Graduate School, Peking Union Medical College, 9, Dongdan Santiao, Dongcheng, Beijing 100730, China.
Biochem Biophys Res Commun. 2012 Jul 13;423(4):895-9. doi: 10.1016/j.bbrc.2012.06.099. Epub 2012 Jun 23.
CITED2, a cardiac transcription factor, plays an important role in cardiac development. CITED2 mutations lead to a constellation of cardiac defects, which include tetralogy of Fallot and outflow tract malformations. However, the mechanisms underlying these mutations are poorly understood. We investigated the function and mechanism of two missense mutations, G184S and S192G, responsible for tetralogy of Fallot and aortic stenosis, respectively. We found that CITED2 variants decreased its ability to mediate the expression of vascular endothelial growth factor (VEGF) and the expression of the paired-like homeodomain transcription factor 2-gamma (PITX2C), both of which are closely related to cardiac development. Luciferase reporter and mammalian two-hybrid assays showed that G184S and S192G in CITED2 restored the expression of VEGF, which was due to a reduction in its competitiveness with hypoxia inducible factor 1-alpha (HIF1-α) for binding to CBP/p300. In addition, we found that the G184S and S192G mutant decreased cooperation between CITED2 and transcription factor AP2-gamma (TFAP2C) in the transactivation of the PITX2C gene. These results provide important evidence that the mutation of CITED2 may play a role in the development of congenital heart disease (CHD) in humans.
CITED2 是一种心脏转录因子，在心脏发育中发挥重要作用。CITED2 突变导致一系列心脏缺陷，包括法洛四联症和流出道畸形。然而，这些突变的机制尚不清楚。我们研究了导致法洛四联症和主动脉瓣狭窄的两个错义突变 G184S 和 S192G 的功能和机制。我们发现，CITED2 变体降低了其介导血管内皮生长因子 (VEGF) 和配对样同源结构域转录因子 2-γ (PITX2C) 表达的能力，这两者都与心脏发育密切相关。荧光素酶报告基因和哺乳动物双杂交实验表明，CITED2 的 G184S 和 S192G 恢复了 VEGF 的表达，这是由于其与缺氧诱导因子 1-α (HIF1-α) 竞争结合 CBP/p300 的能力降低所致。此外，我们发现 G184S 和 S192G 突变降低了 CITED2 与转录因子 AP2-γ (TFAP2C) 在 PITX2C 基因转录激活中的协同作用。这些结果为 CITED2 突变可能在人类先天性心脏病 (CHD) 的发展中发挥作用提供了重要证据。
