TP53 or components of its signaling pathways are inactivated during tumor formation or progression in the majority of human cancers. This suggests that TP53 acts as a block that has to be eliminated for tumor development. Consequently, restoring TP53 function has long been considered an attractive anticancer therapeutic approach. To asses this possibility, we are using a mouse knock-in model that expresses TRP53ERTAM protein, whose function can be reversibly switched on and off in vitro and in vivo. Using this model we have been able to show that transient restoration of TRP53 in a mouse model of chronic myeloid leukemia delays disease onset and prolongs the life of leukemic mice. In recent years, it has been shown that TP53 can induce apoptosis and necrosis acting directly on the mitochondria, independently of its function as a transcription factor. To explore the possible anti tumor activity of mitochondrial TRP53 we have generated a novel knock-in mouse model that expresses a regulatable TRP53 protein fused to a canonical mitochondrial localization signal. This protein, TRP53mitoERTAM, is inactive in the absence of tamoxifen but can be switched to a functional status in the presence of the drug. As expected, in the absence of tamoxifen, these mice behave as Trp53 null mice developing early onset tumors. We will use this model to analyze in vivo the role of mitochondrial TRP53 in tumor suppression and other pathophysiological processes such as ischemic necrosis, and eventually to identify novel therapeutic targets. We will present a progress report of our research using this mouse model.

Resumen del póster presentado al 27th International Mammalian Genome Conference (IMGC) celebrado en Salamanca (España) del 14 al 18 de septiembre de 2013.

Peer Reviewed