Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress

Nicola Micali, Elena Longobardi, Giorgio Iotti, Carmelo Ferrai, Laura Castagnaro, Mario Ricciardi, Francesco Blasi, Massimo P. Crippa

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbergkq019
Pages (from-to)3595-3604
Number of pages10
JournalNucleic Acids Research
Volume38
Issue number11
DOIs
Publication statusPublished - Jan 27 2010

ASJC Scopus subject areas

  • Genetics

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    Micali, N., Longobardi, E., Iotti, G., Ferrai, C., Castagnaro, L., Ricciardi, M., Blasi, F., & Crippa, M. P. (2010). Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress. Nucleic Acids Research, 38(11), 3595-3604. [gkq019]. https://doi.org/10.1093/nar/gkq019