Analysis of organismal and tumor suppressive functions of 14-3sigma

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The p53 transcription factor is encoded by a tumor suppressor gene which is mutated in more than 50% of all cancers. We identified the 14-3-3sigma gene as a direct target of p53 which mediates inhi-bition of progression through the G2/M phase following DNA damage in a human cancer cell line. In tumors the 14-3-3sigma gene is frequently silenced by CpG-methylation. However, the relevance of 14-3-3sigma inactivation for cancer formation and its organismal function is not known. Here I propose to inactivate 14-3-3sigma in adult mice using conditional Cre alleles in several tissues and cell types. This approach will mimic the epigenetic inactivation of 14-3-3sigma which commonly happens during tumor formation. Furthermore, the effect of acute 14-3-3sigma inactivation on chemical carcinogenesis of the skin and the relevance of 14-3-3sigma for the p53-mediated DNA damage response in the intestinal tract will be analysed. In addition, the potential co-operation between loss of 14-3-3sigma and oncogene activation will be studied. The knock-out of two other p53-target genes, p21 and PUMA, also does not lead to an obvious phenotype without additional stress, as DNA damage. We will generate compound knock-out mice deficient for 14-3-3sigma, p21 and PUMA in order to determine the combined effect of these deletions on the p53-mediated tumor suppression and DNA damage response. The ER (repeated epilation) mouse strain carries a point mutation in the 14-3-3sigma gene which causes epidermal hyper-proliferation. The functional consequences of the ER mutation and 14-3-3sigma deletion on a FVB background will be compared, as our results indicate that the ER mut of 14-3-3sigma may not simply represent a loss of function mutation. In summary, these studies will provide an important contribution to the understanding of 14-3-3sigma function in physiology and patho-physiology.