Collavoli Anita, Hatcher Cathy J, He Jie, Okin Daniel, Deo Rahul, Basson Craig T
Department of Medicine, Weill Medical College of Cornell University, 525 E 68th Street, New York, NY 10021, USA.
J Mol Cell Cardiol. 2003 Oct;35(10):1191-5. doi: 10.1016/s0022-2828(03)00231-1.
The TBX5 transcription factor is required for normal cardiogenesis, and human TBX5 mutations cause congenital heart defects. Previous studies have shown that TBX5 can localize to cellular nuclei during embryogenesis and have suggested that altered nuclear localization may contribute to disease pathogenesis. Current analyses suggest that TBX5 nuclear localization is not uniform during organogenesis. To determine the biochemical mechanisms underlying TBX5 nuclear import, we performed site-directed mutagenesis of human TBX5. We identified two distinct nuclear localization signals in TBX5, one monopartite and one bipartite. While each is insufficient to promote complete TBX5 nuclear localization, they act cooperatively to do so. These sequences are evolutionarily conserved and have cognates in other T-box gene family members.
TBX5转录因子是正常心脏发生所必需的，人类TBX5突变会导致先天性心脏缺陷。先前的研究表明，TBX5在胚胎发育过程中可定位于细胞核，并提示核定位改变可能与疾病发病机制有关。目前的分析表明，在器官发生过程中TBX5的核定位并不均匀。为了确定TBX5核输入的生化机制，我们对人类TBX5进行了定点诱变。我们在TBX5中鉴定出两个不同的核定位信号，一个是单分型的，一个是双分型的。虽然每个信号都不足以促进TBX5完全定位于细胞核，但它们协同作用以实现这一目的。这些序列在进化上是保守的，并且在其他T盒基因家族成员中存在同源物。
