Regulation of p53: TRIM24 enters the RING.
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.
Jain
Abhinav K
AK
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.
Barton
Michelle Craig
MC
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics*; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000201:enzymology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D013058:Mass Spectrometry; D051379:Mice; D023421:Models, Animal; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
C502013:Bon protein, Drosophila; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C093517:transcriptional intermediary factor 1; D044767:Ubiquitin-Protein Ligases