Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice

Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of many TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of ZMAT3 in haematopoietic stem/progenitor cells by shRNA caused leukaemia only with the concomitant absence of the pro-apoptotic BCL-2 family member PUMA and the CDK inhibitor p21. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21 , Zmat3 and Puma or all three genes. Puma−/−p21−/−Zmat3−/− triple knockout mice developed tumours at a significantly higher frequency compared to wild type, Puma−/−Zmat3−/− or p21−/− Zmat3−/− deficient mice. Interestingly, we observed that the triple and Puma−/−Zmat3−/− double deficient animals succumbed to lymphoma, while p21−/−Zmat3−/− animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Interestingly, our findings also reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, which suggests that different TRP53 tumour suppressive pathways are more critical in different tissues.