Diaz-Moralli S.,University of Barcelona |
Ramos-Montoya A.,University of Barcelona |
Marin S.,University of Barcelona |
Fernandez-Alvarez A.,Institute of Biomedicine of Valencia |
And 3 more authors.
American Journal of Physiology - Endocrinology and Metabolism
Carbohydrate response element-binding protein (ChREBP) is a transcription factor that mediates glucose signaling in mammalian liver, leading to the expression of different glycolytic and lipogenic genes, such as pyruvate kinase (L-PK) and fatty acid synthase (FAS). The current model for ChREBP activation in response to sugar phosphates holds that glucose metabolization to xylulose 5-phosphate (X-5-P) triggers the activation of protein phosphatase 2A, which dephosphorylates ChREBP and leads to its nuclear translocation and activation. However, evidence indicates that glucose 6-phosphate (G-6-P) is the most likely signal metabolite for the glucose-induced transcription of these genes. The glucose derivative that is responsible for carbohydrate-dependent gene expression remains to be identified. The difficulties in measuring G-6-P and X-5-P concentrations simultaneously and in changing them independently have hindered such identification. To discriminate between these possibilities, we adapted a liquid chromatography mass spectrometry method to identify and quantify sugar phosphates in human hepatocarcinoma cells (Hep G2) and rat hepatocytes in response to different carbon sources and in the presence/absence of a glucose-6-phosphate dehydrogenase inhibitor. We also used this method to demonstrate that these cells could not metabolize 2-deoxyglucose beyond 2-deoxyglucose-6-phosphate. The simultaneous quantification of sugar phosphates and FAS and L-PK expression levels demonstrated that both X-5-P and G-6-P play a role in the modulation of gene expression. In conclusion, this report presents for the first time a single mechanism that incorporates the effects of X-5-P and G-6-P on the enhancement of the expression of carbohydrate-responsive genes. © 2012 the American Physiological Society. Source
Esophageal diseases: Gastroesophageal reflux disease, Barrett's esophagus and eosinophilic esophagitis [Enfermedades esofágicas: Enfermedad por reflujo gastroesofágico, esófago de Barrett y esofagitis eosinofílica]
Calvet X.,Autonomous University of Barcelona |
Calvet X.,Research Center Biomedica En Red Of Enfermedades
Gastroenterologia y Hepatologia
Interesting advances are always reported in Digestive Disease Week. This year's studies on gastroesophageal reflux disease (GERD) stressed the role of weight gain and psychological factors in both symptom production and lack of treatment response. In Barrett's esophagus, radiofrequency ablation has become the treatment of choice in cases associated with dysplasia or neoplasms in situ. Finally, notable studies of eosinophilic esophagitis highlighted the difficulty of distinguishing between this entity and GERD. Topical steroids and exclusion diets are effective therapeutic alternatives. © 2011 Elsevier España S.L. Source
Munoz-Gamez J.A.,Hospital Universitario San Cecilio |
Quiles-Perez R.,Hospital Universitario San Cecilio |
Quiles-Perez R.,Research Center Biomedica En Red Of Enfermedades |
Ruiz-Extremera A.,Hospital Universitario San Cecilio |
And 9 more authors.
The purpose of this study was to investigate whether PARP-1 inhibition sensitizes human liver cancer cell lines to doxorubicin treatment. Both the addition of PARP-1 inhibitor (ANI) and depletion by means of stable siRNA significantly enhanced the growth inhibition induced by the DNA damage agents used. This effect was associated with an accumulation of unrepaired DNA, with a reduction in EGFR and Bcl-xL gene expression as well as with positive annexin-V staining. These results provide novel evidence of the direct role of PARP-1 in tumour chemoresistance in relation to its effects on the transcription of key genes involved in tumour survival. © 2010 Elsevier Ireland Ltd. Source
Rodriguez-Rodero S.,Instituto Universitario Of Oncologia Del Principado Of Asturias |
Fernandez A.F.,Instituto Universitario Of Oncologia Del Principado Of Asturias |
Fernandez-Morera J.L.,Instituto Universitario Of Oncologia Del Principado Of Asturias |
Castro-Santos P.,Instituto Universitario Of Oncologia Del Principado Of Asturias |
And 27 more authors.
Journal of Clinical Endocrinology and Metabolism
Objective: The purpose of this study was to determine the global patterns of aberrant DNA methylation in thyroid cancer. Research Design and Methods: We have used DNA methylation arrays to determine, for the first time, the genome-wide promoter methylation status of papillary, follicular, medullary, and anaplastic thyroid tumors. Results: We identified 262 and 352 hypermethylated and 13 and 21 hypomethylated genes in differentiated papillary and follicular tumors, respectively. Interestingly, the other tumor types analyzed displayed more hypomethylated genes (280 in anaplastic and 393 in medullary tumors) than aberrantly hypermethylated genes (86 in anaplastic and 131 in medullary tumors). Among the genes indentified, we show that 4 potential tumor suppressor genes (ADAMTS8, HOXB4, ZIC1, and KISS1R) and 4 potential oncogenes (INSL4, DPPA2, TCL1B, and NOTCH4) are frequently regulated by aberrant methylation in primary thyroid tumors. In addition, we show that aberrant promoter hypomethylation- associated overexpression of MAP17 might promote tumor growth in thyroid cancer. Conclusions: Thyroid cancer subtypes present differential promoter methylation signatures, and nondifferentiated subtypes are characterized by aberrant promoter hypomethylation rather than hypermethylation. Additional studies are needed to determine the potential clinical interest of the tumor subtype-specific DNA methylation signatures described herein and the role of aberrant promoter hypomethylation in nondifferentiated thyroid tumors. Copyright © 2013 by The Endocrine Society. Source
Errafiy R.,Research Center Principe Felipe |
Errafiy R.,Universite Ibn Tofail |
Aguado C.,Research Center Principe Felipe |
Aguado C.,Research Center Biomedica En Red Of Enfermedades |
And 6 more authors.
Two major mechanisms of intracellular protein degradation, autophagy and the ubiquitin-proteasome pathway, operate in mammalian cells. PTEN, which is frequently mutated in glioblastomas, is a tumor suppressor gene that encodes a dual specificity phosphatase that antagonizes the phosphatidylinositol 3-kinase class I/AKT/mTOR pathway, which is a key regulator of autophagy. Here, we investigated in U87MG human glioma cells the role of PTEN in the regulation of autophagy and the ubiquitin-proteasome pathway, because both are functionally linked and are relevant in cancer progression. Since U87MG glioma cells lack a functional PTEN, we used stable clones that express, under the control of a tetracycline-inducible system (Tet-on), wild-type PTEN and two of its mutants, G129EPTEN and C124S-PTEN, which, respectively, lack the lipid phosphatase activity only and both the lipid and the protein phosphatase activities of this protein. Expression of PTEN in U87MG glioma cells decreased proteasome activity and also reduced protein ubiquitination. On the contrary, expression of PTEN increased the autophagic flux and the lysosomal mass. Interestingly, and although PTEN negatively regulates the phosphatidylinositol 3-kinase class I/AKT/mTOR signaling pathway by its lipid phosphatase activity, both effects in U87MG cells were independent of this activity. These results suggest a new mTOR-independent signaling pathway by which PTEN can regulate in opposite directions the main mechanisms of intracellular protein degradation. © 2013 Errafiy et al. Source