L.A. Donehower

The p53 tumor suppressor is critical for protecting the cell against the deleterious effects of an array of stresses, including damage induced by reactive oxygen species. Stress-activated p53 can effect one of several antiproliferative outcomes, including apoptosis, cell cycle arrest, or cell senescence.

Our focus has been to further understand the biological functions of p53 through the generation and characterization of mouse models with mutations in p53 or p53 signaling pathway components. Recently, we generated a p53 mutant mouse that displays a hypermorphic p53 phenotype (the p53+/m mouse). These p53+/m mice actually display enhanced cancer resistance and exhibit accelerated aging phenotypes such as shortened longevity, early age-associated osteoporosis, muscle, skin, and lymphoid organ atrophy, and reduced stress responses. We believe this model implicates p53 in regulation of the aging process as well as in cancer suppression.

The accelerated loss of cellularity and atrophy of various tissues in the p53+/m mice has led to our current model that increased p53 activity could result in an inability of stem cells to replenish mature cells in each organ with advancing age. Preliminary in vitro stem cell assays on p53+/m mice are consistent with this model. Thus, therapeutic interventions that augment stem cell functional capacity might ameliorate many of the age-associated atrophies in many organ systems. Alternatively, these same effects might be achieved by molecules that could partially abrogate p53 function in a manner that would increase stem cell functionality without increasing cancer risk.

Keywords (Optional): 
mouse aging model
stem cells
accelerated aging