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首页> 外文期刊>Journal of dermatological science >Caveolin-1 is a negative regulator of MMP-1 gene expression in human dermal fibroblasts via inhibition of Erk1/2/Ets1 signaling pathway.
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Caveolin-1 is a negative regulator of MMP-1 gene expression in human dermal fibroblasts via inhibition of Erk1/2/Ets1 signaling pathway.

机译：Caveolin-1是通过抑制Erk1 / 2 / Ets1信号通路在人皮肤成纤维细胞中MMP-1基因表达的负调节剂。

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BACKGROUND: Caveolar raft domains, also termed caveolae, are flask shaped invaginations that require the expression of the structural protein caveolin-1 (cav-1). Matrix metalloproteinase 1 (MMP-1) is a collagenase capable of degrading insoluble triple helical collagens. Deregulation of MMP-1 contributes to various pathological processes, including tissue fibrosis and impaired wound healing. OBJECTIVE: In this study we investigated the role of cav-1 in MMP-1 gene regulation in human dermal fibroblasts. METHODS: Fibroblasts were isolated from healthy subjects. Western blot was used to analyze protein levels and quantitative real time RT-PCR was used to measure mRNA expression. Cells were transiently transfected with siRNA oligos against acid sphingomyelinase (ASMase) and cav-1, or transduced with adenoviruses overexpressing ASMase and cav-1. The specific pharmacological inhibitors UO126 and SP600125 were used to block Erk1/2 and JNK activity. RESULTS: This study shows that siRNA-mediated depletion of ASMase or cav-1, results in upregulation of MMP-1 gene expression. Similarly, MMP-1 expression was decreased after overexpresssion of cav-1 via an adenoviral vector. Depletion of cav-1 had no effect on JNK phosphorylation, while it resulted in an increase in Erk1/2 and Ets1 phosphorylation levels. Furthermore, in cav-1 depleted cells treated with the Erk inhibitor UO126, there was no increase in the levels of phospho-Erk1/2, phospho-Ets1, and MMP-1, suggesting that cav-1 mediated effects on MMP-1 and phospho-Ets1 are Erk1/2 dependent. CONCLUSIONS: In conclusion, this study has revealed an important role for cav-1 as a negative regulator of MMP-1 gene expression via inhibition of Erk1/2/Ets1 signaling. Cav-1 could potentially be a therapeutic target in diseases with deregulated extracellular matrix (ECM) turnover.
机译：背景：小窝筏域，也称为小窝，是烧瓶状的内陷，需要表达结构蛋白小窝蛋白1（cav-1）。基质金属蛋白酶1（MMP-1）是一种能够降解不溶性三螺旋胶原的胶原酶。 MMP-1失调有助于各种病理过程，包括组织纤维化和受损的伤口愈合。目的：在这项研究中，我们研究了cav-1在人类皮肤成纤维细胞中MMP-1基因调控中的作用。方法：从健康受试者中分离成纤维细胞。使用蛋白质印迹法分析蛋白质水平，并使用实时定量RT-PCR测量mRNA表达。用针对酸性鞘磷脂酶（ASMase）和cav-1的siRNA寡核苷酸瞬时转染细胞，或用过表达ASMase和cav-1的腺病毒转导细胞。特定的药物抑制剂UO126和SP600125用于阻断Erk1 / 2和JNK活性。结果：这项研究表明，siRNA介导的ASMase或cav-1耗竭导致MMP-1基因表达上调。同样，在cav-1通过腺病毒载体过度表达后，MMP-1表达降低。 cav-1的消耗对JNK磷酸化没有影响，而导致Erk1 / 2和Ets1磷酸化水平的增加。此外，在用Erk抑制剂UO126处理的cav-1耗竭的细胞中，磷酸化Erk1 / 2，磷酸化Ets1和MMP-1的水平没有增加，这表明cav-1介导了对MMP-1和MMP-1的作用。磷酸化Ets1是Erk1 / 2依赖性的。结论：总的来说，这项研究揭示了cav-1通过抑制Erk1 / 2 / Ets1信号作为MMP-1基因表达的负调节剂的重要作用。 Cav-1可能是细胞外基质（ECM）转换失调的疾病的治疗靶标。

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