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Updated: Jan 31, 2026
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
The role of p53 in developmental syndromes
Margot E Bowen1, Laura D Attardi1,2
1Division of Radiation and Cancer Biology in the Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
Abstract:
While it is well appreciated that loss of the p53 tumor suppressor protein promotes cancer, growing evidence indicates that increased p53 activity underlies the developmental defects in a wide range of genetic syndromes. The inherited or de novo mutations that cause these syndromes affect diverse cellular processes, such as ribosome biogenesis, DNA repair, and centriole duplication, and analysis of human patient samples and mouse models demonstrates that disrupting these cellular processes can activate the p53 pathway. Importantly, many of the developmental defects in mouse models of these syndromes can be rescued by loss of p53, indicating that inappropriate p53 activation directly contributes to their pathogenesis. A role for p53 in driving developmental defects is further supported by the observation that mouse strains with broad p53 hyperactivation, due to mutations affecting p53 pathway components, display a host of tissue-specific developmental defects, including hematopoietic, neuronal, craniofacial, cardiovascular, and pigmentation defects. Furthermore, germline activating mutations in TP53 were recently identified in two human patients exhibiting bone marrow failure and other developmental defects. Studies in mice suggest that p53 drives developmental defects by inducing apoptosis, restraining proliferation, or modulating other developmental programs in a cell type-dependent manner. Here, we review the growing body of evidence from mouse models that implicates p53 as a driver of tissue-specific developmental defects in diverse genetic syndromes.
Insights
While p53 loss prevents cancer, its overactivation causes developmental defects in genetic syndromes. Mouse models show that reducing p53 activity can rescue these defects, highlighting its crucial role.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Loss of the p53 tumor suppressor protein is a known driver of cancer.
- Emerging evidence links increased p53 activity to developmental abnormalities in genetic syndromes.
Purpose of the Study:
- To review evidence implicating p53 in driving tissue-specific developmental defects across various genetic syndromes.
- To highlight the role of p53 pathway activation in the pathogenesis of inherited and de novo genetic disorders.
Main Methods:
- Analysis of human patient samples.
- Studies using mouse models of genetic syndromes with disrupted cellular processes (e.g., ribosome biogenesis, DNA repair, centriole duplication).
- Examination of mouse strains with mutations affecting p53 pathway components.
Main Results:
- Disrupting cellular processes in genetic syndromes activates the p53 pathway.
- Loss of p53 rescues developmental defects in mouse models, indicating p53's direct contribution to pathogenesis.
- Broad p53 hyperactivation in mice leads to diverse tissue-specific developmental defects (hematopoietic, neuronal, craniofacial, cardiovascular, pigmentation).
- Germline activating mutations in TP53 identified in human patients with bone marrow failure and developmental issues.
Conclusions:
- Inappropriate p53 activation is a key driver of developmental defects in diverse genetic syndromes.
- p53 influences development by inducing apoptosis, restraining proliferation, or modulating developmental programs in a cell-type-specific manner.
- Mouse models provide critical insights into the role of p53 in the pathogenesis of human genetic disorders.
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