BACKGROUND TBX3, a member of the T-box family of transcription factors, is essential in development and has emerged as an important player in the oncogenic process. TBX3 is overexpressed in several cancers and has been shown to contribute directly to tumour formation, migration and invasion. However, little is known about the molecular basis for its role in development and oncogenesis because there is a paucity of information regarding its target genes. The cyclin-dependent kinase inhibitor p21(WAF1) plays a pivotal role in a myriad of processes including cell cycle arrest, senescence and apoptosis and here we provide a detailed mechanism to show that it is a direct and biologically relevant target of TBX3. RESULTS Using a combination of luciferase reporter gene assays and in vitro and in vivo binding assays we show that TBX3 directly represses the p21(WAF1) promoter by binding a T-element close to its initiator. Furthermore, we show that the TBX3 DNA binding domain is required for the transcriptional repression of p21(WAF1) and that pseudo-phosphorylation of a serine proline motif (S190) located within this domain may play an important role in regulating this ability. Importantly, we demonstrate using knockdown and overexpression experiments that p21(WAF1) repression by TBX3 is biologically significant and required for TBX3-induced cell proliferation of chondrosarcoma cells. CONCLUSIONS Results from this study provide a detailed mechanism of how TBX3 transcriptionally represses p21(WAF1) which adds to our understanding of how it may contribute to oncogenesis.

中文翻译：

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T-box转录因子TBX3通过直接抑制p21（WAF1）细胞周期蛋白依赖性激酶抑制剂来驱动增殖。

背景技术TBX3是T-box转录因子家族的成员，在发育中至关重要，并已成为致癌过程中的重要角色。TBX3在几种癌症中过表达，并已显示直接导致肿瘤形成，迁移和侵袭。但是，关于其在发育和癌发​​生中作用的分子基础知之甚少，因为关于其靶基因的信息很少。细胞周期蛋白依赖性激酶抑制剂p21（WAF1）在包括细胞周期停滞，衰老和凋亡在内的无数过程中起着关键作用，在这里我们提供了详细的机制来表明它是TBX3的直接生物学相关靶标。结果结合使用萤光素酶报告基因检测和体内外结合检测，我们发现TBX3通过结合靠近其启动子的T元件直接抑制p21（WAF1）启动子。此外，我们表明TBX3 DNA结合结构域是p21（WAF1）转录抑制所必需的，位于该结构域的丝氨酸脯氨酸基序（S190）的伪磷酸化可能在调节此功能中起重要作用。重要的是，我们证明了使用敲低和过表达实验表明，TBX3抑制p21（WAF1）具有生物学意义，并且是TBX3诱导的软骨肉瘤细胞增殖的必需条件。