Janssen Y M, Van Houten B, Borm P J, Mossman B T
Department of Pathology, University of Vermont, Burlington.
Lab Invest. 1993 Sep;69(3):261-74.
A broad array of oxidative stresses modulates gene expression in a variety of mammalian cells. One goal of this review was to characterize cellular responses to oxidative injury, how these processes are regulated, and the outcome for a particular cell or tissue. Many genes induced in response to specific oxidant stresses have been identified and include transcription factors, replication proteins, proteases, protease inhibitors, proteins affecting cell proliferation and various antioxidants, i.e. heme oxygenase, MT, and MnSOD. The latter enzyme is induced after a number of cytokines and oxidant stresses including hyperoxia and mineral dusts causing inflammation. Moreover, increases in mRNA levels of TNF and IL-1, cytokines inducing MnSOD, are observed after exposure to UV and ionizing radiation. Since increased electron flow could lead to generation of more AOS within mitochondria, increased levels of MnSOD might be necessary to maintain normal functioning of the mitochondria after oxidative stress. Alterations in cell growth are intrinsically related to the pathogenesis of many diseases. Paradoxically, some of the responses of cells to oxidative stress reflect cytotoxicity and cytostasis, whereas others result in increased cell proliferation. For example, induction of gadd genes observed after oxidative stress is related to growth arrest of cells, a response which might enable the cell to repair oxidative damage prior to replication. This phenomenon might prevent fixation of mutations associated with oxidative DNA damage. On the other hand, increased mRNA expression and activity of ODC, observed after exposure of cells to UV or asbestos is associated with increased cell proliferation. In addition, increased mRNA expression of cellular proto-oncogenes observed after exposure to oxidants could also be related to increased DNA synthesis or proliferation. Figure 5 provides a general scheme of cell responses to oxidative stress and possible ramifications. AOS can react with a number of target molecules including proteins, lipids, and DNA. These interactions elicit a number of signals including activation of gene regulatory factors (transcription factors) which in turn activate oxidative stress-responsive genes or regulons. Consequently, a number of proteins are produced with distinctive functions including DNA repair enzymes, antioxidants, proteases inhibitors, cytokines and proteins affecting cell proliferation. These cellular responses to AOS can lead to restoration of normal cellular function and adaptation to oxidative stress, cell death or aberrant proliferation. It is the latter two responses which can lead to a variety of disease states including cancer.(ABSTRACT TRUNCATED AT 400 WORDS)
多种氧化应激可调节多种哺乳动物细胞中的基因表达。本综述的一个目标是描述细胞对氧化损伤的反应、这些过程是如何被调控的，以及特定细胞或组织的结果。已经鉴定出许多因特定氧化应激而被诱导的基因，包括转录因子、复制蛋白、蛋白酶、蛋白酶抑制剂、影响细胞增殖的蛋白质以及各种抗氧化剂，如血红素加氧酶、金属硫蛋白和锰超氧化物歧化酶。后一种酶在多种细胞因子和氧化应激后被诱导，包括高氧和导致炎症的矿物粉尘。此外，在暴露于紫外线和电离辐射后，观察到肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）的mRNA水平升高，这两种细胞因子可诱导锰超氧化物歧化酶。由于线粒体中电子流量增加可能导致更多活性氧（AOS）的产生，因此在氧化应激后可能需要增加锰超氧化物歧化酶的水平来维持线粒体的正常功能。细胞生长的改变与许多疾病的发病机制内在相关。矛盾的是，细胞对氧化应激的一些反应反映了细胞毒性和细胞生长停滞，而其他反应则导致细胞增殖增加。例如，氧化应激后观察到的gadd基因的诱导与细胞生长停滞有关，这种反应可能使细胞在复制前修复氧化损伤。这种现象可能会阻止与氧化性DNA损伤相关的突变的固定。另一方面，细胞暴露于紫外线或石棉后观察到的鸟氨酸脱羧酶（ODC）的mRNA表达和活性增加与细胞增殖增加有关。此外，暴露于氧化剂后观察到的细胞原癌基因的mRNA表达增加也可能与DNA合成或增殖增加有关。图5提供了细胞对氧化应激反应的一般示意图以及可能的后果。活性氧可以与许多靶分子反应，包括蛋白质、脂质和DNA。这些相互作用引发了许多信号，包括基因调节因子（转录因子）的激活，进而激活氧化应激反应基因或调节子。因此，产生了许多具有独特功能的蛋白质，包括DNA修复酶、抗氧化剂、蛋白酶抑制剂、细胞因子和影响细胞增殖的蛋白质。细胞对活性氧的这些反应可导致正常细胞功能的恢复和对氧化应激的适应、细胞死亡或异常增殖。正是后两种反应可导致包括癌症在内的多种疾病状态。（摘要截断于400字）
