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Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to
J Parant1, A Chavez-Reyes, N A Little
1The University of Texas M. D. Anderson Cancer Center, Department of Molecular Genetics, Section of Cancer Genetics, Box 11, 1515 Holcombe Blvd., Houston, Texas, USA.
Abstract:
The p53 protein can inhibit cell cycling or induce apoptosis, and is thus a critical regulator of tumorigenesis. This protein is negatively regulated by a physical interaction with MDM2, an E3 ubiquitin ligase. This interaction is critical for cell viability; loss of Mdm2 causes cell death in vitro and in vivo in a p53-dependent manner. The recently discovered MDM2-related protein MDM4 (also known as MDMX) has some of the same properties as MDM2. MDM4 binds and inhibits p53 transcriptional activity in vitro. Unlike MDM2, however, MDM4 does not cause nuclear export or degradation of p53 (refs. 9,10). To study MDM4 function in vivo, we deleted Mdm4 in mice. Mdm4-null mice died at 7.5-8.5 dpc, owing to loss of cell proliferation and not induction of apoptosis. To assess the importance of p53 in the death of Mdm4-/- embryos, we crossed in the Trp53-null allele. The loss of Trp53 completely rescued the Mdm4-/- embryonic lethality. Thus, MDM2 and MDM4 are nonoverlapping critical regulators of p53 in vivo. These data define a new pathway of p53 regulation and raise the possibility that increased MDM4 levels and the resulting inactivation of p53 contribute to the development of human tumors.
Insights
MDM4 is a critical regulator of p53, a tumor suppressor. Loss of MDM4 causes embryonic lethality dependent on p53, revealing a new p53 regulation pathway relevant to human tumors.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The p53 protein is a key regulator of tumorigenesis, inhibiting cell cycling and inducing apoptosis.
- p53 activity is negatively regulated by MDM2, an E3 ubiquitin ligase, through physical interaction.
- MDM4 (MDMX) is a related protein that inhibits p53 transcriptional activity but does not cause degradation.
Purpose of the Study:
- To investigate the in vivo function of MDM4.
- To determine the role of p53 in MDM4-mediated embryonic lethality.
Main Methods:
- Deletion of the Mdm4 gene in mice to create Mdm4-null (Mdm4-/-) embryos.
- Crossing Mdm4-/- mice with Trp53-null mice to assess the genetic interaction.
- Analysis of embryonic development, cell proliferation, and apoptosis.
Main Results:
- Mdm4-null mice exhibited embryonic lethality between 7.5-8.5 days post-coitum (dpc).
- Embryonic lethality was due to loss of cell proliferation, not apoptosis.
- The absence of p53 (Trp53-null) completely rescued the embryonic lethality of Mdm4-/- embryos.
Conclusions:
- MDM2 and MDM4 are non-overlapping, critical regulators of p53 in vivo.
- A novel pathway of p53 regulation involving MDM4 has been identified.
- Increased MDM4 levels and subsequent p53 inactivation may contribute to human tumor development.
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