RESUMEN
Steroid sulfatase (STS) is responsible for the hydrolysis of aryl and alkyl steroid sulfates and has a pivotal role in regulating the formation of biologically active estrogens. STS may be considered a new promising drug target for treating estrogen-mediated carcinogenesis. However, the molecular mechanism of STS expression is not well-known. To investigate whether tumor necrosis factor (TNF)-alpha is able to regulate gene transcription of STS, we studied the effect of TNF-alpha on STS expression in PC-3 human prostate cancer cells. RT-PCR and Western blot analysis showed that TNF-alpha significantly induced the expression of STS mRNA and protein in a concentration- and time-dependent manner. Treatment with TNF-alpha resulted in a strong increase in the phosphorylation of Akt on Ser-473 and when cells were treated with phosphatidylinositol (PI) 3-kinase inhibitors such as LY294002 or wortmannin, or Akt inhibitor (Akt inhibitor IV), induction of STS mRNA expression by TNF-alpha was significantly prevented. Moreover, activation of Akt1 by expressing the constitutively active form of Akt1 increased STS expression whereas dominant-negative Akt suppressed TNF-alpha-mediated STS induction. We also found that TNF-alpha is able to increase STS mRNA expression in other human cancer cells such as LNCaP, MDA-MB-231, and MCF-7 as well as PC-3 cells. Taken together, our results strongly suggest that PI 3-kinase/Akt activation mediates induction of human STS gene expression by TNF-alpha in human cancer cells.
Asunto(s)
Humanos , Masculino , Western Blotting , Técnica del Anticuerpo Fluorescente , Fosfatidilinositol 3-Quinasa/genética , Fosforilación/efectos de los fármacos , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Recombinantes/genética , Transducción de Señal , Esteril-Sulfatasa/genética , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
La ictiosis ligada al cromosoma X es una genodermatosis poco frecuente que afecta a varones a partir de las 2 semanas de vida y se caracteriza por xerodermia, hiperqueratosis, descamación y, en algunos casos, manifestaciones extracutáneas como criptorquidia y opacidad de la córnea. La enfermedad es de evolución crónica y experimenta mejoría parcial en época estival. La deleción total o parcial de la enzima sulfatasa esteroidea es la causa de las manifestaciones clínicas. Presentamos tres pacientes con ictiosis ligada al cromosoma X, a quienes se les realizaron interconsultas con los servicio de Oftalmología y Pediatría. Se encuentran actualmente en tratamiento con emolientes...
Asunto(s)
Humanos , Masculino , Niño , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Esteril-Sulfatasa/genética , Ictiosis Ligada al Cromosoma X/genética , Diagnóstico Diferencial , Piel/patologíaRESUMEN
We describe a 10-year-old boy with X-linked ichthyosis, Kallmann Syndrome and unilateral renal agenesis who presented with nephrotic syndrome. DNA analysis revealed deletion of the Steroid Sulfatase (STS) gene. STS deficiency in X-linked ichthyosis leads to cholesterol sulfate accumulation, which induces transglutaminase-1 dysfunction. Since the slit diaphragm of the glomerular epithelial cell is a modified adherens junction, the accumulation of cholesterol sulfate could interfere with the normal slit diaphragm function of the glomerular visceral epithelial cell, resulting in nephrotic range proteinuria. The child went into remission on oral prednisolone.
Asunto(s)
Niño , Eliminación de Gen , Humanos , Ictiosis Ligada al Cromosoma X/diagnóstico , Síndrome de Kallmann/diagnóstico , Riñón/anomalías , Masculino , Síndrome Nefrótico/diagnóstico , Esteril-Sulfatasa/genéticaRESUMEN
To investigate the gene mutation in a pedigree with X-linked ichthyosis (XLI) and to explore the relationship between the mutation and its clinical manifestations, genomic DNA of affected members, the normal member of the pedigree and 50 unrelated normal members was extracted with a whole blood genomic DNA extraction kit and the DNA was used as a template for the polymerase chain reaction (PCR)-mediated amplification of exon 1 and exon 10 of the STS gene. hHb6 (human hair basic keratin) gene was used as the internal control. Our results showed that the STS gene was deleted in affected members in the pedigree with X-linked ichthyosis. The normal member of the pedigree and 50 unrelated normal members had no such deletion. The proband and his mother had products in the internal control after PCR amplification. The blank control had no product. It is concluded that deletion of the STS gene existed in this pedigree with X-linked ichthyosis, and it is responsible for the unique skin lesions of X-linked ichthyosis.