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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.
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A WW domain protein TAZ is a critical coactivator for TBX5, a transcription factor implicated in Holt-Oram syndrome.

机译：WW域蛋白TAZ是TBX5的关键共激活因子，TBX5是Holt-Oram综合征的转录因子。

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摘要

The T-box transcription factor TBX5 plays essential roles in cardiac and limb development. Various mutations in the TBX5 gene have been identified in patients with Holt-Oram syndrome, which is characterized by congenital defects in the heart and upper extremities. In this study, we identified a WW-domain-containing transcriptional regulator TAZ as a potent TBX5 coactivator. TAZ directly associates with TBX5 and markedly stimulates TBX5-dependent promoters by interacting with the histone acetyltransferases p300 and PCAF. YAP, a TAZ-related protein with conserved functional domains, also stimulates TBX5-dependent transcription, possibly by forming a heterodimer with TAZ. TBX5 lacks a PY motif, which mediates the association of other proteins with TAZ, and interacts with TAZ through multiple domains including its carboxyl-terminal structure. Truncation mutants of TBX5 identified in patients with Holt-Oram syndrome were markedly impaired in their ability to associate with and be stimulated by TAZ. These findings reveal key roles for TAZ and YAP in the control of TBX5-dependent transcription and suggest the involvement of these coactivators in cardiac and limb development.
机译：T-box转录因子TBX5在心脏和四肢发育中起重要作用。在患有Holt-Oram综合征的患者中已经鉴定出TBX5基因的各种突变，其特征是心脏和上肢的先天性缺陷。在这项研究中，我们确定了包含WW域的转录调节因子TAZ作为有效的TBX5共激活因子。 TAZ与TBX5直接缔合，并通过与组蛋白乙酰转移酶p300和PCAF相互作用来显着刺激TBX5依赖性启动子。 YAP，一种具有保守功能域的TAZ相关蛋白，也可能与TAZ形成异二聚体，从而刺激TBX5依赖性转录。 TBX5缺乏PY基序，PY基序介导其他蛋白质与TAZ的缔合，并通过包括其羧基末端结构在内的多个域与TAZ相互作用。在Holt-Oram综合征患者中发现的TBX5截短突变体与TAZ结合并受TAZ刺激的能力明显受损。这些发现揭示了TAZ和YAP在TBX5依赖性转录控制中的关键作用，并暗示了这些共激活因子参与心脏和肢体的发育。

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