title: Down syndrome fibroblasts and mouse Prep1-overexpressing cells display increased sensitivity to genotoxic stress.
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 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.
authors.affiliation: Laboratory of Molecular Dynamics of the Nucleus, Division of Genetics and Cell Biology, S. Raffaele Scientific Institute, via Olgettina 60, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Micali
authors.forename: Elena
authors.initials: E
authors.lastname: Longobardi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iotti
authors.forename: Carmelo
authors.initials: C
authors.lastname: Ferrai
authors.forename: Laura
authors.initials: L
authors.lastname: Castagnaro
authors.forename: Mario
authors.initials: M
authors.lastname: Ricciardi
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
authors.forename: Massimo P
authors.initials: MP
authors.lastname: Crippa
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology; D054278:Embryonal Carcinoma Stem Cells; D005047:Etoposide / Q000633:toxicity; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010641:Phenotype; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C491412:Pknox1 protein, mouse; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D005047:Etoposide