Regulation of p53: TRIM24 enters the RING

 Abstract

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 TIF1α, 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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3668 - 3674
doi
10.4161/cc.8.22.9979
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Regulation of p53: TRIM24 enters the RING