C-terminal α Domain of p63 Binds to p300 to Coactivate β-Catenin
C-terminal α Domain of p63 Binds to p300 to Coactivate β-Catenin
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DOI：
10.1016/j.neo.2019.03.010
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发表时间：
2019-05-01
期刊：
影响因子：
4.8
通讯作者：
Kurata, Shun-ichi
中科院分区：
文献类型：
--
作者：
Katoh, Iyoko;Maehata, Yojiro;Kurata, Shun-ichi
TP 63（p63）是肿瘤抑制基因TP 53（p53）家族的一员，是外胚层组织发育所必需的，并抑制癌的恶性进展。最丰富的同种型Delta Np 63 α（称为p63）缺乏N-末端反式激活（TA）结构域，最初被表征为针对p53家族蛋白的显性负型抑制因子。它还与TCF/LEF结合以抑制β-连环蛋白。然而，在不同的系统中也观察到p63的转录激活。为了理解这个令人困惑的结果，我们分析了p63在控制β-连环蛋白依赖的转录中的结构功能关系。p63作为中度诱导的β-连环蛋白的抑制剂。然而，当应用核靶向S33 Y β-连环蛋白以引起最大增强子激活时，p63显示β-连环蛋白共激活功能。重要的是，我们新发现，尽管没有TA结构域，p63与p300，一个通用的衔接蛋白和染色质修饰剂引起转录激活。p63的C-末端a结构域对于p300结合和共激活因子功能是必需的。这些结果与鳞状细胞癌细胞系中内源性p63-p300复合物的形成和p63对Wnt/β-catenin应答基因的调控有关。新的p63-p300相互作用可能参与组织发育和癌变过程中基因表达的正向调节。
TP63 (p63), a member of the tumor suppressor TP53 (p53) gene family, is essential for ectodermal tissue development and suppresses malignant progression of carcinomas. The most abundant isoform, Delta Np63 alpha (referred to as p63), lacks the N-terminal transactivation (TA) domain, and was originally characterized as a dominant-negative type suppressor against p53 family proteins. It also binds to TCF/LEF to inhibit beta-catenin. Nevertheless, transcriptional activation by p63 has also been observed in varied systems. To understand the puzzling results, we analyzed the structure function relationship of p63 in the control of beta-catenin-dependent transcription. p63 acted as a suppressor of moderately induced beta-catenin. However, when nuclear targeted S33Y beta-catenin was applied to cause the maximum enhancer activation, p63 displayed a beta-catenin-coactivating function. The DNA-binding domain of p63 and the target sequence facilitated it. Importantly, we newly found that, despite the absence of TA domain, p63 was associated with p300, a general adaptor protein and chromatin modifier causing transcriptional activation. C-terminal a domain of p63 was essential for p300-binding and for the coactivator function. These results were related to endogenous p63-p300 complex formation and Wnt/beta-catenin-responsive gene regulation by p63 in squamous cell carcinoma lines. The novel p63-p300 interaction may be involved in positive regulation of gene expression in tissue development and carcinogenesis.