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Tapia M.,Instituto Cajal | Tapia M.,Research Center Biomedica en Red Sobre Enfermedades Neurodegenerativas | Del Puerto A.,Instituto Cajal | Del Puerto A.,Research Center Biomedica en Red Sobre Enfermedades Neurodegenerativas | And 16 more authors.
Cellular and Molecular Life Sciences | Year: 2013

Neuronal action potentials are generated through voltage-gated sodium channels, which are tethered by ankyrinG at the membrane of the axon initial segment (AIS). Despite the importance of the AIS in the control of neuronal excitability, the cellular and molecular mechanisms regulating sodium channel expression at the AIS remain elusive. Our results show that GSK3α/β and β-catenin phosphorylated by GSK3 (S33/37/T41) are localized at the AIS and are new components of this essential neuronal domain. Pharmacological inhibition of GSK3 or β-catenin knockdown with shRNAs decreased the levels of phosphorylated-β-catenin, ankyrinG, and voltage-gated sodium channels at the AIS, both in vitro and in vivo, therefore diminishing neuronal excitability as evaluated via sodium current amplitude and action potential number. Thus, our results suggest a mechanism for the modulation of neuronal excitability through the control of sodium channel density by GSK3 and β-catenin at the AIS. © 2012 Springer Basel AG.


Fernandez-Barral A.,Autonomous University of Madrid | Fernandez-Barral A.,Institute Investigaciones Biomedicas Alberto Sols | Orgaz J.L.,Autonomous University of Madrid | Orgaz J.L.,Institute Investigaciones Biomedicas Alberto Sols | And 28 more authors.
Neoplasia (United States) | Year: 2014

Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma. © 2014 Neoplasia Press, Inc.


PubMed | Complutense University of Madrid, Institute Investigaciones Biomedicas Alberto Sols, University of Glasgow, University of Strasbourg and 7 more.
Type: Journal Article | Journal: Neoplasia (New York, N.Y.) | Year: 2014

Pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor superfamily, has potent anti-metastatic effects in cutaneous melanoma through its direct actions on endothelial and melanoma cells. Here we show that PEDF expression positively correlates with microphthalmia-associated transcription factor (MITF) in melanoma cell lines and human samples. High PEDF and MITF expression is characteristic of low aggressive melanomas classified according to molecular and pathological criteria, whereas both factors are decreased in senescent melanocytes and naevi. Importantly, MITF silencing down-regulates PEDF expression in melanoma cell lines and primary melanocytes, suggesting that the correlation in the expression reflects a causal relationship. In agreement, analysis of Chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) data sets revealed three MITF binding regions within the first intron of SERPINF1, and reporter assays demonstrated that the binding of MITF to these regions is sufficient to drive transcription. Finally, we demonstrate that exogenous PEDF expression efficiently halts in vitro migration and invasion, as well as in vivo dissemination of melanoma cells induced by MITF silencing. In summary, these results identify PEDF as a novel transcriptional target of MITF and support a relevant functional role for the MITF-PEDF axis in the biology of melanoma.


Prieto Munoz I.,Capio Fundacion Jimenez Diaz | Pardo Masferrer J.,Hospital Universitari Son Espases | Olivera Vegas J.,Capio Fundacion Jimenez Diaz | Fortes Alen J.R.,Capio Fundacion Jimenez Diaz | Perez Casas A.M.,Capio Fundacion Jimenez Diaz
Clinical and Translational Oncology | Year: 2012

Merkel cell carcinoma (MCC) is a rare primary cutaneous carcinoma of the skin that is highly aggressive, and has a high risk of locoregional and distant spread, a mortality rate considerably higher than that of cutaneous melanoma and poor survival. Its incidence has increased during the past twenty years. The studies published since 2008 have introduced changes in the understanding of its epidemiology and pathogenesis, and consequently the therapeutic approach. Despite this, there is still controversy surrounding its optimal management, which requires clarification. This is the purpose of this review.


PubMed | Capio Fundacion Jimenez Diaz
Type: Journal Article | Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico | Year: 2012

Merkel cell carcinoma (MCC) is a rare primary cutaneous carcinoma of the skin that is highly aggressive, and has a high risk of locoregional and distant spread, a mortality rate considerably higher than that of cutaneous melanoma and poor survival. Its incidence has increased during the past twenty years. The studies published since 2008 have introduced changes in the understanding of its epidemiology and pathogenesis, and consequently the therapeutic approach. Despite this, there is still controversy surrounding its optimal management, which requires clarification. This is the purpose of this review.

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