Probing p53 biological functions through the use of genetically engineered mouse models
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Published on: August 4, 2019
Laura D Attardi1, Lawrence A Donehower
1Department of Radiation Oncology and Genetics, Stanford University School of Medicine, CCSR South, CA 94305-5152, USA. attardi@stanford.edu
Abstract:
The p53 tumor suppressor gene is rendered dysfunctional in the majority of human cancers. To model the effects of p53 dysfunction in an experimentally manipulable organismal context, genetically engineered inbred mice have been the models of choice. Transgenic and knock-out technologies have been utilized to generate an array of different p53 germ line alterations. As expected, many (though not all) of the mutant p53 mouse models are susceptible to enhanced spontaneous and carcinogen-induced tumors of a variety of types. A number of different variables affect the incidence and spectrum of tumors in p53 mutant mice. These include strain background, the nature of the p53 mutation, the presence of wild-type p53 (in addition to mutant p53), exposure to physical and chemical mutagens, or introduction of other cancer-associated genes into the mutant p53 background. In addition to their role in furthering our understanding of the mechanisms of cancer initiation and progression, these models have led to unexpected insights into p53 function in embryogenesis and aging. With the development of ever more sophisticated methods for manipulating the mouse genome, new p53 models are on the horizon, which should deliver advances that will provide not only important mechanistic insights but also discoveries of great clinical relevance.
Insights
Genetically engineered mouse models with a dysfunctional p53 tumor suppressor gene are crucial for cancer research. These models help understand cancer initiation, aging, and embryogenesis, with future advancements promising clinical relevance.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- The p53 tumor suppressor gene is frequently dysfunctional in human cancers.
- Genetically engineered mouse models are essential for studying p53 dysfunction in vivo.
- Various p53 alterations have been generated using transgenic and knock-out technologies.
Purpose of the Study:
- To model the effects of p53 gene dysfunction in a tractable organismal context.
- To investigate the mechanisms of cancer initiation and progression.
- To explore the broader roles of p53 in embryogenesis and aging.
Main Methods:
- Utilizing transgenic and knock-out technologies to create diverse p53 germ line alterations in mice.
- Analyzing spontaneous and carcinogen-induced tumor development in p53 mutant mouse models.
- Investigating the impact of genetic background and additional genetic modifications on tumor phenotypes.
Main Results:
- Many p53 mutant mouse models exhibit increased susceptibility to various tumor types.
- Tumor incidence and spectrum are influenced by factors including genetic background and specific p53 mutations.
- These models provide insights into p53's role beyond cancer, including embryogenesis and aging.
Conclusions:
- p53 mutant mouse models are invaluable tools for understanding cancer biology.
- These models offer unexpected insights into fundamental biological processes regulated by p53.
- Future sophisticated mouse models are expected to yield significant mechanistic and clinical advancements.
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