Abstract:
:The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro. In cell-based assays, MDM2 exhibits superior binding to, hyperdegradation of, and increased nuclear exclusion of dimeric p53 when compared with tetrameric wild-type p53. Correspondingly, impairing the hydrophobicity of the newly identified N-terminal MDM2 region leads to p53 stabilization. Interestingly, we found that dimeric mutant p53 is partially unfolded and is a target for ubiquitin-independent degradation by the 20S proteasome. Finally, forcing certain tumor-derived mutant forms of p53 into dimer configuration results in hyperdegradation of mutant p53 and inhibition of p53-mediated cancer cell migration. Gaining insight into different oligomeric forms of p53 may provide novel approaches to cancer therapy.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Katz C,Low-Calle AM,Choe JH,Laptenko O,Tong D,Joseph-Chowdhury JN,Garofalo F,Zhu Y,Friedler A,Prives Cdoi
10.1101/gad.304071.117subject
Has Abstractpub_date
2018-03-01 00:00:00pages
430-447issue
5-6eissn
0890-9369issn
1549-5477pii
gad.304071.117journal_volume
32pub_type
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