Gressner Olav, Schilling Tobias, Lorenz Katja, Schulze Schleithoff Elisa, Koch Andreas, Schulze-Bergkamen Henning, Lena Anna Maria, Candi Eleonora, Terrinoni Alessandro, Catani Maria Valeria, Oren Moshe, Melino Gerry, Krammer Peter H, Stremmel Wolfgang, Müller Martina
Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital, Heidelberg, Germany.
EMBO J. 2005 Jul 6;24(13):2458-71. doi: 10.1038/sj.emboj.7600708. Epub 2005 Jun 9.
TP63, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DeltaNp63. We investigated the downstream mechanisms by which TAp63alpha elicits apoptosis. TAp63alpha directly transactivates the CD95 gene via the p53 binding site in the first intron resulting in upregulation of a functional CD95 death receptor. Stimulation and blocking experiments of the CD95, TNF-R and TRAIL-R death receptor systems revealed that TAp63alpha can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63alpha and the mitochondrial apoptosis pathway. TAp63alpha upregulates expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of RAD9, DAP3 and APAF1. Of clinical relevance is the fact that TAp63alpha is induced by many chemotherapeutic drugs and that inhibiting TAp63 function leads to chemoresistance. Thus, beyond its importance in development and differentiation, we describe an important role for TAp63alpha in the induction of apoptosis and chemosensitivity.
TP63是一个重要的上皮发育基因，与p53具有显著的同源性。与p53不同，p63的表达受两个不同启动子调控，产生功能相反的蛋白质：全长具有转录活性的TAp63和显性负性的DeltaNp63。我们研究了TAp63α引发细胞凋亡的下游机制。TAp63α通过第一个内含子中的p53结合位点直接反式激活CD95基因，导致功能性CD95死亡受体上调。CD95、TNF-R和TRAIL-R死亡受体系统的刺激和阻断实验表明，TAp63α可触发这些死亡受体中每一个的表达。此外，我们的研究结果表明TAp63α与线粒体凋亡途径之间存在联系。TAp63α上调促凋亡Bcl-2家族成员如Bax和BCL2L11的表达以及RAD9、DAP3和APAF1的表达。具有临床相关性的事实是，许多化疗药物可诱导TAp63α表达，抑制TAp63功能会导致化疗耐药。因此，除了其在发育和分化中的重要性外，我们描述了TAp63α在诱导细胞凋亡和化疗敏感性方面的重要作用。
