Tbx3 impinges on the p53 pathway to suppress apoptosis, facilitate cell transformation and block myogenic differentiation
Tbx3 impinges on the p53 pathway to suppress apoptosis, facilitate cell transformation and block myogenic differentiation
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DOI：
10.1038/sj.onc.1205476
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发表时间：
2002-05-30
期刊：
影响因子：
8
通讯作者：
Hurlin, PJ
中科院分区：
文献类型：
--
作者：
Carlson, H;Ota, S;Hurlin, PJ
Tbx3是T-box转录因子家族的一员。Tbx3基因突变导致尺乳综合征，这是一种常染色体显性遗传病，其特征为上肢缺陷、经旁腺缺陷（包括乳腺发育不全）以及牙齿、头发和生殖器缺陷。在细胞培养中，Tbx3及其近亲Tbx2能够使小鼠胚胎成纤维细胞永生化。我们发现Tbx3与Myc或致癌Ras（H-Ras(Val17)）的表达导致小鼠胚胎成纤维细胞的有效转化。Tbx3的癌基因合作与Tbx3抑制p19ARF和p53的诱导能力相关，p19ARF和p53通常是由Myc和Ras的过度表达引起的，并保护Myc诱导的细胞凋亡。Tbx3能够干扰Myc水平过高引起的细胞凋亡，而缺乏其c端抑制结构域的Tbx3突变体没有抗凋亡活性，也不能抑制p19ARF或p53的水平。与抑制p53通路功能的能力一致，我们发现Tbx3，而不是Tbx3 c端突变体，有效地阻断C2C12成肌细胞的成肌分化。我们的研究结果支持这样一种观点，即在体内，放松管制和/或过量的Tbx3可能具有致癌潜力。
Tbx3 is a member of the T-box family of transcription factors. Mutations in Tbx3 cause ulnar-mammary syndrome, an autosomal dominant disorder characterized by upper limb defects, apocrine-gland defects including mammary hypoplasia, and tooth, hair and genital defects. In cell culture, Tbx3 and its close relative Tbx2 are capable of immortalizing mouse embryo fibroblasts. We show that expression of Tbx3 together with Myc or oncogenic Ras (H-Ras(Val17)) leads to efficient transformation of mouse embryo fibroblasts. Oncogene cooperation by Tbx3 correlates with an ability of Tbx3 to suppress the induction of p19ARF and p53 that is typically caused by overexpression Myc and Ras, and to protect against Myc-induced apoptosis. Whereas Tbx3 is capable of interfering with apoptosis caused by excessive Myc levels, a Tbx3 mutant lacking its C-terminal repression domain shows no anti-apoptotic activity and fails to repress levels of p19ARF or p53. Consistent with an ability to suppress p53 pathway function, we find that Tbx3, but not a Tbx3 C-terminal mutant, efficiently blocks myogenic differentiation of C2C12 myoblasts. Our results support the idea that deregulation and/or excessive levels of Tbx3 may have oncogenic potential in vivo.