National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, 48 Vassileos Constantinou Avenue, Athens 11635, Greece.
J Biol Chem. 2010 Mar 12;285(11):8171-84. doi: 10.1074/jbc.M109.031575. Epub 2010 Jan 12.
Replicative senescence in human fibroblasts is accompanied with alterations of various biological processes, including the impaired function of the proteasome. The proteasome is responsible for the removal of both normal and damaged proteins. Due to its latter function, proteasome is also considered a representative secondary antioxidant cellular mechanism. Nrf2 is a basic transcription factor responsible for the regulation of the cellular antioxidant response that has also been shown to regulate several proteasome subunits in mice. We have established in this study the proteasome-related function of Nrf2 in human fibroblasts undergoing replicative senescence. We demonstrate that Nrf2 has a declined function in senescence, whereas its silencing leads to premature senescence. However, upon its activation by a novel Nrf2 inducer, elevated levels of proteasome activity and content are recorded only in cell lines possessing a functional Nrf2. Moreover, treatment by the Nrf2 inducer results in the enhanced survival of cells following oxidative stress, whereas continuous treatment leads to lifespan extension of human fibroblasts. Importantly the Nrf2-proteasome axis is functional in terminally senescent cultures as these cells retain their responsiveness to the Nrf2 stimuli. In conclusion, these findings open up new directions for future manipulation of the senescence phenotype.
人源成纤维细胞的复制性衰老伴随着多种生物学过程的改变，包括蛋白酶体功能受损。蛋白酶体负责清除正常和受损的蛋白质。由于其后者的功能，蛋白酶体也被认为是代表性的次级抗氧化细胞机制。Nrf2 是一种基本的转录因子，负责调节细胞抗氧化反应，也已被证明在小鼠中调节几种蛋白酶体亚基。我们在这项研究中建立了人源成纤维细胞复制性衰老过程中 Nrf2 与蛋白酶体相关的功能。我们证明 Nrf2 在衰老过程中功能下降，而其沉默会导致过早衰老。然而，当用一种新型的 Nrf2 诱导剂激活 Nrf2 时，只有在具有功能性 Nrf2 的细胞系中才会记录到蛋白酶体活性和含量的升高。此外，Nrf2 诱导剂的处理会导致细胞在氧化应激后存活能力增强，而持续处理则会延长人源成纤维细胞的寿命。重要的是，Nrf2-蛋白酶体轴在终末衰老培养物中是功能性的，因为这些细胞保留了对 Nrf2 刺激的反应性。总之，这些发现为未来对衰老表型的操作开辟了新的方向。
