Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53

Abstract

The gene p53 encodes a transcriptional activator of genes involved in growth arrest, DNA repair and apoptosis. Loss of p53 function contributes to tumour development in vivo. The transcriptional activation function of p53 is inactivated by interaction with the mdm2 gene product. Amplification of mdm2 has been observed in 36% of human sarcomas, indicating that it may represent an alternative mechanism of preventing p53 function in tumour development. To study mdm2 function in vivo, we generated an mdm2 null allele by homologous recombination. Mdm2 null mice are not viable, and further analysis revealed embryonic lethality around implantation. To examine the importance of the interaction of MDM2 with p53 in vivo, we crossed mice heterozygous for mdm2 and p53 and obtained progeny homozygous for both p53 and mdm2 null alleles. Rescue of the mdm2-/- lethality in a p53 null background suggests that a critical in vivo function of MDM2 is the negative regulation of p53 activity.

Abnormalities of developmental cell death in Dad1‐deficient mice

“…B6´F1, offspring from backcrosses of Dad1 /À males with C57Bl/6 females; F1´B6, offspring from backcrosses of C57Bl/6 males with Dad1 /À females. from the previous reports which dealt with early postimplantation lethality (Spyropoulos & Capecchi 1994;Fa Èssler & Meyer 1995;Feldman et al 1995;Jones et al 1995;Montes de Oca Luna et al 1995;Stephens et al 1995;Lim & Hasty 1996;Liu et al 1996;Tsuzuki et al 1996;Xanthoudakis et al 1996;Murphy et al 1997;Takeda et al 1997). Dad1 À/À embryos displayed many cells containing fragmented, TUNEL-positive nuclei, ®ndings which differed markedly from those of the previous reports, indicating that apoptosis had occurred simultaneously in the embryo itself (Fig.…”

Rhabdomyosarcoma – working out the pathways

“…Signi®cantly, RMS and other sarcomas demonstrate either MDM2 overexpression or p53 mutations, but not both, indicating that these genetic lesions are redundant. The functional relationship between these two is dramatically corroborated by the ®nding that p53 de®ciency rescues the lethality observed in MDM2 null embryos (Montes de Oca Luna et al, 1995;Jones et al, 1995). However, forced MDM2 overexpression induced sarcomas in transgenic mice irrespective of the presence of functional p53, providing genetic proof for the existence of a p53-independent MDM2 pathway in sarcomagenesis (Jones et al, 1998).…”

Mdm2: keeping p53 under control

“…The absence of visible defects in p53-Mdm2 double knockout mice compared to p53 null mice should bring some doubt on the physiological relevance of these functions (Montes de Oca Luna et al, 1995;Jones et al, 1995). Nevertheless, two important aspects were not taken into consideration in these studies, i.e.…”

“…Thus, the activation of Mdm2 by p53 would automatically lead to the repression of the activity of the latter protein. Probably the most convincing argument in favor of this model is the observation that additional knock-out of the p53 alleles rescues Mdm2 null mice which normally die around the time of implantation (Montes de Oca Luna et al, 1995;Jones et al, 1995). Also, in vitro experimental evidence was provided for a direct role of Mdm2 in the reversal of cell cycle arrest by p53 (Chen et al, , 1996.…”