Laboratory of Molecular Dynamics of the Nucleus, Division of Genetics and Cell Biology, S. Raffaele Scientific Institute, via Olgettina 60, Milan, Italy.
Nucleic Acids Res. 2010 Jun;38(11):3595-604. doi: 10.1093/nar/gkq019. Epub 2010 Jan 27.
PREP1 (PKNOX1) maps in the Down syndrome (DS) critical region of chromosome 21, is overexpressed in some DS tissues and might be involved in the DS phenotype. By using fibroblasts from DS patients and by overexpressing Prep1 in F9 teratocarcinoma and Prep1(i/i) MEF to single out the role of the protein, we report that excess Prep1 increases the sensitivity of cells to genotoxic stress and the extent of the apoptosis directly correlates with the level of Prep1. The apoptotic response of Prep1-overexpressing cells is mediated by the pro-apoptotic p53 protein that we show is a direct target of Prep1, as its depletion reverts the apoptotic phenotype. The induction of p53 overcomes the anti-apoptotic role of Bcl-X(L), previously shown to be also a Prep1 target, the levels of which are increased in Prep1-overexpressing cells as well. Our results provide a rationale for the involvement of PREP1 in the apoptotic phenotype of DS tissues and indicate that differences in Prep1 level can have drastic effects.
PKNOX1（PREP1）定位于唐氏综合征（DS）的 21 号染色体关键区域，在一些 DS 组织中过表达，可能与 DS 表型有关。通过使用 DS 患者的成纤维细胞，以及在 F9 畸胎瘤和 Prep1(i/i) MEF 中转染 PREP1，我们发现过量的 PREP1 增加了细胞对遗传毒性应激的敏感性，细胞凋亡的程度与 PREP1 的水平直接相关。我们发现，过表达 PREP1 的细胞的凋亡反应是由促凋亡的 p53 蛋白介导的，p53 蛋白是 PREP1 的直接靶标，其缺失可逆转凋亡表型。p53 的诱导克服了 Bcl-XL 的抗凋亡作用，Bcl-XL 先前也被证明是 PREP1 的靶标，过表达 PREP1 的细胞中 Bcl-XL 的水平也增加了。我们的研究结果为 PREP1 参与 DS 组织的凋亡表型提供了依据，并表明 PREP1 水平的差异可能会产生巨大的影响。
