RESUMO
Sjögren's syndrome (SS) is a chronic, systemic, inflammatory autoimmune disease characterized by lymphocyte proliferation and progressive damage to exocrine glands. The diagnosis of SS is challenging due to its complicated clinical manifestations and non-specific signs. Salivary gland biopsy plays an important role in the diagnosis of SS, especially with anti-Sjögren's syndrome antigen A (SSA) and anti-SSB antibody negativity. Histopathology based on biopsy has clinical significance for disease stratification and prognosis evaluation, such as risk assessment for the development of non-Hodgkin's lymphoma. Furthermore, histopathological changes of salivary gland may be implicated in evaluating the efficacy of biological agents in SS. In this review, we summarize the histopathological features of salivary gland, the mechanism of histopathological changes and their clinical significance, as well as non-invasive imaging techniques of salivary glands as a potential alternative to salivary gland biopsy in SS.
RESUMO
The forkhead box A1 (FOXA1), one of the forkhead class of DNA-binding proteins, functions as a transcription factor and plays a vital role in cellular control of embryonic development and cancer progression. Downregulation of FOXA1 has reported in several types of cancer, which contributes to cancer cell survival and chemoresistance. However, the mechanism for FOXA1 downregulation in cancer remains unclear. Here, we report that the ubiquitination enzyme zinc finger protein 91 (ZFP91) ubiquitinates and destabilizes FOXA1, which promotes cancer cell growth. High level of ZFP91 expression correlates with low level of FOXA1 protein in human gastric cancer (GC) cell lines and patient samples. Furthermore, ZFP91 knockdown reduces FOXA1 polyubiquitination, which decreases FOXA1 turnover and enhances cellular sensitivity to chemotherapy. Taken together, our findings reveal ZFP91-FOXA1 axis plays an important role in promoting GC progression and provides us a potential therapeutic intervention in the treatment of GC.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Neoplasias Gástricas/genética , Ubiquitina-Proteína Ligases/metabolismo , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação para Baixo , Feminino , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Estabilidade Proteica , Proteólise , RNA Interferente Pequeno/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48-linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Carcinogênese , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Lisina/metabolismo , Camundongos , Transplante de Neoplasias , Estabilidade Proteica , Proteólise , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Fatores de Transcrição , Ubiquitinação , Proteínas de Sinalização YAPRESUMO
An increased hippocampal neurogenesis has been observed in Alzheimer disease (AD), the most common neurodegenerative disorder characterized with accumulation of ß-amyloid (Aß) and hyperphosphorylated tau (p-tau). Studies in transgenic mouse models suggest that the amyloidosis suppresses adult neurogenesis. Although emerging evidence links tau to neurodevelopment, the direct data regarding tau phosphorylation in adult neurogenesis is missing. Here, we found that the immature neurons, identified by doublecortin (DCX) and neurogenic differentiation factor (neuroD), were only immunoreactive to p-tau but not to the non-p-tau in adult rat brain and human patients with AD, and the p-tau was coexpressed temporally and spatially with DCX and neuroD in the hippocampal dentate gyrus (DG) of the rat brains during postnatal development. A correlative increase of immature neuron markers and tau phosphorylation was induced in rat hippocampal DG by upregulating glycogen synthase kinase-3 (GSK-3), a crucial tau kinase, and the increased neurogenesis was due to an enhanced proliferation but not survival or differentiation of the newborn neurons. The hippocampal neurogenesis was severely impaired in tau knockout mice and activation of GSK-3 in these mice did not rescue the deficits. These results reveal an essential role of tau phosphorylation in adult hippocampal neurogenesis. It suggests that spatial/temporal manipulation of tau phosphorylation may be compensatory for the neuron loss in neurological disorders, including AD.