Cellular senescence is a phenomenon of irreversible growth arrest of mammalian somatic cells. Senescent cells increase the production of secretory proteins such as inflammatory cytokines, a phenomenon termed senescence-associated secretory phenotype (SASP). SASP is known to have profound effects on organismal health and aging; however, the molecular mechanisms of SASP are not precisely understood. In our previous studies, we have shown that senescent cells show decreased function of lamin B receptor (LBR), a nuclear membrane protein that regulates heterochromatin organization. Here we examined the implication of LBR in the regulation of SASP because senescent cells show altered heterochromatin organization, which would affect gene expression. We found that knock-down of LBR up-regulated the expression of the SASP factors such as IL-6, IL-8, and MMP1 in HeLa cells, even though cellular senescence was not induced by LBR knock-down. Conversely, enforced expression of LBR suppressed their up-regulated expression in senescent cells induced by excess thymidine. Further, our gene expression profile analysis also showed that many secretory proteins were up-regulated by LBR knock-down. We then analyzed the regulatory mechanisms of the expression of SASP factors by LBR, and found that the promotors of these SASP factors associated with LBR in normally growing cells, but dissociated from it in senescent cells. Additionally, we found that enforced expression of LBR decreased the generation of cytoplasmic DNA, which could be involved in SASP, in senescent cells. These findings suggested that LBR would play crucial roles in the regulation of SASP.

中文翻译：

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核纤层蛋白 B 受体在衰老相关分泌表型 (SASP) 调节中的作用。


细胞衰老是哺乳动物体细胞不可逆的生长停滞现象。衰老细胞会增加炎症细胞因子等分泌蛋白的产生，这种现象称为衰老相关分泌表型（SASP）。众所周知，SASP 对机体健康和衰老具有深远的影响；然而，SASP 的分子机制尚不清楚。在我们之前的研究中，我们发现衰老细胞的核纤层蛋白 B 受体 (LBR) 功能下降，LBR 是一种调节异染色质组织的核膜蛋白。在这里，我们研究了 LBR 在 SASP 调节中的含义，因为衰老细胞表现出异染色质组织的改变，这会影响基因表达。我们发现，敲低LBR会上调HeLa细胞中SASP因子（例如IL-6、IL-8和MMP1）的表达，尽管敲低LBR不会诱导细胞衰老。相反，LBR 的强制表达抑制了过量胸苷诱导的衰老细胞中表达的上调。此外，我们的基因表达谱分析还表明，许多分泌蛋白因 LBR 敲低而上调。然后我们分析了LBR对SASP因子表达的调控机制，发现这些SASP因子的启动子在正常生长的细胞中与LBR相关，但在衰老细胞中与LBR解离。此外，我们发现 LBR 的强制表达减少了衰老细胞中细胞质 DNA 的产生，而细胞质 DNA 可能参与 SASP。这些发现表明 LBR 将在 SASP 的监管中发挥至​​关重要的作用。