Alarcon-Vargas D, Fuchs S Y, Deb S, Ronai Z
Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029, USA.
Oncogene. 2000 Feb 10;19(6):831-5. doi: 10.1038/sj.onc.1203311.
The p53 homologue p73 efficiently activates p53-responsive genes. The well documented over-expression of p73 spliced forms in a wide variety of tumor types promoted us to elucidate the mechanisms underlying p73-mediated transcription. Using the luciferase reporter gene driven by Mdm2-minimal promoter in p53 null cells, we demonstrate that the weak transcriptional activity mediated by p73alpha was increased by the mutant form p73beta292, which by itself is transcriptionally inactive. Similarly, cooperation between p73beta and an inactive form of p73alpha increased p73beta-mediated transcriptional activities. Conversely, p73beta elicited a silencing effect on a gain of function mutant, p53(281), which by itself mediated efficient transactivation of the MDR promoter. Neither anisomycin nor actinomycin D altered p73-mediated transcriptional activities, whereas sorbitol profoundly inhibited them through a rapid proteasome-dependent degradation of p73. Our observations point to plausible scenarios in which p73, through cooperation between p73 spliced forms and suppression of gain of function mutant p53 may elicit changes in the transcription of p53 target genes that play key roles in cell growth and death.
p53 同源物 p73 能有效激活 p53 反应基因。多种肿瘤类型中 p73 剪接形式的过度表达已有充分记录，这促使我们去阐明 p73 介导转录的潜在机制。在 p53 基因缺失的细胞中，我们利用由 Mdm2 最小启动子驱动的荧光素酶报告基因，证明 p73α 介导的微弱转录活性被突变形式 p73β292 增强，而 p73β292 本身无转录活性。同样，p73β 与无活性形式的 p73α 之间的协同作用增强了 p73β 介导的转录活性。相反，p73β 对功能获得性突变体 p53(281) 产生沉默效应，p53(281) 本身可有效介导多药耐药（MDR）启动子的反式激活。茴香霉素和放线菌素 D 均未改变 p73 介导的转录活性，而山梨醇通过依赖蛋白酶体的 p73 快速降解深刻抑制了它们。我们的观察结果表明了一些合理的情况，即 p73 通过 p73 剪接形式之间的协同作用以及对功能获得性突变体 p53 的抑制，可能引发 p53 靶基因转录的变化，这些变化在细胞生长和死亡中起关键作用。
