The mechanisms by which TP53, the most frequently mutated gene in human cancer, suppresses tumorigenesis remain unclear. p53 modulates various cellular processes, such as apoptosis and proliferation, which has led to distinct cellular mechanisms being proposed for p53-mediated tumor suppression in different contexts. Here, we asked whether during tumor suppression p53 might instead regulate a wide range of cellular processes. Analysis of mouse and human oncogene-expressing wild-type and p53-deficient cells in physiological oxygen conditions revealed that p53 loss concurrently impacts numerous distinct cellular processes, including apoptosis, genome stabilization, DNA repair, metabolism, migration, and invasion. Notably, some phenotypes were uncovered only in physiological oxygen. Transcriptomic analysis in this setting highlighted underappreciated functions modulated by p53, including actin dynamics. Collectively, these results suggest that p53 simultaneously governs diverse cellular processes during transformation suppression, an aspect of p53 function that would provide a clear rationale for its frequent inactivation in human cancer.
Reproductive senescence is ubiquitous in mammals. However, patterns of senescence vary across reproductive traits, even within populations, perhaps because of differences in selection pressures, physiological constraints, and responses to environmental conditions. We investigated reproductive senescence in wild female polar bears (Ursus maritimus), using 31 years of capture-recapture data from the Svalbard area. We studied the influence of environmental conditions on age-specific litter production and litter size using generalized linear mixed models. Further, using a capture-recapture model that handles the dependency between vital rates of individuals belonging to the same family unit, we assessed maternal-age-related changes in first year cub and litter survival. We provide clear evidence for reproductive senescence in female polar bears. Litter production and litter size peaked in middle-aged females and declined sharply afterward. By contrast cub and litter survival did not decline after prime age. We found no evidence of terminal investment. The reproductive output of all females was affected by sea-ice conditions during the previous year and the Arctic Oscillation, with some effects differing greatly between age groups. Old females were affected the most by environmental conditions. Our results suggest that the decline in reproductive output is a combination of fertility and body-condition senescence, with a weak contribution of maternal-effect senescence, possibly due to benefits of experience. Further, as predicted by evolutionary theory, senescence appears to be a consequence of failures in early stages of the reproductive cycle rather than in late stages, and environmental variation affected old females more than prime-aged females. Our study emphasizes the need to study several reproductive traits and account for environmental variation when investigating reproductive senescence. Differences in senescence patterns across reproductive traits should be interpreted in light of evolutionary theory and while considering underlying physiological drivers.
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