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1.
J Mol Med (Berl) ; 101(9): 1073-1082, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37420139

RESUMO

Hemoglobinopathies affect patients in the wider Mediterranean area consisting of 4 distinct subgroups: beta thalassemia major (TM), beta thalassemia intermedia (TI), sickle cell disease (SCD) and hemoglobin H disease (alpha thalassemia). The clinical spectrum varies from mild to severe. Complex interactions between genes and environmental factors form the clinical manifestations. There is an unmet need to clarify these multifactorial mechanisms. This is the first Greek study describing mutational alleles (HBB and HBA1/HBA2 gene variants) in 217 patients with hemoglobinopathies of two large centers in Greece (Larissa and Athens) and associating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). Thus, the complex interplay between corresponding genotypes and phenotypes was investigated. Our results are in accordance with previous national studies with limited variations, due to regional prevalence of specific gene variants, as expected. It is also a description of the prevalence of hemoglobinopathies in the Greek population. The type and prevalence of beta and alpha globin gene variants differ significantly among countries. We also confirm the well-known observation of many studies that in our beta thalassemic or SCD patients, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course, whereas the inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype. In cases in whom the genotype and phenotype did not correlate, factors like the function or modification of possible regulatory genes or additional nutritional-environmental effects should be investigated. KEY MESSAGES: • This is the first Greek study, fully molecularly defining the beta and alpha mutational alleles in 217 patients with hemoglobinopathies of two large centers in Greece and correlating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). • In the beta thalassemic or SCD patients of our cohort, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course (confirmation of a well-known previous observation). • The inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype (confirmation of a well known previous observation). • The function or modification of possible regulatory genes should be investigated in cases in whom the genotype and phenotype did not correlate.


Assuntos
Hemoglobinopatias , Talassemia alfa , Talassemia beta , Humanos , Relevância Clínica , Grécia , Genótipo , Hemoglobinopatias/genética , Fenótipo , Mutação , Talassemia beta/epidemiologia , Talassemia beta/genética , Talassemia alfa/epidemiologia , Talassemia alfa/genética , alfa-Globinas/genética , Progressão da Doença
2.
Cell Signal ; 27(6): 1129-40, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25744540

RESUMO

Proliferation of cells under hypoxia is facilitated by metabolic adaptation, mediated by the transcriptional activator Hypoxia Inducible Factor-1 (HIF-1). HIF-1α, the inducible subunit of HIF-1 is regulated by oxygen as well as by oxygen-independent mechanisms involving phosphorylation. We have previously shown that CK1δ phosphorylates HIF-1α in its N-terminus and reduces its affinity for its heterodimerization partner ARNT. To investigate the importance of this mechanism for cell proliferation under hypoxia, we visually monitored HIF-1α interactions within the cell nucleus using the in situ proximity ligation assay (PLA) and fluorescence recovery after photobleaching (FRAP). Both methods show that CK1δ-dependent modification of HIF-1α impairs the formation of a chromatin binding HIF-1 complex. This is confirmed by analyzing expression of lipin-1, a direct target of HIF-1 that mediates hypoxic neutral lipid accumulation. Inhibition of CK1δ increases lipid droplet formation and proliferation of both cancer and normal cells specifically under hypoxia and in an HIF-1α- and lipin-1-dependent manner. These data reveal a novel role for CK1δ in regulating lipid metabolism and, through it, cell adaptation to low oxygen conditions.


Assuntos
Caseína Quinase Idelta/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Gotículas Lipídicas/fisiologia , Fosfatidato Fosfatase/metabolismo , Hipóxia Celular , Linhagem Celular , Proliferação de Células , Recuperação de Fluorescência Após Fotodegradação , Células HeLa , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Metabolismo dos Lipídeos , Fosforilação , Interferência de RNA , RNA Interferente Pequeno/metabolismo
3.
J Proteomics ; 75(17): 5356-69, 2012 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-22800643

RESUMO

Mutation of RAS genes is one of the most common oncogenic alterations in cancer and acquisition of activating RAS mutations has been demonstrated to cause progression of colorectal adenoma to cancer. The aim of this study was to identify changes in the proteome of the intermediate-stage colorectal cancer cell line Caco2, induced by ectopic expression of two distinct RAS proteins, KRAS(V12) and HRAS(V12), in their mutated, constitutively active form. Using 2D-gel electrophoresis, followed by LC-MS/MS we identified almost 200 differentially expressed proteins in pair-wise comparisons of Caco2 vs Caco2-KRAS(V12) and Caco2 vs Caco2-HRAS(V12). Although many of the affected proteins were unique for each pair, there were also substantial similarities. Interestingly, transformation by the mutant KRAS(V12) gene resulted in elevated expression levels and activity of endogenous H-ras protein. Silencing the latter with a specific RNAi reversed several proteomic changes observed in KRAS(V12)-transformed cells, suggesting that oncogenic K-ras partly exerts its effects through endogenous H-ras activation. Alterations in the expression of cytoskeletal and cell adhesion proteins, caused by HRAS siRNA treatment, correlated with a reduction in the invasive properties of Caco2-KRAS(V12) cells. Our data suggest a novel interplay between K-ras and H-ras, with possible implications for colorectal carcinogenesis.


Assuntos
Adenocarcinoma/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/metabolismo , Genes ras/fisiologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Células CACO-2 , Linhagem Celular Tumoral , Análise por Conglomerados , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Eletroforese em Gel Bidimensional , Células HCT116 , Humanos , Redes e Vias Metabólicas/genética , Modelos Biológicos , Oncogenes/fisiologia , Proteômica/métodos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Espectrometria de Massas em Tandem
4.
Crit Rev Clin Lab Sci ; 46(5-6): 319-42, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19958217

RESUMO

Colorectal cancer usually develops in clearly defined stages, with distinct molecular alterations characterizing each transition. This often slow process makes colorectal cancer an ideal target for early detection programs. The blossoming of global, -omics approaches in recent years has led to greatly increased expectations for novel diagnostic and prognostic tools. Despite many early disappointments and the resulting skepticism, real progress has been made with exciting new prospects for cancer research. This review summarizes currently available proteomic tools for identifying novel biomarkers and drug targets, as well as an overview of their application in research on molecular mechanisms of carcinogenesis. Emphasis is given to novel sample preparation methods, protein separation and identification techniques, and advanced mass spectrometry tools for quantitative proteomic. The most important applications of these technologies in colorectal cancer research are discussed.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias Colorretais/metabolismo , Proteínas de Neoplasias/metabolismo , Proteômica/métodos , Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/metabolismo , Cromatografia Líquida de Alta Pressão , Neoplasias Colorretais/diagnóstico , Eletroforese , Humanos , Espectrometria de Massas , Proteínas de Neoplasias/química , Prognóstico , Análise Serial de Proteínas , Processamento de Proteína Pós-Traducional
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