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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >Linking ABCC6 Deficiency in Primary Human Dermal Fibroblasts of PXE Patients to p21-Mediated Premature Cellular Senescence and the Development of a Proinflammatory Secretory Phenotype
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Linking ABCC6 Deficiency in Primary Human Dermal Fibroblasts of PXE Patients to p21-Mediated Premature Cellular Senescence and the Development of a Proinflammatory Secretory Phenotype

机译：将ABCC6缺乏与PXE患者的原发性人体真皮成纤维细胞联系在P21介导的过早细胞衰老和促炎性分泌表型的发育

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摘要

Pseudoxanthoma elasticum (PXE) is a rare autosomal-recessive disorder that is mainly caused by mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene. Clinically PXE is characterized by a loss of skin elasticity, arteriosclerosis or visual impairments. It also shares some molecular characteristics with known premature aging syndromes like the Hutchinson–Gilford progeria syndrome (HGPS). However, little is known about accelerated aging processes, especially on a cellular level for PXE now. Therefore, this study was performed to reveal a potential connection between premature cellular aging and PXE pathogenesis by analyzing cellular senescence, a corresponding secretory phenotype and relevant factors of the cell cycle control in primary human dermal fibroblasts of PXE patients. Here, we could show an increased senescence-associated β-galactosidase (SA-β-Gal) activity as well as an increased expression of proinflammatory factors of a senescence-associated secretory phenotype (SASP) like interleukin 6 (IL6) and monocyte chemoattractant protein-1 (MCP1). We further observed an increased gene expression of the cyclin-dependent kinase inhibitor (CDKI) p21, but no simultaneous induction of p53 gene expression. These data indicate that PXE is associated with premature cellular senescence, which is possibly triggered by a p53-independent p21-mediated mechanism leading to a proinflammatory secretory phenotype.
机译：伪瘤瘤Elasticum（PXE）是一种稀有的常血剂 - 隐性疾病，主要是由ATP结合盒亚族CEMER 6（ABCC6）基因中的突变引起的。临床PXE的特征是丧失皮肤弹性，动脉硬化或视觉损伤。它还分享了一些具有已知过早老化综合征的分子特征，如Hutchinson-Gilford Progeria综合征（HGPS）。然而，关于加速老化过程的少量众所周知，尤其是现在对PXE的细胞水平。因此，进行该研究以揭示通过分析细胞衰老，相应的分泌物表型和PXE患者原发性人皮肤成纤维细胞细胞周期控制的相应分泌表型和相关因子之间的潜在联系。在这里，我们可以表现出增加的衰老相关的β-半乳糖苷酶（SA-β-GAL）活性，以及​​白细胞介素6（IL6）和单核细胞化学蛋白如白细胞介素6（IL6）和单核细胞培养物蛋白-1（MCP1）。我们进一步观察到细胞周期蛋白依赖性激酶抑制剂（CDKI）P21的基因表达增加，但不能同时诱导P53基因表达。这些数据表明PXE与过早细胞衰老相关，这可能是由P53独立的P21介导的机制触发，导致促炎性分泌表型。

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