Salnikow K, Wang S, Costa M
Department of Environmental Medicine, New York University Medical Center, New York 10016, USA.
Cancer Res. 1997 Nov 15;57(22):5060-6.
Thrombospondin I (TSP I) is an extracellular matrix glycoprotein that influences cell adhesion, motility, and growth. On the basis of its effects on endothelial cell proliferation, TSP I has attracted interest as a potential regulator of solid tumor growth through modulation of tumor blood supply. The regulation of TSP I expression is of critical importance for designing new approaches in tumor therapy. Recently, we have shown that TSP I expression is lost in nickel-transformed cells. In this paper, we identified an activating transcription factor (ATF)/cAMP-responsive element-binding protein binding site as a negative regulatory site in the 5'-flanking sequence of mouse TSP I promoter. We identified ATF-1 as a major component of the ATF/cAMP-responsive element-binding protein binding complex. This Mr 35,000 nuclear ATF-1 protein was shown to be present in higher amounts in nickel-transformed 3T3 cells that do not express TSP 1. Acute treatment of 3T3 cells with NiCl2 resulted in the induction of this transcription factor, and this induction was correlated temporally with the suppression of TSP I expression in the same cells. These results show that nickel exposure causes accumulation of the ATF-1 transcription factor, which is responsible for the down-regulation of transcription of TSP I, and possibly other tumor suppressor genes during nickel-induced cellular transformation.
血小板反应蛋白I（TSP I）是一种细胞外基质糖蛋白，可影响细胞黏附、运动和生长。基于其对内皮细胞增殖的影响，TSP I作为一种通过调节肿瘤血液供应来调控实体瘤生长的潜在因子而受到关注。TSP I表达的调控对于设计肿瘤治疗新方法至关重要。最近，我们发现镍转化细胞中TSP I表达缺失。在本文中，我们确定了一个激活转录因子（ATF）/cAMP反应元件结合蛋白结合位点为小鼠TSP I启动子5'侧翼序列中的负调控位点。我们确定ATF-1是ATF/cAMP反应元件结合蛋白结合复合物的主要成分。这种分子量为35000的核ATF-1蛋白在不表达TSP 1的镍转化3T3细胞中含量更高。用NiCl2对3T3细胞进行急性处理导致该转录因子的诱导，且这种诱导与同一细胞中TSP I表达的抑制在时间上相关。这些结果表明，镍暴露导致ATF-1转录因子积累，其在镍诱导的细胞转化过程中负责TSP I转录的下调，以及可能其他肿瘤抑制基因的下调。
