RESUMO
Cytokine receptors often act via the Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway to form a signalling cascade that is essential for processes such as haematopoiesis, immune responses and tissue homeostasis. In order to transduce ligand activation, cytokine receptors must dimerise. However, mechanisms regulating their dimerisation are poorly understood. In order to better understand the processes regulating cytokine receptor levels, and their activity and dimerisation, we analysed the highly conserved JAK/STAT pathway in Drosophila, which acts via a single receptor, known as Domeless. We performed a genome-wide RNAi screen in Drosophila cells, identifying MASK as a positive regulator of Domeless dimerisation and protein levels. We show that MASK is able to regulate receptor levels and JAK/STAT signalling both in vitro and in vivo We also show that its human homologue, ANKHD1, is also able to regulate JAK/STAT signalling and the levels of a subset of pathway receptors in human cells. Taken together, our results identify MASK as a novel regulator of cytokine receptor levels, and suggest functional conservation, which may have implications for human health.This article has an associated First Person interview with the first author of the paper.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Genoma de Inseto , Interferência de RNA , Receptores de Citocinas/genética , Receptores de Interleucina/química , Motivos de Aminoácidos , Animais , Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Regulação da Expressão Gênica , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores de Citocinas/metabolismo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de SinaisRESUMO
Primary lymphoproliferative disorders of the uterus are rare, with the majority being B-cell diseases or aggressive T-cell disease. We present the case of a 31-yr old in whom an Indolent T-cell lymphoproliferative disorder (iTCLPD) was identified in resection chippings for a suspected fibroid, following presentation with menorrhagia. Laboratory investigations revealed an oligoclonal T-cell infiltrate with the immunophenotype of nonactivated cytotoxic T cells, and a proliferative fraction of 10% to 15%. There was no clinical or radiologic evidence of systemic disease, and the patient remained well with no indication of relapse 1 yr from resection and diagnosis. iTCLPD of the uterine corpus has features in common with the recently described iTCLPD of the gastrointestinal tract and primary cutaneous acral CD8 T-cell lymphoma. Recognition of these parallels is important as few other cases of iTCLPD have been described, and it suggests local resection rather than systemic treatment as the best therapeutic strategy.
Assuntos
Transtornos Linfoproliferativos/diagnóstico , Adulto , Feminino , Humanos , Imunofenotipagem , Transtornos Linfoproliferativos/patologia , Linfócitos T/patologia , Útero/patologiaRESUMO
Variable phenotype is common in neurological disorders with single-gene inheritance patterns. In Huntington's disease, mood and cognitive symptoms are variably co-expressed with motor symptoms. There is also variable degeneration of neurons in the two major neurochemical compartments of the striatum, the striosomes and the extrastriosomal matrix. To determine whether the phenotypic variability in Huntington's disease is related to this compartmental organization, we carried out a double-blind study in which we used GABA(A) receptor immunohistochemistry to analyse the status of striosomes and matrix in the brains of 35 Huntington's disease cases and 13 control cases, and collected detailed data on the clinical symptomatology expressed by the patients from family members and records. We report here a significant association between pronounced mood dysfunction in Huntington's disease patients and differential loss of the GABA(A) receptor marker in striosomes of the striatum. This association held for both clinical onset and end-stage assessments of symptoms. The cases with accentuated striosome abnormality further exhibited later onset age, lower disease grade and lower CAG repeat length in the HD gene. We found no independent association, however, between CAG repeat length or age of onset and mood dysfunction. We suggest that variation in clinical symptomatology in Huntington's disease is associated with variation in the relative abnormality of GABA(A) receptor expression in the striosome and matrix compartments of the striatum, and that striosome-related circuits may modulate mood functioning.