Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress |
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| Authors: | Nicola Micali Elena Longobardi Giorgio Iotti Carmelo Ferrai Laura Castagnaro Mario Ricciardi Francesco Blasi Massimo P. Crippa |
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| Affiliation: | 1.Laboratory of Molecular Dynamics of the Nucleus, Division of Genetics and Cell Biology, S. Raffaele Scientific Institute, via Olgettina 60, Milan 20132, 2.IFOM (Fondazione Istituto FIRC di Oncologia Molecolare), via Adamello 16, Milan 20139, 3.Laboratory of Molecular Genetics, Division of Genetics and Cell Biology, S. Raffaele Scientific Institute, via Olgettina 60, Milan 20132 and 4.Università Vita e Salute S. Raffaele, via Olgettina 58, Milan 20132, Italy |
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| Abstract: | 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 Prep1i/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-XL, 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. |
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