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Published on: May 7, 2014
The p53-Mdm2 network in progenitor cell expansion during mouse postnatal development
1Department of Cancer Genetics, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA. gglozano@mdanderson.org
Abstract:
Mdm2, an E3 ubiquitin ligase, negatively regulates the tumour suppressor p53. Loss of Mdm2 in mice results in p53-dependent apoptosis and embryonic lethality. This phenotype was rescued by the p53(515C) allele, which encodes an apoptosis-deficient p53R172P protein. However, these mice died within 2 weeks of birth, due to a severe impairment of progenitor cell expansion during postnatal haematopoiesis and cerebellar development, leading to p53-dependent cell cycle arrest. Loss of Mdm2 led to phosphorylation of the p53R172P protein, p53R172P stability and activation of the cell cycle inhibitor p21 in proliferating cells, but not in differentiated cells, in multiple tissue compartments. Proliferating cells of epithelial origin were not affected. The haematopoietic and neural defects were alleviated in mice lacking Mdm2 and containing one p53(515C) and one p53-null allele, but spermatogenesis was arrested. These findings establish a crucial role for the p53-Mdm2 network in regulating proliferation and progenitor expansion in many cell lineages and have important implications for the use of drugs that aim to disrupt the p53-Mdm2 interaction.
Insights
Mice lacking Mdm2 experienced embryonic lethality, rescued by a p53 variant. However, this led to impaired cell expansion and developmental defects, highlighting the p53-Mdm2 network's role in proliferation.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Mdm2 is an E3 ubiquitin ligase that inhibits the tumor suppressor p53.
- Loss of Mdm2 function in mice leads to p53-dependent apoptosis and embryonic lethality.
Purpose of the Study:
- To investigate the role of the p53-Mdm2 interaction in progenitor cell expansion and development.
- To understand the consequences of disrupting the p53-Mdm2 axis on various cell lineages.
Main Methods:
- Utilized genetically modified mice with specific Mdm2 and p53 alleles (p53(515C), p53-null).
- Analyzed p53R172P protein stability, phosphorylation, and p21 activation in different cell types.
- Assessed developmental phenotypes, including haematopoiesis, cerebellar development, and spermatogenesis.
Main Results:
- Mice with Mdm2 loss and a p53(515C) allele (apoptosis-deficient p53) survived embryonic development but exhibited postnatal lethality due to impaired progenitor cell expansion and cell cycle arrest.
- p53R172P protein stability and p21 activation were observed in proliferating cells but not differentiated cells, affecting multiple tissues.
- Alleviation of hematopoietic and neural defects was noted in mice lacking Mdm2 with one p53(515C) and one p53-null allele, though spermatogenesis was arrested.
Conclusions:
- The p53-Mdm2 network is critical for regulating proliferation and progenitor expansion across diverse cell lineages.
- Disruption of the p53-Mdm2 interaction has significant implications for development and raises considerations for therapeutic strategies targeting this pathway.
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