer;17(1):311, 2017 05 03.
[Is] ISSN:1471-2407
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The molecular profiles of tumors may inform the selection of appropriate targeted therapies. Circulating tumor cells (CTCs) reflect the real-time status of tumor genotypes. CTCs exhibit high genetic heterogeneity within a patient; accordingly, the analysis of individual CTCs, including their heterogeneity, may enable more precise treatments. We analyzed KRAS mutations in single CTCs from patients with metastatic colorectal cancer (mCRC) using a new single-cell picking system. METHODS: Blood samples were obtained from 61 patients with mCRC. CTCs were enriched and fluorescently labeled using the CellSearch® System. They were recovered using the single-cell picking system based on the fluorescence intensity of marker dyes. Single CTCs and tumor tissue samples were examined for mutations in codons 12 and 13 of the KRAS gene. RESULTS: CTCs were detected in 27 of 61 patients with mCRC. We isolated at least two CTCs from 15 of 27 patients. KRAS genotype was evaluated in a total of 284 CTCs from 11 patients, and 15 cells with mutations were identified in four patients. In 10 of 11 patients, the KRAS status was the same in the primary tumor and CTCs. In one patient, the KRAS status was discordant between the primary tumor and CTCs. In two patients, different KRAS mutations were found among individual CTCs. CONCLUSIONS: We successfully isolated single CTCs and detected KRAS mutations in individual cells from clinical samples using a novel application of single-cell isolation system. Using the system, we detected CTC heterozygosity and heterogeneity in KRAS status among CTCs within a patient and between CTCs and tumor tissues.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
Células Neoplásicas Circulantes/patologia
Proteínas Proto-Oncogênicas p21(ras)/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Neoplasias Colorretais/sangue
Neoplasias Colorretais/patologia
Feminino
Heterogeneidade Genética
Heterozigoto
Seres Humanos
Masculino
Meia-Idade
Mutação
Metástase Neoplásica
Proteínas Proto-Oncogênicas p21(ras)/sangue
Análise de Célula Única
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KRAS protein, human); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180217
[Lr] Data última revisão:
180217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1186/s12885-017-3305-6


  6 / 8439 MEDLINE  
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[PMID]:29199977
[Au] Autor:Xu S; Long BN; Boris GH; Chen A; Ni S; Kennedy MA
[Ad] Endereço:Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.
[Ti] Título:Structural insight into the rearrangement of the switch I region in GTP-bound G12A K-Ras.
[So] Source:Acta Crystallogr D Struct Biol;73(Pt 12):970-984, 2017 Dec 01.
[Is] ISSN:2059-7983
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:K-Ras, a molecular switch that regulates cell growth, apoptosis and metabolism, is activated when it undergoes a conformation change upon binding GTP and is deactivated following the hydrolysis of GTP to GDP. Hydrolysis of GTP in water is accelerated by coordination to K-Ras, where GTP adopts a high-energy conformation approaching the transition state. The G12A mutation reduces intrinsic K-Ras GTP hydrolysis by an unexplained mechanism. Here, crystal structures of G12A K-Ras in complex with GDP, GTP, GTPγS and GppNHp, and of Q61A K-Ras in complex with GDP, are reported. In the G12A K-Ras-GTP complex, the switch I region undergoes a significant reorganization such that the Tyr32 side chain points towards the GTP-binding pocket and forms a hydrogen bond to the GTP γ-phosphate, effectively stabilizing GTP in its precatalytic state, increasing the activation energy required to reach the transition state and contributing to the reduced intrinsic GTPase activity of G12A K-Ras mutants.
[Mh] Termos MeSH primário: Guanosina 5´-O-(3-Tiotrifosfato)/metabolismo
Guanosina Difosfato/metabolismo
Guanosina Trifosfato/metabolismo
Conformação Proteica
Proteínas Proto-Oncogênicas p21(ras)/química
Proteínas Proto-Oncogênicas p21(ras)/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Cristalografia por Raios X
Seres Humanos
Ligações de Hidrogênio
Hidrólise
Modelos Moleculares
Mutação
Proteínas Proto-Oncogênicas p21(ras)/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KRAS protein, human); 146-91-8 (Guanosine Diphosphate); 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate)); 86-01-1 (Guanosine Triphosphate); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171205
[St] Status:MEDLINE
[do] DOI:10.1107/S2059798317015418


  7 / 8439 MEDLINE  
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[PMID]:29374690
[Au] Autor:Lundberg IV; Wikberg ML; Ljuslinder I; Li X; Myte R; Zingmark C; Löfgren-Burström A; Edin S; Palmqvist R
[Ad] Endereço:Department of Medical Biosciences, Pathology, Umeå University, Umea, Sweden ida.lundberg@umu.se.
[Ti] Título:MicroRNA Expression in - and -mutated Colorectal Cancers.
[So] Source:Anticancer Res;38(2):677-683, 2018 02.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: KRAS and BRAF are two genes commonly mutated in colorectal cancer (CRC). Even though BRAF is a downstream target of KRAS in the MAPK signalling pathway, KRAS- and BRAF-mutated CRCs are found to display several different clinical and histopathological features. We investigated whether a differential expression of microRNAs (miRNAs) could explain the clinicopathological differences seen between KRAS- and BRAF-mutated CRCs. MATERIALS AND METHODS: Using a PCR array, we analyzed the expression of 84 different miRNAs in CRC cell lines wild-type in KRAS and BRAF, or mutated in KRAS or BRAF. RESULTS: Ten miRNAs were selected for further analyses in tumor tissue specimens (let-7a, let-7i, miR-10a, miR-10b, miR-31, miR-100, miR-181a, miR-181b, miR-372, and miR-373). BRAF-mutated tumors were found to express significantly higher levels of miR-31 as well as significantly lower levels of miR-373, compared to wild-type tumors. CONCLUSION: Our results suggest that KRAS- and BRAF-mutated CRCs may have different miRNA signatures compared to CRC tumors wild-type in KRAS and BRAF. However, no difference in expression levels between KRAS- and BRAF-mutated tumors was evident for the miRNAs analyzed in this study.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
MicroRNAs/genética
Proteínas Proto-Oncogênicas B-raf/genética
Proteínas Proto-Oncogênicas p21(ras)/genética
[Mh] Termos MeSH secundário: Células CACO-2
Regulação Neoplásica da Expressão Gênica
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KRAS protein, human); 0 (MicroRNAs); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180129
[St] Status:MEDLINE


  8 / 8439 MEDLINE  
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[PMID]:28448716
[Au] Autor:Zhang SY; Sperlich B; Li FY; Al-Ayoubi S; Chen HX; Zhao YF; Li YM; Weise K; Winter R; Chen YX
[Ad] Endereço:Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University , Beijing 100084, China.
[Ti] Título:Phosphorylation Weakens but Does Not Inhibit Membrane Binding and Clustering of K-Ras4B.
[So] Source:ACS Chem Biol;12(6):1703-1710, 2017 06 16.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:K-Ras4B is one of the most frequently mutated Ras isoforms in cancer. The signaling activity of K-Ras4B depends on its localization to the plasma membrane (PM), which is mainly mediated by its polybasic farnesylated C-terminus. On top of the constitutive cycles that maintain the PM enrichment of K-Ras4B, conditional phosphorylation at Ser181 located within this motif has been found to be involved in regulating K-Ras4B's cell distribution and signaling activity. However, discordant observations have undermined our understanding of the role this phosphorylation plays. Here, we report an efficient strategy for producing K-Ras4B simultaneously bearing phosphate, farnesyl, and methyl modifications on a preparative scale, a very useful in vitro system when used in concert with model biomembranes. By using this system, we determined that phosphorylation at Ser181 does not fully inhibit membrane binding and clustering of K-Ras4B but reduces its membrane binding affinity, depending on membrane fluidity. In addition, phosphorylated K-Ras4B maintains tight association with its cytosolic shuttle protein PDEδ. After delivering K-Ras4B containing nonhydrolyzable phosphoserine mimetic into cells, the protein displayed a decreasing PM distribution compared with nonphosphorylable K-Ras4B, implying that phosphorylation might facilitate the dissociation of K-Ras4B from the PM. In addition, phosphorylation does not alter the localization of K-Ras4B in the liquid-disordered lipid subdomains of the membrane but slightly alters the thermotropic properties of K-Ras4B-incorporated membranes probably due to minor differences in membrane partitioning and dynamics. These results provide novel mechanistic insights into the role that phosphorylation at Ser181 plays in regulating K-Ras4B's distribution and activity.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Proteínas Proto-Oncogênicas p21(ras)/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Modelos Biológicos
Fosforilação/fisiologia
Agregados Proteicos
Serina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protein Aggregates); 452VLY9402 (Serine); EC 3.6.1.- (K-Ras4B protein, human); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00165


  9 / 8439 MEDLINE  
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[PMID]:29183007
[Au] Autor:Fan Q; Hu X; Zhang H; Wang S; Zhang H; You C; Zhang CY; Liang H; Chen X; Ba Y
[Ad] Endereço:Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
[Ti] Título:MiR-193a-3p is an Important Tumour Suppressor in Lung Cancer and Directly Targets KRAS.
[So] Source:Cell Physiol Biochem;44(4):1311-1324, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: MicroRNAs (miRNAs) have emerged as major regulators of tumour development and progression in non-small cell lung cancer (NSCLC). However, the role of miR-193a-3p in NSCLC is still unclear. METHODS: Quantitative RT-PCR was used to detect miR-193a-3p expression levels in NSCLC tumour tissues. CCK8, EdU and cell migration assays were performed to analyse the biological functions of miR-193a-3p in NSCLC cells. Luciferase reporter assays were used to validate the bioinformatics-predicted target genes of miR-193a-3p. Western blotting and RNA/DNA interference carried out to evaluate the association between miR-193a-3p and KRAS. RESULTS: miR-193a-3p expression was decreased in the NSCLC tumour tissues. We investigated the biological effects of miR-193a-3p both in vivo and in vitro and found that enforced expression of miR-193a-3p inhibited tumour formation and suppressed cell proliferation and cell migration. KRAS was found to be a potential target of miR-193a-3p, and dual luciferase reporter assays showed that miR-193a-3p directly binds to the 3'-untranslated region (3'-UTR) of KRAS mRNA. In addition, we found that changing the expression of KRAS had the opposite results to those induced by miR-193a-3p in the NSCLC cells. Importantly, simultaneous overexpression of miR-193a-3p and KRAS could counteract the effects of both on cellular functions. CONCLUSION: These findings highlight an important role for miR-193a-3p as a tumour suppressor in NSCLC pathogenesis via the regulation of KRAS expression.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/patologia
Neoplasias Pulmonares/patologia
MicroRNAs/metabolismo
Proteínas Proto-Oncogênicas p21(ras)/metabolismo
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Células A549
Idoso
Animais
Antagomirs/metabolismo
Sequência de Bases
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Carcinoma Pulmonar de Células não Pequenas/metabolismo
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Sobrevivência Celular
Feminino
Seres Humanos
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/metabolismo
Masculino
Camundongos Endogâmicos BALB C
Camundongos Nus
MicroRNAs/antagonistas & inibidores
MicroRNAs/uso terapêutico
Meia-Idade
Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores
Proteínas Proto-Oncogênicas p21(ras)/genética
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Alinhamento de Sequência
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (Antagomirs); 0 (KRAS protein, human); 0 (MIRN193 microRNA, human); 0 (MicroRNAs); 0 (RNA, Small Interfering); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE
[do] DOI:10.1159/000485491


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[PMID]:29246442
[Au] Autor:Coelho MA; de Carné Trécesson S; Rana S; Zecchin D; Moore C; Molina-Arcas M; East P; Spencer-Dene B; Nye E; Barnouin K; Snijders AP; Lai WS; Blackshear PJ; Downward J
[Ad] Endereço:Oncogene Biology, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
[Ti] Título:Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA.
[So] Source:Immunity;47(6):1083-1099.e6, 2017 Dec 19.
[Is] ISSN:1097-4180
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. The relative importance of the tumor microenvironment and cancer cell-intrinsic signaling in the regulation of PD-L1 expression remains unclear. We report that oncogenic RAS signaling can upregulate tumor cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability via modulation of the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3' UTR of PD-L1 mRNA. MEK signaling downstream of RAS leads to phosphorylation and inhibition of TTP by the kinase MK2. In human lung and colorectal tumors, RAS pathway activation is associated with elevated PD-L1 expression. In vivo, restoration of TTP expression enhances anti-tumor immunity dependent on degradation of PD-L1 mRNA. We demonstrate that RAS can drive cell-intrinsic PD-L1 expression, thus presenting therapeutic opportunities to reverse the innately immunoresistant phenotype of RAS mutant cancers.
[Mh] Termos MeSH primário: Antígeno B7-H1/imunologia
Neoplasias Colorretais/imunologia
Regulação Neoplásica da Expressão Gênica
Neoplasias Pulmonares/imunologia
Proteínas Proto-Oncogênicas p21(ras)/imunologia
Tristetraprolina/imunologia
Evasão Tumoral
[Mh] Termos MeSH secundário: Animais
Antígeno B7-H1/genética
Linhagem Celular Tumoral
Neoplasias Colorretais/genética
Neoplasias Colorretais/patologia
Células Epiteliais/imunologia
Células Epiteliais/patologia
Feminino
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/imunologia
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
MAP Quinase Quinase Quinases/genética
MAP Quinase Quinase Quinases/imunologia
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Transplante de Neoplasias
Ligação Proteica
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/imunologia
Proteínas Proto-Oncogênicas p21(ras)/genética
Clivagem do RNA
Estabilidade de RNA
RNA Mensageiro/genética
RNA Mensageiro/imunologia
Transdução de Sinais
Tristetraprolina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Cd274 protein, mouse); 0 (Intracellular Signaling Peptides and Proteins); 0 (RNA, Messenger); 0 (Tristetraprolin); 0 (Zfp36 protein, mouse); EC 2.7.1.- (MAP-kinase-activated kinase 2); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.25 (MAP Kinase Kinase Kinases); EC 3.6.5.2 (Kras2 protein, mouse); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE



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