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Title: Sharp-1 Mediates p53 - dependent cellular senescence through antagonism of Sirt1
Keywords: p53, Sirt1, Sharp1, Acetylation, Stress, Senescence
Issue Date: 1-Aug-2013
Citation: JOCELYN JIN YU (2013-08-01). Sharp-1 Mediates p53 - dependent cellular senescence through antagonism of Sirt1. ScholarBank@NUS Repository.
Abstract: Cellular senescence is important in tumor suppression. However, the molecular mechanisms are not completely understood. Here we show that overexpression of Sharp-1 induces growth arrest and premature senescence in fibroblast cells which is accompanied by increased intracellular ROS production and elevated acetyl and total p53 levels. On the other hand, Sirt1, a NAD+ dependent class III HDAC, inhibits cellular senescence by deacetylating p53 to inhibit p53 mediated functions. Thus, we hypothesized that Sirt1 may antagonize Sharp-1 induced senescence. We show that increasing Sirt1 activity using resveratrol or increasing its expression in Sharp-1 overexpressing cells inhibits Sharp-1 mediated senescence concomitant with deacetylation of p53 at lysine 379. Interaction studies demonstrate that associations between Sharp-1-Sirt1 and Sirt1-p53 weaken upon cellular stress but not the association between Sharp-1-p53. This suggests that Sirt1 antagonizes Sharp-1 to modulate p53 activity and functions might via regulation of protein-protein interaction.
Appears in Collections:Ph.D Theses (Open)

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