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Cell Cycle. 2009 Nov 15;8(22):3668-74. Epub 2009 Nov 2.

Regulation of p53: TRIM24 enters the RING.

Author information

1
Department of Biochemistry and Molecular Biology, Center for Stem Cell and Developmental Biology, Graduate Program in Genes and Development, UT-Houston Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center, Houston, TX, USA.

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 TIF1alpha, 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.

PMID:
19844164
DOI:
10.4161/cc.8.22.9979
[Indexed for MEDLINE]

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