Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53

Abstract

The Mdm2 proto-oncogene was originally identified as one of several genes contained on a mouse double minute chromosome present in a transformed derivative of 3T3 cells. Overexpression of Mdm2 can immortalize primary cultures of rodent fibroblasts. Human MDM2 is amplified in 30-40% of sarcomas, and is overexpressed in leukaemic cells. The Mdm2 oncoprotein forms a complex with the p53 tumour-suppressor protein and inhibits p53-mediated transregulation of gene expression. Because Mdm2 expression increases in response to p53, Mdm2-p53 binding may autoregulate Mdm2 expression and modulate the activity of p53 in the cell. We have created Mdm2-null and Mdm2/p53-null mice to determine whether Mdm2 possesses developmental functions in addition to the ability to complex with p53, and to investigate the biological role of Mdm2-p53 complex formation in development. Mice deficient for Mdm2 die early in development. In contrast, mice deficient for both Mdm2 and p53 develop normally and are viable. These results suggest that a critical role of Mdm2 in development is the regulation of p53 function.

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.…”