RESUMO
BACKGROUND: HPV16 infection is one of the main risk factors involved in the development of cervical cancer, mainly due to the high oncogenic potential of the viral proteins E6 and E7, which are involved in the different processes of malignant transformation. There is a broad spectrum of intratypical variation of E6, which is reflected in its high diversity, biological behavior, global distribution and risk of causing cervical cancer. Experimental studies have shown that the intratypical variants of the protein E6 from the European variants (E-G350, E-A176/G350, E-C188/G350) and Asian-American variants (AAa and AAc), are capable of inducing the differential expression of genes involved in the development of cervical cancer. RESULTS: An in silico analysis was performed to characterize the molecular effects of these variations using the structure of the HPV16 E6 oncoprotein (PDB: 4XR8; chain H) as a template. In particular, we evaluated the 3D structures of the intratypical variants by structural alignment, ERRAT, Ramachandran plots and prediction of protein disorder, which was further validated by molecular dynamics simulations. Our results, in general, showed no significant changes in the protein 3D structure. However, we observed subtle changes in protein physicochemical features and structural disorder in the N- and C-termini. CONCLUSIONS: Our results showed that mutations in the viral oncogene E6 of six high-risk HPV16 variants are effectively neutral and do not cause significant structural changes except slight variations of structural disorder. As structural disorder is involved in rewiring protein-protein interactions, these results suggest a differential pattern of interaction of E6 with the target protein P53 and possibly different patterns of tumor aggressiveness associated with certain types of variants of the E6 oncoprotein.
Assuntos
Simulação por Computador , Variação Genética , Proteínas Oncogênicas Virais/química , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas/química , Proteínas Oncogênicas/genética , Proteínas Repressoras/química , Proteínas Repressoras/genética , Sequência de Aminoácidos , Humanos , Simulação de Dinâmica Molecular , Estrutura Secundária de ProteínaRESUMO
Breast and cervical cancer are the first and fourth cancer types with the highest prevalence in women, respectively. The developmental profiles of cancer in women can vary by genetic markers and cellular events. In turn, age and lifestyle influence in the cellular response and also on the cancer progression and relapse. The human DEK protein, a histone chaperone, belongs to a specific subclass of chromatin topology modulators, being involved in the regulation of DNA-dependent processes. These epigenetic mechanisms have dynamic and reversible nature, have been proposed as targets for different treatment approaches, especially in tumor therapy. The expression patterns of DEK vary between healthy and cancer cells. High expression of DEK is associated with poor prognosis in many cancer types, suggesting that DEK takes part in oncogenic activities via different molecular pathways, including inhibition of senescence and apoptosis. The focus of this review was to highlight the role of the DEK protein in these two female cancers.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Oncogênicas/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Neoplasias do Colo do Útero/metabolismo , Saúde da Mulher , Animais , Biomarcadores Tumorais/química , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/genética , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Oncogênicas/química , Proteínas Oncogênicas/genética , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/genética , Prognóstico , Conformação Proteica , Relação Estrutura-Atividade , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapiaRESUMO
Biosynthesis of nucleoside triphosphates is critical for bioenergetics and nucleic acid replication, and this is achieved by nucleoside diphosphate kinase (NDK). As an emerging biological model and the global importance of shrimp culture, we have addressed the study of the Pacific whiteleg shrimp (Litopenaeus vannamei) NDK. We demonstrated its activity and affinity towards deoxynucleoside diphosphates. Also, the quaternary structure obtained by gel filtration chromatography showed that shrimp NDK is a trimer. Affinity was in the micro-molar range for dADP, dGDP, dTDP and except for dCDP, which presented no detectable interaction by isothermal titration calorimetry, as described previously for Plasmodium falciparum NDK. This information is particularly important, as this enzyme could be used to test nucleotide analogs that can block white spot syndrome virus (WSSV) viral replication and to study its bioenergetics role during hypoxia and fasting.
Assuntos
Nucleosídeo NM23 Difosfato Quinases/metabolismo , Animais , Domínio Catalítico , Modelos Moleculares , Nucleosídeo NM23 Difosfato Quinases/química , Nucleosídeo NM23 Difosfato Quinases/genética , Proteínas Oncogênicas/química , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Frutos do MarRESUMO
Con objeto de caracterizar la expresión inmunohistoquímica de la oncoproteína p53 en neoplasias melanocíticas de la piel, se estudiaron 100 casos de nevos y melanoma maligno primario de la piel del período enero 1990 agosto 1994. Se recolectaron 68 casos de nevo melanocítico y 32 casos de melanoma maligno. Reacción positiva se encontró en 8 nevos melanocíticos (11,8 por ciento) y 17 melanomas (53,1 por ciento). Del total de nevos, reacción positiva se observó en 1 compuesto, 2 nevos dérmicos, 3 nevos de Clark y 2 nevos de Spitz. La reacción positiva en melanoma maligno varió de 33 a 71 por ciento en las distintas variedades de melanoma. Los resultados muestran una expresión de oncoproteína p53 de aproximadamente 53 por ciento en melanoma maligno y 12 por ciento en nevos melanocíticos. La reacción positiva se observó en menos del 5 por ciento de las células. La expresión de oncoproteína p53 no está limitada a neoplasias melanocíticas malignas y las mutaciones del gen p53 parecen acumularse en la fase de progresión del melanoma maligno de la piel