The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator
The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator
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DOI：
10.1074/jbc.m200403200
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发表时间：
2002-07-19
影响因子：
4.8
通讯作者：
van Lohuizen, M
中科院分区：
文献类型：
--
作者：
Lingbeek, ME;Jacobs, JJL;van Lohuizen, M
鼠类肿瘤抑制因子 p19(ARF)（人类为 p14(ARF)）被认为通过其在 p53 途径中的作用，在防止原代细胞致癌转化方面发挥着重要的保护作用。迄今为止，已知多种与疾病相关的 p19(ARF) 调节因子，其中包括 T 盒基因 TBX2（位于原发性乳腺肿瘤的扩增子上）和 TBX3（在人类发育障碍尺乳综合症中发生突变）。在这里，我们鉴定了一个变体 T 位点，与共有 T 位点的 20 个核苷酸中的 13 个相匹配，作为人 p14(ARF) 启动子中必需的 TBX2/TBX3 结合元件。突变分析表明共有 T 盒和 C 端保守抑制域对于 p14(ARF) 抑制至关重要。虽然原型 T 盒蛋白 Brachyury 与共有 T 位点相互作用所需的核心核苷酸在变体位点中是保守的，但额外的侧翼核苷酸有助于 TBX2 结合的特异性。 TBX1A 或 Xbra 无法通过变体 p14(ARF) T 位点激活就说明了这一点。重要的是，这表明与 T-box 因子和相应的识别位点在体内调节其靶基因相关的特异性水平达到了前所未有的水平。
The murine tumor suppressor p19(ARF) (p14(ARF) in humans) is thought to fulfill an important protective role in preventing primary cells from oncogenic transformation via its action in the p53 pathway. Several disease-implicated regulators of p19(ARF) are known to date, among which are the T-box genes TBX2, which resides on an amplicon in primary breast tumors, and TBX3, which is mutated in the human developmental disorder Ulnar-Mammary syndrome. Here we identify a variant T-site, matching 13 of 20 nucleotides of a consensus T-site, as the essential TBX2/TBX3-binding element in the human p14(ARF) promoter. Mutant analysis indicates that both the consensus T-box and a C-terminal conserved repression domain are essential for p14(ARF) repression. Whereas the core nucleotides required for interaction of the archetypal T-box protein Brachyury with a consensus T-site are conserved in the variant site, additional flanking nucleotides contribute to the specificity of TBX2 binding. This is illustrated by the inability of TBX1A or Xbra to activate via the variant p14(ARF) T-site. Importantly, this suggests a hitherto unsuspected level of specificity associated with T-box factors and corresponding recognition sites in regulating their target genes in vivo.