Benoit V, Hellin A C, Huygen S, Gielen J, Bours V, Merville M P
Laboratory of Medical Chemistry and Medical Oncology, Pathology B23, University of Liège, Sart-Tilman, Belgium.
Oncogene. 2000 Sep 28;19(41):4787-94. doi: 10.1038/sj.onc.1203831.
The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-specific manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported. In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identified in the human p53 promoter a novel potential p53-responsive element that binds wild-type p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-kappaB binding site, we demonstrated an additive effect when NF-kappaB subunits and p53 protein combined to transactivate the human p53 promoter.
肿瘤抑制因子p53在细胞对DNA损伤的反应中起关键作用，因为它控制DNA修复、细胞周期阻滞和细胞凋亡。我们研究了人p53基因转录在结肠癌细胞系中的自动调节。野生型p53已被证明可正向或负向自动调节其自身转录，且可能以细胞类型特异性方式进行。实际上，在人和小鼠的p53启动子中已描述了一个p53结合位点，但野生型p53蛋白与该位点的直接结合从未被报道过。在本研究中，我们证明了野生型p53在人结肠癌细胞中对人p53启动子的反式激活作用。我们在人p53启动子中鉴定出一个新的潜在p53反应元件，它可结合野生型p53。此外，野生型p53蛋白反式激活了一个报告质粒，该质粒含有由带有此p53结合位点的最小启动子驱动的荧光素酶基因。最后，由于p53启动子含有一个NF-κB结合位点，我们证明了NF-κB亚基和p53蛋白联合反式激活人p53启动子时具有累加效应。
