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首页> 外文期刊>Molecular and Cellular Biology >DNA-Binding and Transactivation Activities Are Essential for TAp63 Protein Degradation
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DNA-Binding and Transactivation Activities Are Essential for TAp63 Protein Degradation

机译：DNA结合和反式激活活性对于TAp63蛋白降解至关重要

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The p53-related p63 gene encodes six isoforms with differing N and C termini. TAp63 isoforms possess a transactivation domain at the N terminus and are able to transactivate a set of genes, including some targets downstream of p53. Accumulating evidence indicates that TAp63 plays an important role in regulation of cell proliferation, differentiation, and apoptosis, whereas transactivation-inert ΔNp63 functions to inhibit p63 and other p53 family members. Mutations in the p63 gene that abolish p63 DNA-binding and transactivation activities cause human diseases, including ectrodactyly ectodermal dysplasia and facial clefting (EEC) syndrome. In this study, we show that mutant p63 proteins with a single amino acid substitution found in EEC syndrome are DNA binding deficient, transactivation inert, and highly stable. We demonstrate that TAp63 protein expression is tightly controlled by its specific DNA-binding and transactivation activities and that p63 is degraded in a proteasome-dependent, MDM2-independent pathway. In addition, the N-terminal transactivation domain of p63 is indispensable for its protein degradation. Furthermore, the wild-type TAp63γ can act in trans to promote degradation of mutant TAp63γ defective in DNA binding, and the TA domain deletion mutant of TAp63γ inhibits transactivation activity and stabilizes the wild-type TAp63 protein. Taken together, these data suggest a feedback loop for p63 regulation, analogous to the p53-MDM2 feedback loop.
机译：与p53相关的p63基因编码N和C末端不同的六个同工型。 TAp63亚型在N末端具有反式激活结构域，并且能够反式激活一组基因，包括p53下游的一些靶标。越来越多的证据表明，TAp63在调节细胞增殖，分化和凋亡中起着重要作用，而反式激活ΔNp63则具有抑制p63和其他p53家族成员的功能。废除p63 DNA结合和反式激活活性的p63基因突变会导致人类疾病，包括外胚层外胚层发育不良和面部裂痕（EEC）综合征。在这项研究中，我们显示在EEC综合征中发现的具有单个氨基酸取代的突变型p63蛋白是DNA结合缺陷，反式激活惰性和高度稳定的蛋白。我们证明，TAp63蛋白的表达受到其特定的DNA结合和反式激活活动的严格控制，并且p63在蛋白酶体依赖性，MDM2依赖性途径中被降解。另外，p63的N末端反式激活结构域对于其蛋白质降解是必不可少的。此外，野生型TAp63γ可以在反转录中起作用，以促进DNA结合缺陷的突变体TAp63γ的降解，而TAp63γ的TA结构域缺失突变体抑制反式激活活性并稳定野生型TAp63蛋白。综上所述，这些数据暗示了一个用于p63调节的反馈回路，类似于p53-MDM2反馈回路。

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