ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway

被引:76
|
作者
Wolvetang, EJ
Wilson, TJ
Sanij, E
Busciglio, J
Hatzistavrou, T
Seth, A
Hertzog, PJ
Kola, I
机构
[1] Monash Univ, Ctr Funct Genom & Human Dis, Monash Inst Reprod & Dev, Clayton, Vic 3168, Australia
[2] Univ Connecticut, Ctr Hlth, Dep0t Neurosci MC 3401, Farmington, CT 06030 USA
[3] Univ Toronto, Fac Med, Dept Pathol, Toronto, ON, Canada
[4] Univ Toronto, Fac Dent, Toronto, ON, Canada
[5] Womens Coll Hosp, Toronto, ON M5S 1B2, Canada
关键词
D O I
10.1093/hmg/ddg015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
ETS2 is a transcription factor encoded by a gene on human chromosome 21 and alterations in its expression have been implicated in the pathophysiological features of Down syndrome (DS). This study demonstrates that overexpression of ETS2 results in apoptosis. This is shown in a number of circumstances, including ETS2-overexpressing transgenic mice and cell lines and in cells from subjects with DS. Indeed we report for the first time that the ETS2 overexpression transgenic mouse develops a smaller thymus and lymphocyte abnormalities similar to that observed in DS. In all circumstances of ETS2 overexpression, the increased apoptosis correlated with increased p53 and alterations in downstream factors in the p53 pathway. In the human HeLa cancer cell line, transfection with functional p53 enables ETS2 overexpression to induce apoptosis. Furthermore, crossing the ETS2 transgenic mice with p53(-/-) mice genetically rescued the thymic apoptosis phenotype. Therefore, we conclude that overexpression of human chromosome 21-encoded ETS2 induces apoptosis that is dependent on p53. These results have important consequences for understanding DS and oncogenesis and may provide new insights into therapeutic interventions.
引用
收藏
页码:247 / 255
页数:9
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