Senescence associated with telomere dysfunction, oxidative damage or oncogene stress represents a distinct cell fate decision from other terminal differentiation programs including programmed cell death. We and others have shown that forced expression of tumor suppressor genes such as p53 or p16 in tumor cells, in which such functions have been inactivated, can trigger a phenotype of permanent arrest indistinguishable from senescence. Moreover, normal cells gain extended lifespan in culture by inactivation of genes such as p53 or Rb. These findings have implied that the senescence program must be inactivated during tumor evolution.
The aims of this proposal are to continue to characterize the molecular pathways of senescence in normal cells, elucidate genes and pathways that influence p53 cell fate decisions determining senescence and apoptosis, and investigate an animal model and human syndromes with early aging to assess the impact of tumor suppressor pathways on the aging phenotype.
In Aim 1, we will characterize Hzf, a novel p53 target, which we have identified and shown to inhibit cell proliferation independently of p53 by a mechanism that appears to involve its ability to increase p2lWaf1 protein but not RNA levels.
In Aim 2, we will further explore mechanisms by which p53 effectors involved in mitochondrial and ROS pathways contribute to p53-mediated cell fate decisions, and identify biochemical effectors that convert a p53-mediated senescence response to apoptosis.
In Aim 3, we will explore involvement of p53 tumor suppressor pathways in the early aging phenotype of the Ku80-/- mouse, and in fibroblasts from human progeroid syndromes. We will also explore the hypothesis that human melanocytic nevi with BRAF mutations may represent a prototype of oncogene stress-induced senescence in vivo. Thus, we are poised to continue making important discoveries concerning the role of cellular senescence in aging and cancer.
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