TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines
TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines
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DOI：
10.1158/0008-5472.can-04-0615
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Huang, TS
中科院分区：
文献类型：
--
作者：
Fan, WW;Huang, X;Huang, TS
TBX3是T-box基因家族的转录因子。TBX3突变导致人类尺乳综合征（MIM 181450），这是一种常染色体显性遗传病，其特征是乳腺缺失或发育不足以及其他先天性异常。最近发现TBX3能够使小鼠胚胎成纤维细胞（ME）永生化。此外，TBX3的同系物TBX2在啮齿类动物细胞中具有预防衰老的活性，并在一些人类乳腺癌中被发现扩增，提示TBX3在乳腺癌中发挥作用。本研究检测了TBX3及其异构体TBX3 + 2a的功能。TBX3 + 2a与TBX3在DNA结合域上的不同之处在于，它通过选择性剪接产生了额外的20个氨基酸。我们首先研究了这两种异构体的组织表达和选择性剪接模式。我们发现TBX3和TBX3 + 2a在人和小鼠中广泛表达，并且选择性剪接可能具有组织特异性和物种特异性。TBX3的过表达能够使MEF细胞长生不老，而TBX3 + 2a则表现出衰老的加速，这一功能差异可能是由于这两种同工异构体可能具有不同的下游靶点。TBX3，而不是TBX3 + 2a，能够在凝胶移位试验中结合到先前确定的T-box结合位点。人乳腺癌细胞系的一个亚群过表达TBX3。我们的研究结果表明TBX3和TBX3 + 2a在抑制MEF细胞衰老方面功能独特，可能在乳腺癌中发挥作用。
TBX3 is a transcription factor of the T-box gene family. Mutations of TBX3 cause ulnar-mammary syndrome (MIM 181450) in humans, an autosomal dominant disorder characterized by the absence or underdevelopment of the mammary glands and other congenital anomalies. It recently was found that TBX3 was able to immortalize mouse embryo fibroblast (ME) cells. In addition, TBX2, a homologue of TBX3, is active in preventing senescence in rodent cells and was found to be amplified in some human breast cancers, suggesting TBX3 plays a role in breast cancer. This study examined the function of TBX3 and its isoform, TBX3 + 2a. TBX3 + 2a differs from TBX3 in the DNA binding domain with an extra 20 amino acids produced by alternative splicing. We first examined the tissue expression and alternative splicing patterns of these two isoforms. We found that TBX3 and TBX3 + 2a are widely expressed in humans and mice, and alternative splicing could be tissue specific and species specific. Overexpression of TBX3 is able to immortalize MEF cells, whereas TBX3 + 2a shows an acceleration of senescence, a functional difference that may be explained by the fact that these two isoforms may have different downstream targets. TBX3, but not TBX3 + 2a, is able to bind to the previously identified T-box binding site in a gel shift assay. A subset of human breast cancer cell lines overexpresses TBX3. Our results indicate that TBX3 and TBX3 + 2a are functionally distinctive in inhibition of senescence of MEF cells and may play a role in breast cancer.