Journal
CELL CYCLE
Volume 8, Issue 22, Pages 3668-3674Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.8.22.9979
Keywords
tumor suppressor; proteasome; protein degradation; E3-ligase; apoptosis; cell cycle arrest
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Funding
- National Institutes of Health [GM081627, DK070824]
- Laura and John Arnold Foundation Odyssey Fellow
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Negative regulation of p53 in normal, unstressed cells maintains levels of this tumor suppressor below a threshold for cell cycle arrest or apoptosis, and is rapidly reversed in the face of cellular stresses to permit p53 response. Recently, we created a new mouse and stem cell model by knock-in addition of an epitope tag at Trp53. Biochemical purification of endogenous, tagged p53-protein complexes from mouse embryonic stem cells, and peptide analysis by mass spectrometry, revealed a new RING-domain E3-ubiquitin ligase TRIM24 that targets p53 for degradation. Depletion of TRIM24, formerly named TIF1 alpha, in tumor-derived cells induces p53-dependent apoptosis. In Drosophila, bonus is a single copy gene homologous to the mammalian Tif1 family. Mosaic deletion of bonus induces cell death in vivo, which is rescued by depletion of D-p53. Bonus is the first identified regulator of p53 protein levels in Drosophila, which lacks an ortholog of Mdm2. TRIM24/bonus may be the ancestral precursor of the large group of mammalian E3-ligases that target p53 for ubiquitin modification. Understanding the specific roles that these numerous E3-ligases have in the hierarchy of p53-regulation remains a challenge for the field. We discuss various scenarios for selectivity in choice of E3-ligase targeting p53 for degradation.
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