Puma- and Caspase9-mediated apoptosis is dispensable for p53-driven neural crest-based developmental defects.

Inappropriate activation of the p53 transcription factor is thought to contribute to the developmental phenotypes in a range of genetic syndromes. Whether p53 activation drives these developmental phenotypes by triggering apoptosis, cell cycle arrest, or other p53 cellular responses, however, has remained elusive. As p53 hyperactivation in embryonic neural crest cells (NCCs) drives a number of phenotypes, including abnormal craniofacial and neuronal development, we investigate the basis for p53 action in this context. We show that p53-driven developmental defects are associated with the induction of a robust pro-apoptotic transcriptional signature. Intriguingly, however, deleting Puma or Caspase9, which encode key components of the intrinsic apoptotic pathway, does not rescue craniofacial, neuronal or pigmentation defects triggered by p53 hyperactivation in NCCs. Immunostaining analyses for two key apoptosis markers confirm that deleting Puma or Caspase9 does indeed impair p53-hyperactivation-induced apoptosis in NCCs. Furthermore, we demonstrate that p53 hyperactivation does not trigger a compensatory dampening of cell cycle progression in NCCs upon inactivation of apoptotic pathways. Together, our results indicate that p53-driven craniofacial, neuronal and pigmentation defects can arise in the absence of apoptosis and cell cycle arrest, suggesting that p53 hyperactivation can act via alternative pathways to trigger developmental phenotypes.

The Spatiotemporal Pattern and Intensity of p53 Activation Dictates Phenotypic Diversity in p53-Driven Developmental Syndromes.

Inappropriate activation of the p53 transcription factor contributes to numerous developmental syndromes characterized by distinct constellations of phenotypes. How p53 drives exquisitely specific sets of symptoms in diverse syndromes, however, remains enigmatic. Here, we deconvolute the basis of p53-driven developmental syndromes by leveraging an array of mouse strains to modulate the spatial expression pattern, temporal profile, and magnitude of p53 activation during embryogenesis. We demonstrate that inappropriate p53 activation in the neural crest, facial ectoderm, anterior heart field, and endothelium induces distinct spectra of phenotypes. Moreover, altering the timing and degree of p53 hyperactivation substantially affects the phenotypic outcomes. Phenotypes are associated with p53-driven cell-cycle arrest or apoptosis, depending on the cell type, with gene expression programs, rather than extent of mitochondrial priming, largely governing the specific response. Together, our findings provide a critical framework for decoding the role of p53 as a mediator of diverse developmental syndromes.

Cardiorespiratory Fitness, Adiposity, and Cancer Mortality in Men.

OBJECTIVE: This study sought to evaluate the association between cardiorespiratory fitness (CRF) and cancer mortality in men with overweight and obesity. METHODS: Maximal exercise testing was performed in 3,610 men (58.8 ± 17.5 years) (n = 2,100 with overweight and n = 1,510 with obesity) free from malignancy at baseline who were followed for 12.3 ± 7.4 years. Body mass index of 25.0 to 29.9 kg/m2 for overweight and ≥ 30.0 for obesity categories was used. Hazard ratios and population-attributable risks (PAR) were determined. RESULTS: During the follow-up period, 11.1% and 9.1% died from cancer among those who had overweight and obesity, respectively. CRF had an inverse and graded association with cancer mortality. Compared with low CRF (< 5 metabolic equivalents), moderate and high CRF levels were associated with 48% and 79% reduced risks for cancer mortality in men who had overweight (P < 0.001) and 55% and 83% lower risks in those who had obesity (P < 0.001), respectively. Low CRF had PARs of 9.3% and 10.5% for cancer mortality in subjects who had overweight and obesity, respectively. CONCLUSIONS: Among men with overweight and obesity, higher CRF is associated with lower cancer mortality. Eliminating low CRF as a risk factor would potentially prevent a considerable number of cancer deaths and reduce the associated societal and economic burden in these high-risk populations.