Zacchi Paola, Gostissa Monica, Uchida Takafumi, Salvagno Clio, Avolio Fabio, Volinia Stefano, Ronai Ze'ev, Blandino Giovanni, Schneider Claudio, Del Sal Giannino
Laboratorio Nazionale CIB, AREA Science Park, Padriciano 99, 34012 Trieste, Italy.
Nature. 2002 Oct 24;419(6909):853-7. doi: 10.1038/nature01120. Epub 2002 Oct 2.
The tumour suppressor p53 is important in the cell decision to either arrest cell cycle progression or induce apoptosis in response to a variety of stimuli. p53 post-translational modifications and association with other proteins have been implicated in the regulation of its stability and transcriptional activities. Here we report that, on DNA damage, p53 interacts with Pin1, a peptidyl-prolyl isomerase, which regulates the function of many proteins involved in cell cycle control and apoptosis. The interaction is strictly dependent on p53 phosphorylation, and requires Ser 33, Thr 81 and Ser 315. On binding, Pin1 generates conformational changes in p53, enhancing its transactivation activity. Stabilization of p53 is impaired in UV-treated Pin1(-/-) cells owing to its inability to efficiently dissociate from Mdm2. As a consequence, a reduced p53-dependent response was detected in Pin1(-/-) cells, and this correlates with a diminished transcriptional activation of some p53-regulated genes. Our results suggest that, following stress-induced phosphorylation, p53 needs to form a complex with Pin1 and to undergo a conformational change to fulfil its biological roles.
肿瘤抑制因子p53在细胞因应各种刺激而决定阻滞细胞周期进程或诱导凋亡的过程中起着重要作用。p53的翻译后修饰以及与其他蛋白质的结合与它的稳定性和转录活性的调控有关。在此我们报告，在DNA损伤时，p53与肽基脯氨酰顺反异构酶Pin1相互作用，Pin1可调节许多参与细胞周期控制和凋亡的蛋白质的功能。这种相互作用严格依赖于p53的磷酸化，且需要Ser 33、Thr 81和Ser 315。结合后，Pin1使p53产生构象变化，增强其反式激活活性。在紫外线处理的Pin1(-/-)细胞中，由于p53无法有效地与Mdm2解离，其稳定性受损。因此，在Pin1(-/-)细胞中检测到p53依赖性反应减弱，这与一些p53调控基因的转录激活减弱相关。我们的结果表明，在应激诱导的磷酸化之后，p53需要与Pin1形成复合物并经历构象变化以发挥其生物学作用。
