Bertram Catharina, Hass Ralf
Department of Gynecology, Biochemistry and Tumor Biology Unit, Medical School, Hannover, Germany.
Sci Signal. 2008 Mar 25;1(12):pt1. doi: 10.1126/stke.112pt1.
A detailed understanding of aging and senescence is limited by the complex interplay of the effects of extracellular and environmental stimuli on cellular metabolic, mutational, and epigenetic phenomena. For example, STASIS (stress or aberrant signaling-induced senescence) is affected by the exposure to free radicals and conditions that cause an increased cellular production of reactive oxygen species (ROS) during normal life span. In addition, progressive telomere erosion and telomeric dysfunction contribute to a cellular feature termed replicative or cellular senescence. To focus on distinct cellular pathways that contribute to these different forms of senescence, we investigated the reversible differentiation and aging process of the human U937 leukemia cell line. This was compared to cellular senescence that occurred in normal primary human mammary epithelial cells (HMECs). These two cell systems revealed an important role of the proteolytic activity of the 20S proteasome and its activation by the nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) during "retrodifferentiation" and rejuvenation of the leukemic cells. Moreover, reduced extracellular proteolytic activity of certain matrix metalloproteinases-for example, MMP-7-is associated with accelerated aging and senescence in normal HMECs.
对衰老和细胞衰老的详细理解受到细胞外和环境刺激对细胞代谢、突变和表观遗传现象影响的复杂相互作用的限制。例如，STASIS（应激或异常信号诱导的衰老）受到自由基暴露以及在正常寿命期间导致细胞活性氧（ROS）产生增加的条件的影响。此外，端粒的渐进性侵蚀和端粒功能障碍导致一种称为复制性或细胞衰老的细胞特征。为了关注导致这些不同形式衰老的不同细胞途径，我们研究了人U937白血病细胞系的可逆分化和衰老过程。并将其与正常原代人乳腺上皮细胞（HMECs）中发生的细胞衰老进行了比较。这两种细胞系统揭示了20S蛋白酶体的蛋白水解活性及其在白血病细胞“逆向分化”和年轻化过程中被核蛋白聚（ADP-核糖）聚合酶-1（PARP-1）激活的重要作用。此外，某些基质金属蛋白酶（如MMP-7）的细胞外蛋白水解活性降低与正常HMECs的加速衰老和细胞衰老有关。
