International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 85 - FIRST APPROACH TO A NEW DOUBLE KO MOUSE: P21 AND P53 NULL. THE EPIGENETIC AS A KEY ANSWER FOR TUMORS

de la Cueva E
Spanish National Cancer Centre

Co-Authors: Herranz M, Fraga MF, Esteller M, Martín-Caballero J.
Institutions: Spanish National Cancer Centre

In the present work we described the generation of double Knock-out mice (DKO) for p21 and p53 genes in a C56BL/6J background, its phenotyping and preliminary studies of epigenetic patterns in the spontaneous and gamma-induced tumors.

An exhaustive analysis of the tumor types developed by these animals demonstrated a higher prevalence of sarcomas compare with single p53 KO. The tumor spectrum in DKO mice is similar to p21 KO one but with shorter latency.

Preliminary analysis of single KO for p53 or p21 genes shows a great variability in the global methylation levels displayed by control healthy individuals, spontaneous and gama-induced tumors. Accord with these data, we decided to analyze methylation patterns, global and promoter specific. This analysis shows a general diminution of global methylation around 17% but being more extreme in tumors (induced and spontaneous). The global methylation variation has been significant in comparisons between C57BL/6J, p21KO, p53 KO and DKO, being the highest one between C57BL/6J and DKO, while the lowest was display by KO p53 versus DKO. Preliminary analysis of promoter specific methylation in MLH1, MLT1, p15, p19, p16, Snail, E-cadherin and MGMT genes has shown rigorous differences for each one of the genetic backgrounds. Preliminary data show that epigenetics hits are important in the tumor development. A Hypothesis around p53 and p21 pathways through PCNA and their interaction with the methyltranfersase DNMT1 has been postulate.


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