Stiewe Thorsten, Theseling Carmen C, Pützer Brigitte M
Centre for Cancer Research and Cancer Therapy, Institute of Molecular Biology, University of Essen, Medical School, D-45122 Essen, Germany.
J Biol Chem. 2002 Apr 19;277(16):14177-85. doi: 10.1074/jbc.M200480200. Epub 2002 Feb 13.
The p53 family member p73 displays significant structural and functional homology to p53. However, instead of mutational inactivation, overexpression of wild-type p73 has been reported in various tumor types compared with normal tissues, arguing against a classical tumor suppressor function. Recently, N-terminally truncated, transactivation-deficient p73 isoforms (DeltaTA-p73) have been identified as a second class of p73 proteins. Because overexpression of p73 in tumors includes DeltaTA-p73, we further characterized these novel p73 isoforms. We show that DeltaTA-p73 retains DNA-binding competence but lacks transactivation functions, resulting in an inability to induce growth arrest and apoptosis. Importantly, DeltaTA-p73 acts as a dominant-negative inhibitor of p53 and full-length p73 (TA-p73). We demonstrate that inhibition of p53 involves competition for DNA binding, whereas TA-p73 can be inhibited by direct protein-protein interaction. Further, we show that up-regulation of endogenous p73 just like ectopic overexpression of DeltaTA-p73 confers resistance to p53-mediated apoptosis induced by the chemotherapeutic agent H-7. Because inhibition of p53 is a common theme in human cancer, our data strongly support a role of DeltaTA-p73 expression for tumor formation.
p53家族成员p73与p53在结构和功能上具有显著的同源性。然而，与正常组织相比，在多种肿瘤类型中野生型p73呈过表达而非发生突变失活，这与经典的肿瘤抑制功能相悖。最近，N端截短、缺乏反式激活功能的p73异构体（ΔTA-p73）被鉴定为另一类p73蛋白。由于肿瘤中p73的过表达包括ΔTA-p73，我们进一步对这些新型p73异构体进行了表征。我们发现，ΔTA-p73保留了DNA结合能力，但缺乏反式激活功能，导致无法诱导生长停滞和凋亡。重要的是，ΔTA-p73作为p53和全长p73（TA-p73）的显性负性抑制剂发挥作用。我们证明，对p53的抑制涉及对DNA结合的竞争，而TA-p73可通过直接的蛋白质-蛋白质相互作用被抑制。此外，我们表明，内源性p73的上调与ΔTA-p73的异位过表达一样，赋予了对化疗药物H-7诱导的p53介导的凋亡的抗性。由于对p53的抑制是人类癌症中的一个常见现象，我们的数据有力地支持了ΔTA-p73表达在肿瘤形成中的作用。
