Assuntos
Diferenciação Celular/efeitos dos fármacos , Granulócitos/citologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Neutrófilos/citologia , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Translocação Genética , Crise Blástica/tratamento farmacológico , Crise Blástica/genética , Crise Blástica/patologia , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Dasatinibe , Citometria de Fluxo , Granulócitos/efeitos dos fármacos , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The molecular characteristics of the nude phenotype (alopecia and thymic aplasia) in humans and rodents are unknown. The nude locus encodes Whn, a transcription factor of the forkhead/winged-helix class. Expression of Whn in HeLa cells induced expression of human hair keratin genes Ha3-II and Hb5. Correspondingly, in nude mice, which are homozygous for a loss-of-function mutation of Whn, expression of mouse mHa3 and mHb5 hair keratin genes is severely reduced. Characterization of a previously identified nude allele, nu(Y), revealed a mis-sense mutation (R320C) in the DNA binding domain of Whn. This mutant protein is unable to activate hair keratin gene expression in HeLa cells. When the Whn transcription factor was expressed in two parts, one containing the N-terminal DNA binding domain and the other the C-terminal activation domain, no activation of hair keratin genes in HeLa cells was observed. However, when these two proteins were noncovalently linked by means of synthetic dimerizers, hair keratin gene expression was induced. This finding suggests that target gene activation by Whn depends on the structural integrity and physical proximity of DNA binding and activation domains, providing a molecular framework to explain the loss-of-function phenotypes of all previously characterized nude mutations. Our results implicate Whn as a transcriptional regulator of hair keratin genes and reveal the nude phenotype as the first example of an inherited skin disorder that is caused by loss of expression rather than mutation of keratin genes.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Queratinas/genética , Fatores de Transcrição/metabolismo , Animais , Proteínas de Ligação a DNA/genética , Fatores de Transcrição Forkhead , Regulação da Expressão Gênica , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Camundongos Nus , Fatores de Transcrição/genética , Ativação TranscricionalRESUMO
Six young female patients suffering from recurrent uveitis, all of them HLA B-5 positive, were followed-up 2-7 years (mean 4.5 years). Anterior hypopyon uveitis was present in two patients, retinal vasculitis in all, exudative recurrent retinal detachment in two, resulting in phthysis in one patient. Complete clinical work-up as well as serology were within normal limits. The effect of the corticosteroid therapy applied in all patients was dubious, while Cyclosporine gave only temporary relief in one patient. Promising vitreoretinal surgery was suggested to one patient.
