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1.
Folia Biol (Praha) ; 66(4): 133-141, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33745260

RESUMEN

Von Willebrand disease is a commonly inherited bleeding disorder caused by defects of von Willebrand factor (vWF). In the most common valve diseases, aortic valve stenosis (AVS) and mitral valve regurgitation (MVR), a bleeding tendency has been described in a number of patients. This has been associated to a high turbulence of blood flow through the compromised valve, promoting degradation of vWF with loss of high-molecular-weight multimers of vWF (HMWM), leading to an acquired von Willebrand syndrome (AvWS). We analysed three groups of patients, one affected by AVS, treated with transcatheter aortic valve implantation (TAVI), the second group of patients affected by MVR, treated with Mitraclip® mitral valve repair. The third group was represented by patients also affected by AVS, but not eligible for TAVI and treated with standard surgery. A fourth group of patients that underwent percutaneous coronary intervention (PCI) with stenting was used as a control. Our results demonstrated that the level of vWF measured as antigen concentration (vWF:Ag) increases in all cohorts of patients after treatment, while in control PCI patients, no modification of vWF:Ag has been registered. Western blot analysis showed only a quantitative loss of vWF in the pre-treatment time, but without significant HMWM modification. The monitoring of the vWF:Ag concentration, but not the quality of HMWM, can indicate the status of blood flow in the treated patients, thus introducing the possibility of using the vWF antigen detection in monitoring the status of replaced or repaired valves.


Asunto(s)
Estenosis de la Válvula Aórtica/sangre , Insuficiencia de la Válvula Mitral/sangre , Factor de von Willebrand/análisis , Estenosis de la Válvula Aórtica/diagnóstico , Humanos , Insuficiencia de la Válvula Mitral/diagnóstico , Intervención Coronaria Percutánea , Plasma , Reemplazo de la Válvula Aórtica Transcatéter , Enfermedades de von Willebrand
2.
Folia Biol (Praha) ; 65(4): 170-180, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31903890

RESUMEN

The pathogenic molecular mechanisms underlying the insurgence of nasal polyps has not been completely defined. In some patients, these lesions can have a recurrence after surgery removal, and the difference between recurrent and not recurrent patients is still unclear. To molecularly characterize and distinguish between these two classes, a cohort of patients affected by nasal polyposis was analysed. In all patients we analysed the p63 isoform expression using fresh tissues taken after surgery. Moreover, confocal immunofluorescence analysis of fixed sections was performed. The results show high ΔNp63 expression in samples from the nasal polyps of patients compared to the normal epithelia. Analysis of the expression level of the TAp63 isoform shows differential expression between the patients with recurrence compared to those not recurring. The data, considered as the ΔN/TAp63 ratio, really discriminate the two groups. In fact, even though ΔNp63 is expressed in non-recurrent patients, the resulting ratio ΔN/TAp63 is significantly lower in these patients. This clearly indicates that the status of TAp63 expression, represented by the ΔN/TAp63 ratio, could be considered a prognostic marker of low recurrence probability. In these samples we also investigated the expression of OTX2 transcription factor, known to be a selective activator of TAp63, detecting a significant correlation. Database analysis of HNSCC patients showed increased survival for the patients presenting OTX2 amplification and/or overexpression. These results, together with the fact that TAp63 can be selectively upregulated by HDAC inhibitors, open the possibility to consider local treatment of recurrent nasal polyps with these molecules.


Asunto(s)
Pólipos Nasales/metabolismo , Isoformas de Proteínas/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica , Humanos , Pólipos Nasales/genética , Factores de Transcripción Otx/genética , Factores de Transcripción Otx/metabolismo , Isoformas de Proteínas/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética
3.
J Eur Acad Dermatol Venereol ; 30(5): 847-51, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-25904304

RESUMEN

BACKGROUND: Epidermolytic ichthyosis (BCIE, OMIM 113800), is an autosomal dominant disorder of the skin caused by mutations in keratin genes KRT1 and KRT10. We present two sporadic patients showing a mild diffuse ichthyosis with palmoplantar keratoderma. Interestingly, one of them shows a significant hyperkeratosis of palms and soles similar to those present in the Meleda disease (OMIM 248300). OBJECTIVE: In this paper we would clarify the genetic difference between the two patients, giving rise to the different phenotype. METHODS: Clinical evaluation, followed by histological and molecular analysis has been established for these patients. RESULTS: We demonstrated the presence of a genetic cutaneous mosaicism. Both patients carry the KRT1 pI479T substitution, but in the palmoplantar areas of one of them, only the mutated allele is expressed (hemizygous). This leads to highlight a new type of cutaneous mosaic, the palmoplantar mosaicism.


Asunto(s)
Alelos , Queratina-1/genética , Mosaicismo , Enfermedades de la Piel/genética , Adolescente , Femenino , Humanos , Mutación , Índice de Severidad de la Enfermedad
5.
Dermatol Online J ; 19(2): 2, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-23473272

RESUMEN

BACKGROUND: Cerebral cavernous malformations (CCM) comprise enlarged capillary cavities in the central nervous system, with possible retinal or cutaneous vascular malformations. This condition is associated with CCM1, CCM2, and CCM3 gene mutations. OBJECTIVE: Cutaneous clinical, histological and cerebral MRI findings, including CCM1, CCM2, and CCM3 gene sequencing, of two unrelated, neurological symptom-free patients who consulted for late-onset of deep multiple cutaneous angiomatoid lesions, are described. RESULTS: The diagnosis of multiple cutaneous angiomatosis was confirmed and related to CCM as detected by MRI in both cases. Analysis of our patients showed normal nucleotide sequences of the genes proposed. CONCLUSIONS: A progressive late-onset of multiple, deep cutaneous venous malformations may indicate the need to investigate a potential coexistence of CCM by MRI. Early diagnosis and prompt treatment is required in these patients. The absence of CCM1, CCM2, and CCM3 mutations might indicate that different genes could be involved in the pathogenesis of these late-onset patients. Careful questioning about family history of CCM is important; our first patient's daughter had a history of cerebral cavernoma.


Asunto(s)
Angiomatosis/etiología , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Enfermedades Cutáneas Vasculares/etiología , Adulto , Angiomatosis/patología , Femenino , Predisposición Genética a la Enfermedad , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Mutación/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Enfermedades Cutáneas Vasculares/patología
6.
J Exp Med ; 188(9): 1763-8, 1998 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-9802988

RESUMEN

p73 has been recently identified as a new structural and functional homologue of the transcription factor p53. It is expressed in either a full-length form, alpha, or a shorter beta mRNA variant, with exon 13 spliced out. Here we report the identification and functional characterization of two new p73 splicing variants, gamma (splicing out exon 11) and delta (splicing out exons 11, 12, and 13). Both gamma and delta p73 variants are expressed in human peripheral blood lymphocytes, primary keratinocytes, and different tumor cell lines, including neuroblastoma, glioblastoma, melanoma, hepatoma, and leukemia. The expression pattern of the four p73 splicing variants differs in both primary cells of different lineage and established cell lines even within the same type of tumor. A two-hybrid assay was used to characterize the homodimeric and heterodimeric interactions between the p73 variants, and showed that neither p73gamma nor p73delta interact with p53, whereas p73gamma showed strong interactions with all p73 isoforms, and p73delta binds efficiently p73alpha and p73gamma but only weakly p73beta. At the functional level, p73gamma is significantly less efficient in activating transcription of the p21(Waf1/Cip1) promoter than p53 or p73beta, whereas the effect of p73delta is intermediate and comparable to that of p73alpha. The ability of the different p73 variants to affect cell growth in p53 null osteosarcoma SAOS-2 cells correlates with their transcriptional activity on the p21(Waf1/Cip1) promoter: p73beta is the most efficient in inhibiting colony formation, whereas p73gamma is almost ineffective. Our results suggest that p73 isoforms may be differentially regulated, with four different isoforms capable of interacting among themselves and with p53. The relative expression level of each splice variant may modulate p73 transcriptional and growth suppression activities by affecting heterodimer formation.


Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Empalme Alternativo , Secuencia de Aminoácidos , Apoptosis , Secuencia de Bases , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , Cartilla de ADN/genética , Proteínas de Unión al ADN/química , Dimerización , Genes Supresores de Tumor , Variación Genética , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares/química , Regiones Promotoras Genéticas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Factores de Transcripción/química , Transfección , Células Tumorales Cultivadas , Proteína Tumoral p73 , Proteínas Supresoras de Tumor
7.
Hum Mutat ; 28(11): 1150, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17939176

RESUMEN

Transglutaminase 2 (TG2 or TGM2) is a multi-functional enzyme which catalyzes transamidation reactions or acts as a G-protein in intracellular signalling. Tgm2-/- Mice lacking TG2 activity are glucose intolerant and show impairment of insulin secretion, suggesting an important physiological role for TG2 in the pancreatic beta cell. We have previously described a TGM2 heterozygous missense mutation ((c.998A>G, p.N333S) in a 14 year-old patient with insulin-treated diabetes and in his diabetic father. The aim of this study was to further investigate the role of TG2 in early-onset type 2 diabetes. We analysed the TGM2 gene in 205 patients with clinically defined Maturity Onset Diabetes of the Young (MODY) or early-onset type 2 diabetes. We found two novel heterozygous mutations (c.989T>G, p.M330R; c.992T>A, p.I331N), which were not detected in 300 normoglycemic controls. All mutations were in residues which are located close to the catalytic site and impaired transamidating activity in vitro. Gene expression of TGM family genes and localization of TG2 in normal human pancreas indicated that TG2 is the only transglutaminase significantly expressed in human pancreatic islet cells. We conclude that reduced TG2 activity can contribute to disorders of glucose metabolism possibly via an impairment of insulin secretion.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Proteínas de Unión al GTP/genética , Mutación Missense , Transglutaminasas/genética , Adolescente , Adulto , Edad de Inicio , Animales , Células COS , Chlorocebus aethiops , Heterocigoto , Humanos , Inmunohistoquímica , Proteína Glutamina Gamma Glutamiltransferasa 2
8.
Cell Death Differ ; 13(6): 1037-47, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16601749

RESUMEN

Epidermal development requires the transcription factor p63, as p63-/- mice are born dead, without skin. The gene expresses two proteins, one with an amino-terminal transactivation domain (TAp63) and one without (deltaNp63), although their relative contribution to epidermal development is unknown. To address this issue, we reintroduced TAp63alpha and/or deltaNp63alpha under the K5 promoter into p63-/- mice by in vivo genetic complementation. Whereas p63-/- and p63-/-;TA mice showed extremely rare patches of poorly differentiated keratinocytes, p63-/-;deltaN mice showed significant epidermal basal layer formation. Double TAp63alpha/deltaNp63alpha complementation showed greater patches of differentiated skin; at the ultrastructural level, there was clear reformation of a distinct basal membrane and hemidesmosomes. At the molecular level, deltaNp63 regulated expression of genes characteristic of the basal layer (K14), interacting (by Chip, luc assay) with the third p53 consensus site. Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin). Therefore, the two p63 isoforms appear to play distinct cooperative roles in epidermal formation.


Asunto(s)
Epidermis/metabolismo , Regulación del Desarrollo de la Expresión Génica , Fosfoproteínas/metabolismo , Piel/metabolismo , Transactivadores/metabolismo , Animales , Animales Recién Nacidos , Línea Celular , Proliferación Celular , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/patología , Epidermis/embriología , Epidermis/crecimiento & desarrollo , Epidermis/patología , Proteínas Filagrina , Perfilación de la Expresión Génica/métodos , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/metabolismo , Queratina-14/genética , Queratina-14/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Fosfoproteínas/genética , Regiones Promotoras Genéticas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Piel/embriología , Piel/crecimiento & desarrollo , Piel/patología , Transactivadores/genética , Transfección
10.
Cell Death Dis ; 7(8): e2344, 2016 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-27537526

RESUMEN

The epidermis is a dynamic tissue in which keratinocytes proliferate in the basal layer and undergo a tightly controlled differentiation while moving into the suprabasal layers. The balance between keratinocyte proliferation, differentiation, and death is essential, and its perturbation can result in pathological changes. Some common skin diseases, such as psoriasis, are characterized by hyperproliferation accompanied by inflammatory reactions, suggesting that molecules with topical anti-inflammatory and ROS scavenging abilities may be useful for their treatment. Here we investigate the potential of the flavone Luteolin-7-glucoside (LUT-7G) as a treatment for psoriasis. We show that LUT-7G leads to a modification of the cell cycle and the induction of keratinocyte differentiation, with modification of energy, fatty acid, and redox metabolism. LUT-7G treatment also neutralizes the proliferative stimulus induced by the proinflammatory cytokines IL-22 and IL-6 in HEKn. Moreover, in the Imiquimod (IMQ) mouse model of psoriasis, topical administration of LUT-7G leads to a marked reduction of acanthosis and re-expression of epidermal differentiation markers. Dissection of the IL-22 signalling pathway, activated by IMQ treatment, demonstrates that LUT-7G impairs the nuclear translocation of phosphorylated (activated) STAT3, blocking the IL-22 signalling cascade. Thus LUT-7G appears to be a promising compound for the treatment of hyperproliferative and inflammatory skin diseases, such as psoriasis.


Asunto(s)
Acantosis Nigricans/tratamiento farmacológico , Glucósidos/farmacología , Inflamación/tratamiento farmacológico , Interleucinas/metabolismo , Queratinocitos/patología , Luteolina/farmacología , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Factor de Transcripción STAT3/metabolismo , Acantosis Nigricans/complicaciones , Acantosis Nigricans/metabolismo , Acantosis Nigricans/patología , Aminoquinolinas/farmacología , Aminoquinolinas/uso terapéutico , Animales , Diferenciación Celular/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Glucósidos/uso terapéutico , Humanos , Imiquimod , Inmunohistoquímica , Inflamación/complicaciones , Inflamación/patología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Lípidos/biosíntesis , Luteolina/uso terapéutico , Ratones Endogámicos C57BL , Oxidación-Reducción/efectos de los fármacos , Fenotipo , Transporte de Proteínas/efectos de los fármacos , Psoriasis/metabolismo , Transducción de Señal/efectos de los fármacos , Interleucina-22
11.
J Invest Dermatol ; 114(6): 1136-40, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10844556

RESUMEN

Palmoplantar keratodermas are a group of heterogeneous diseases characterized by thickening, and marked hyperkeratosis, of the epidermis of the palms and soles. Palmoplantar keratodermas can be divided into four major classes: diffuse, focal, punctate, and palmoplantar ectodermal dysplasias. All forms are genetic diseases inherited as autosomal dominant disorders. We studied a patient exhibiting a localized thickening of the skin in parts of the right palm and the right sole, following Blaschko's lines, that does not fit into any classes already described. We sequenced the keratin 16 cDNA derived from skin biopsy material from affected and non affected palms. The keratin 16 cDNA sequence from lesional epidermis showed a 12 base pair deletion (309-320del), which deletes codons 104-107. The mutation is predicted to delete four amino acids, GGFA, from the V1 domain of the keratin 16 polypeptide, close to the 1A domain. Full-length keratin 16 cDNA sequence derived from the unaffected palm was completely normal, consistent with a postzygotic mutation as is suggested by the mosaicism observed. We defined this new clinical entity, "unilateral palmoplantar verrucous nevus", rather than localized or focal epidermolytic palmoplantar keratodermas, as the lesions are present only on one side of the body and follow Blaschko's lines. This study is a report of a mosaic mutation in keratin 16 and also the association of a mutation in the V1 domain of a type I keratin associated with a human disease.


Asunto(s)
Queratinas/genética , Queratodermia Palmoplantar/genética , Adolescente , Análisis Mutacional de ADN , Femenino , Expresión Génica , Hamartoma/genética , Humanos , Queratinas/química , Mutación , Estructura Terciaria de Proteína/genética , Enfermedades de la Piel/genética
12.
J Invest Dermatol ; 114(2): 388-91, 2000 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-10652003

RESUMEN

White Sponge Nevus (WSN) is a rare, autosomal dominant disorder that predominantly affects noncornified stratified squamous epithelia. Clinically, it is characterized by the presence of soft, white, and "spongy" plaques in the oral mucosa. The characteristic histopathologic features are epithelial thickening, parakeratosis, and vacuolization of the suprabasal layer of oral epithelial keratinocytes. Mutations in keratin 4 (K4) and keratin 13 (K13) genes have already been demonstrated to be responsible for WSN; the identification of new keratin mutations in a stratified squamous epithelia closely related to epidermis is of relevance for the understanding of the biochemistry of intermediate filaments, and for genotype phenotype correlations. In this study we investigated a 27-y-old, female Italian patient, affected by white asymptomatic oral plaques. Sequence analysis revealed a 3 bp (ACA) heterozygous insertion localized in the helix initiation motif of the 1A alpha helical domain of K4. We report this new K4 gene mutation and describe an amino acid insertion, in the 1A domain, responsible for a keratin disease.


Asunto(s)
Glutamina/genética , Hamartoma/genética , Queratinas/genética , Enfermedades de la Boca/genética , Mucosa Bucal , Adulto , Análisis Mutacional de ADN , Elementos Transponibles de ADN , Salud de la Familia , Femenino , Humanos , Linaje , Estructura Terciaria de Proteína
13.
J Invest Dermatol ; 117(6): 1391-6, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11886499

RESUMEN

Thirteen patients with pachyonychia congenita types 1 and 2 were studied, two of which had a family history of pachyonychia and 11 of which were sporadic cases. Heterozygous mis-sense or small in-frame insertion/deletion mutations were detected in the genes encoding keratins K6a, K16, and K17 in all cases. Three novel mutations, F174V, E472K, and L469R were found in the K6a gene. Two novel mutations, M121T and L128Q were detected in K16. Similarly, three novel mutations, L95P, S97del, and L99P were found in K17. In addition, we identified recurrent mutations N171del (three instances) and F174S in K6a and R94H in K17. Analysis of both phenotype and genotype data led to the following conclusions: (i) K6a or K16 mutations produce the pachyonychia congenita type 1 phenotype, whereas K17 (or K6b) mutations cause pachyonychia congenita type 2; (ii) the presence of pilosebaceous cysts following puberty is the best indicator of pachyonychia congenita type 2; (iii) prepubescent patients are more difficult to classify due to the lack of cysts; and (iv) natal teeth are indicative of pachyonychia congenita type 2, although their absence does not preclude the pachyonychia congenita type 2 phenotype. This study establishes useful diagnostic criteria for pachyonychia congenita types 1 and 2, which will help limit unnecessary DNA analysis in the diagnosis and management of this genetically heterogeneous group of genodermatoses.


Asunto(s)
Displasia Ectodérmica/genética , Eliminación de Gen , Queratinas/genética , Queratodermia Palmoplantar/genética , Mutación Missense , Análisis Mutacional de ADN , Cartilla de ADN , Genotipo , Humanos , Enfermedades de la Uña/genética , Fenotipo , Mapeo Restrictivo
14.
J Dent Res ; 80(3): 919-23, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11379896

RESUMEN

White sponge nevus (WSN) is an autosomal-dominantly inherited form of mucosal leukokeratosis. Defects in keratins, proteins that form the stress-bearing cytoskeleton in epithelia, have been shown to cause several epithelial fragility disorders. Recently, mutations in the genes encoding mucosal-specific keratins K4 and K13 were shown to be the underlying cause of WSN. We have studied a large Scottish family with 19 persons affected by WSN in four generations. The K4 locus was excluded by genetic linkage analysis; however, genetic linkage consistent with a K13 defect was obtained. Subsequently, a heterozygous missense mutation 335A>G was detected in exon 1 of the KRT13 gene, predicting the amino acid change N112S in the 1A domain of the K13 polypeptide. The mutation was confirmed in affected family members and was excluded from 50 unaffected people by restriction enzyme analysis. These results confirm that mucosal keratin defects are the cause of WSN.


Asunto(s)
Hamartoma/genética , Queratinas/genética , Enfermedades de la Boca/genética , Mutación Missense/genética , Adenina , Adolescente , Asparagina/genética , Mapeo Cromosómico , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 17/genética , Codón/genética , Epitelio/metabolismo , Exones/genética , Ligamiento Genético/genética , Guanina , Humanos , Leucoplasia Bucal/genética , Masculino , Estructura Terciaria de Proteína/genética , Escocia , Serina/genética
15.
Oncogene ; 32(40): 4758-65, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23128396

RESUMEN

ΔNp63 is a transcription factor that is critical for the development of stratified epithelia and is overexpressed or amplified in >80% of squamous cell carcinomas (SCCs). We identified the RING finger E3 ubiquitin ligase PIR2/Rnf144b as a direct transcriptional target of ΔNp63α and showed that its expression parallels that of ΔNp63α in keratinocytes, SCC cell lines and SCCs. We used primary keratinocytes as a model system to investigate the function of PIR2/Rnf144b in stratified epithelia. Depletion of PIR2/Rnf144b severely impaired keratinocyte proliferation and differentiation, associated with accumulation of p21(WAF1/CIP1); a known target of PIR2/Rnf144b. More importantly, we found that PIR2/Rnf144b binds and mediates proteasomal degradation of ΔNp63α, generating a hitherto unknown auto-regulatory feedback loop. These findings substantiate PIR2/Rnf144b as a potentially critical component of epithelial homeostasis, acting downstream of ΔNp63α to regulate cellular levels of p21(WAF1/CIP1) and ΔNp63α.


Asunto(s)
Proteínas Portadoras/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Epitelio/metabolismo , Homeostasis/fisiología , Proteínas de la Membrana/metabolismo , Ubiquitina-Proteína Ligasas/fisiología , Empalme Alternativo , Diferenciación Celular , Línea Celular , Proliferación Celular , Humanos , Queratinocitos/citología , Proteolisis , Activación Transcripcional , Ubiquitina-Proteína Ligasas/genética
16.
Cell Death Dis ; 3: e416, 2012 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-23096117

RESUMEN

Lamellar Ichthyosis (LI) is a form of congenital ichthyosis that is caused by mutations in the TGM1 gene that encodes for the transglutaminase 1 (TG1) enzyme. Functional inactivation of TG1 could be due to mutations, deletion or insertions. In this study, we have screened 16 patients affected by LI and found six new mutations: two transition/transversion (R37G, V112A), two nonsense mutations and two putative splice site both leading to a premature stop codon. The mutations are localized in exons 2 (N-terminal domain), 5, 11 (central catalytic domain), and none is located in the two beta-barrel C-terminal domains. In conclusion, this study expands the current knowledge on TGM1 mutation spectrum, increasing the characterization of mutations would provide more accurate prenatal genetic counselling for parents at-risk individuals.


Asunto(s)
Ictiosis Lamelar/enzimología , Ictiosis Lamelar/genética , Mutación , Transglutaminasas/genética , Codón sin Sentido/genética , Exones , Humanos , Mutación Missense , Mutación Puntual , Estructura Terciaria de Proteína , Empalme del ARN , Transglutaminasas/química
17.
Oncogene ; 30(27): 3096-103, 2011 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-21478910

RESUMEN

The p53 transcription factor has a critical role in cell stress response and in tumor suppression. Wild-type p53 protein is a growth modulator and its inactivation is a critical event in malignant transformation. It has been recently demonstrated that wild-type p53 has developmental and differentiation functions. Indeed an over-expression of p53 in tumor cells induces asymmetrical division avoiding self-renewal of cancer stem cells (CSCs) and instead promoting their differentiation. In this study, 28 human breast carcinomas have been analyzed for expression of wild-type p53 and of a pool of non-clustered homeobox genes. We demonstrated that orthodenticle homolog 1 gene (OTX1) is transcribed in breast cancer. We established that the p53 protein directly induces OTX1 expression by acting on its promoter. OTX1 has been described as a critical molecule for axon refinement in the developing cerebral cortex of mice, and its activity in breast cancer suggests a synergistic function with p53 in CSC differentiation. Wild-type p53 may regulate cellular differentiation by an alternative pathway controlling OTX1 signaling only in breast cancer cells and not in physiological conditions.


Asunto(s)
Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Factores de Transcripción Otx/genética , Proteína p53 Supresora de Tumor/fisiología , Neoplasias de la Mama/genética , Femenino , Humanos
19.
Proc Natl Acad Sci U S A ; 103(40): 14808-12, 2006 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-17003125

RESUMEN

Cajal bodies are nuclear subdomains that are involved in maturation of small ribonucleoproteins and frequently associate with small nuclear RNA and histone gene clusters in interphase cells. We have recently identified FADD-like IL-1beta-converting enzyme (FLICE) associated huge protein (FLASH) as an essential component of Cajal bodies. Here we show that FLASH associates with nuclear protein, ataxia-telangiectasia, a component of the cell-cycle-dependent histone gene transcription machinery. Reduction of FLASH expression by RNA interference results in disruption of the normal Cajal body architecture and relocalization of nuclear protein, ataxia-telangiectasia. Furthermore, FLASH down-regulation results in a clear reduction of histone transcription and a dramatic S-phase arrest of the cell cycle. Chromatin immunoprecipitation reveals that FLASH interacts with histone gene promoter sequences. These results identify FLASH as an important component of the machinery required for histone precursor mRNA expression and cell-cycle progression.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de Unión al Calcio/metabolismo , Histonas/genética , Fase S/fisiología , Transcripción Genética , Animales , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Regulación hacia Abajo/genética , Células HeLa , Histonas/metabolismo , Humanos , Ratones , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo
20.
J Mol Evol ; 45(2): 145-53, 1997 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9236274

RESUMEN

The intragenomic location of the elements of the I, G, jockey, F, and Doc transposon families has been studied by the Southern blot analysis, in 12 laboratory Drosophila melanogaster stocks. Elements located in euchromatin, heterochromatin, and on the Y chromosome are identified, and their stability has been assessed by comparing the autoradiographs detected in different stocks and analysis of individual flies. Evidence is shown suggesting that preferential location in euchromatin or heterochromatin and the distribution within heterochromatin are distinctive of transposon families. Elements located in heterochromatin can be unstable. These results are discussed in the context of the relationship between transposable elements and the host genome.


Asunto(s)
Cromatina/genética , Drosophila melanogaster/genética , Heterocromatina/genética , Retroelementos/genética , Animales , Mapeo Cromosómico , Eucromatina , Femenino , Larva , Masculino , Polimorfismo Genético , Cromosoma Y/genética
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