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Ramos L.,University of Cantabria | Ramos L.,Fundacion Institute Investigacion Marques Of Valdecilla Idival | Piedra M.,University of Cantabria | Piedra M.,Fundacion Institute Investigacion Marques Of Valdecilla Idival | And 4 more authors.
Calcified Tissue International | Year: 2014

Ectopic calcifications and even bone formation have been linked to GNAS gene mutations. A 51-year-old Caucasian female had been diagnosed of pseudo-pseudohypoparathyroidism (PPHP) in 1989. She has always had normal serum parathyroid hormone, calcium, and phosphorus levels. A non-contrast computed tomography of the head was done in 2013 and it showed finely speckled subcutaneous calcifications in the high convexity of the head. Cutaneous exploration did not show any abnormality. We herein report an unusual case of late-onset scalp calcifications in a patient with PPHP. © 2014 Springer Science+Business Media.


Freije A.,Fundacion Institute Investigacion Marques Of Valdecilla Idival | Molinuevo R.,Fundacion Institute Investigacion Marques Of Valdecilla Idival | Ceballos L.,Fundacion Institute Investigacion Marques Of Valdecilla Idival | Cagigas M.,Fundacion Institute Investigacion Marques Of Valdecilla Idival | And 9 more authors.
Cell Reports | Year: 2014

Tumor suppressor p53 is a major cellular guardian ofgenome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show thateither loss of endogenous p53 or overexpressionofa temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear. © 2014 The Authors.


PubMed | Fundacion Institute Investigacion Marques Of Valdecilla Idival, University of Michigan and Vanderbilt University
Type: Journal Article | Journal: Oncogene | Year: 2016

Epidermal growth factor receptor (EGFR) is central to epithelial cell physiology, and deregulated EGFR signaling has an important role in a variety of human carcinomas. Here we show that silencing of the EGF-related factor amphiregulin (AREG) markedly inhibits the expansion of human keratinocytes through mitotic failure and accumulation of cells with 4n DNA content. RNA-sequencing-based transcriptome analysis revealed that tetracycline-mediated AREG silencing significantly altered the expression of 2331 genes, 623 of which were not normalized by treatment with EGF. Interestingly, genes irreversibly upregulated by suppression of AREG overlapped with genes involved in keratinocyte differentiation. Moreover, a significant proportion of the irreversibly downregulated genes featured upstream binding sites recognized by forkhead box protein M1 (FoxM1), a key transcription factor in the control of mitosis that is widely dysregulated in cancer. The downregulation of FoxM1 and its target genes preceded mitotic arrest. Constitutive expression of FoxM1 in AREG knockdown cells normalized cell proliferation, reduced the number of cells with 4n DNA content and rescued expression of FoxM1 target genes. These results demonstrate that AREG controls G2/M progression and cytokinesis in keratinocytes via activation of a FoxM1-dependent transcriptional program, suggesting new avenues for treatment of epithelial cancer.


PubMed | Fundacion Institute Investigacion Marques Of Valdecilla Idival, University of Barcelona, French Institute of Health and Medical Research, Hospital Universitario Marques Of Valdecilla Humv and Instituto Universitario Of Oncologia Of Asturias Iuopa Hospital Universitario Central Of Asturias Huca
Type: Journal Article | Journal: Cell reports | Year: 2014

Tumor suppressor p53 is a major cellular guardian of genome integrity, and its inactivation is the most frequent genetic alteration in cancer, rising up to 80% in squamous cell carcinoma (SCC). By adapting the small hairpin RNA (shRNA) technology, we inactivated endogenous p53 in primary epithelial cells from the epidermis of human skin. We show that either loss of endogenous p53 or overexpression of a temperature-sensitive dominant-negative conformation triggers a self-protective differentiation response, resulting in cell stratification and expulsion. These effects follow DNA damage and exit from mitosis without cell division. p53 preserves the proliferative potential of the stem cell compartment and limits the power of proto-oncogene MYC to drive cell cycle stress and differentiation. The results provide insight into the role of p53 in self-renewal homeostasis and help explain why p53 mutations do not initiate skin cancer but increase the likelihood that cancer cells will appear.

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