Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid
Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid
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DOI：
10.15252/embj.201490594
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发表时间：
2015-07-14
期刊：
影响因子：
11.4
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
--
作者：
Gutierrez-Fernandez, Ana;Soria-Valles, Clara;Lopez-Otin, Carlos
MT 1-MMP（MMP 14）是一种位于细胞表面的胶原溶解酶，与细胞外基质（ECM）重塑有关。mmp 14（-/-）小鼠表现出侏儒症、骨异常和过早死亡。我们在此证明，MT 1-MMP的损失也会导致心脏缺陷和严重的代谢变化，并改变细胞骨架和核纤层结构。此外，MT 1-MMP的缺乏诱导衰老表型，其特征在于p16（INK 4a）和p21（CIP 1/WAF 1）的上调、衰老相关β-半乳糖苷酶活性的增加、衰老相关分泌表型的产生和促生长素轴改变。与视黄酸信号在核纤层稳定中的作用一致，用全反式视黄酸治疗Mmp 14（-/-）小鼠逆转了核纤层的改变，部分挽救了细胞衰老表型，改善了骨骼、皮肤和心脏的病理缺陷，并延长了它们的寿命。这些结果表明，核结构和细胞衰老可以通过膜蛋白酶调节，在涉及ECM作为细胞应激条件下核硬度的关键调节剂的过程中。
MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14(-/-) mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure. Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16(INK4a) and p21(CIP1/WAF1), increased activity of senescence-associated beta-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations. Consistent with the role of retinoic acid signaling in nuclear lamina stabilization, treatment of Mmp14(-/-) mice with all-trans retinoic acid reversed the nuclear lamina alterations, partially rescued the cell senescence phenotypes, ameliorated the pathological defects in bone, skin, and heart, and extended their life span. These results demonstrate that nuclear architecture and cell senescence can be modulated by a membrane protease, in a process involving the ECM as a key regulator of nuclear stiffness under cell stress conditions.