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Background  While it is now more than a decade since the first description of the gene mutation underlying the tumour predisposition syndrome multiple endocrine neoplasia type 1 (MEN1), the mechanism by which its protein product menin acts to prevent development of tumours is still poorly understood.    Methods  We undertook a genetic experiment to assess whether menin synergises with p53. Mice carrying various combinations of  Men1  and  Trp53  mutations were generated then survival and pathology assessed.    Results  While homozygous loss of  Trp53  in mice resulted in early onset, aggressive tumours and profoundly reduced lifespan, heterozygous loss of either  Trp53  or  Men1  caused later onset disease, with a spectrum of tumours characteristic of each tumour suppressor gene. Loss of one copy of  Men1  in animals also lacking both alleles of  Trp53  did not exacerbate phenotype, based on survival, animal weight or sites of pathology, compared to  Trp53  deletion alone. Dual heterozygous deletion of  Men1  and  Trp53  resulted in a small reduction in lifespan compared to the individual mutations, without new tumour sites. In the adrenal, we observed development of cortical tumours in dual heterozygous animals, as we have previously seen in  Men1  +/−  animals, and there was loss of heterozygosity at the  Men1  allele in these tumours. Median number of pathology observations per animal was increased in dual heterozygous animals compared with heterozygous loss of  Trp53  alone.    Conclusions  Simultaneous heterozygous deletion of  Men1  in animals with either heterozygous or homozygous deletion of  Trp53  did not result in formation of tumours at any new sites, implying additive rather than synergistic effects of these pathways. Mice that were  Men1  +/−  in addition to  Trp53  +/−  had tumours in endocrine as well as other sites, implying that increase in total tumour burden, at sites typically associated with either  Men1  or  Trp53  loss, contributed to the slight decrease in survival in  Men1  +/− :  Trp53  +/−  animals in comparison with their littermates.

Menin and p53 have non-synergistic effects on tumorigenesis in mice