Forrester K, Ambs S, Lupold S E, Kapust R B, Spillare E A, Weinberg W C, Felley-Bosco E, Wang X W, Geller D A, Tzeng E, Billiar T R, Harris C C
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2442-7. doi: 10.1073/pnas.93.6.2442.
The tumor suppressor gene product p53 plays an important role in the cellular response to DNA damage from exogenous chemical and physical mutagens. Therefore, we hypothesized that p53 performs a similar role in response to putative endogenous mutagens, such as nitric oxide (NO). We report here that exposure of human cells to NO generated from an NO donor or from overexpression of inducible nitric oxide synthase (NOS2) results in p53 protein accumulation. In addition, expression of wild-type (WT) p53 in a variety of human tumor cell lines, as well as murine fibroblasts, results in down-regulation of NOS2 expression through inhibition of the NOS2 promoter. These data are consistent with the hypothesis of a negative feedback loop in which endogenous NO-induced DNA damage results in WT p53 accumulation and provides a novel mechanism by which p53 safeguards against DNA damage through p53-mediated transrepression of NOS2 gene expression, thus reducing the potential for NO-induced DNA damage.
肿瘤抑制基因产物p53在细胞对外源化学和物理诱变剂所致DNA损伤的反应中发挥重要作用。因此，我们推测p53在对一氧化氮（NO）等假定的内源性诱变剂的反应中发挥类似作用。我们在此报告，将人类细胞暴露于由NO供体产生的NO或诱导型一氧化氮合酶（NOS2）过表达所产生的NO中，会导致p53蛋白积累。此外，在多种人类肿瘤细胞系以及小鼠成纤维细胞中表达野生型（WT）p53，会通过抑制NOS2启动子导致NOS2表达下调。这些数据与负反馈回路的假设一致，即内源性NO诱导的DNA损伤导致WT p53积累，并提供了一种新机制，通过该机制p53通过p53介导的对NOS2基因表达的反式抑制来保护细胞免受DNA损伤，从而降低NO诱导DNA损伤的可能性。
