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Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
S N Jones1, A E Roe, L A Donehower
1Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
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.
Insights
Mice lacking the Mdm2 gene die during development. However, mice lacking both Mdm2 and the p53 tumor suppressor gene survive, indicating Mdm2
Area of Science:
- Oncology
- Developmental Biology
- Molecular Biology
Background:
- The Mdm2 proto-oncogene is implicated in cancer, with its overexpression linked to sarcomas and leukemia.
- Mdm2 oncoprotein interacts with the p53 tumor suppressor protein, inhibiting p53's gene regulation activity.
- Mdm2 expression is upregulated by p53, suggesting a feedback loop that modulates p53 activity.
Purpose of the Study:
- To investigate the developmental functions of Mdm2 beyond its interaction with p53.
- To elucidate the biological significance of the Mdm2-p53 complex during development.
Main Methods:
- Generation of Mdm2-null mice.
- Generation of Mdm2/p53-null mice.
Main Results:
- Mice deficient in Mdm2 exhibit embryonic lethality, indicating essential developmental roles.
- Mice lacking both Mdm2 and p53 are viable and develop normally.
- The absence of p53 rescues the developmental lethality caused by Mdm2 deficiency.
Conclusions:
- Mdm2 plays a critical role in embryonic development, primarily through its regulation of p53 function.
- The Mdm2-p53 interaction is crucial for normal development, and its disruption leads to developmental failure.
- Targeting the Mdm2-p53 pathway could offer therapeutic strategies for cancers involving these proteins.