TBP-like Protein (TLP) Disrupts the p53-MDM2 Interaction and Induces Long-lasting p53 Activation

Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated nega...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2017-02, Vol.292 (8), p.3201-3212
Main Authors: Maeda, Ryo, Tamashiro, Hiroyuki, Takano, Kazunori, Takahashi, Hiro, Suzuki, Hidefumi, Saito, Shinta, Kojima, Waka, Adachi, Noritaka, Ura, Kiyoe, Endo, Takeshi, Tamura, Taka-Aki
Format: Article
Language:English
Subjects:
Apoptosis
Cell Biology
HCT116 Cells
HeLa Cells
Humans
Neoplasms - metabolism
Neoplasms - pathology
Protein Interaction Maps
Protein Stability
Proteolysis
Proto-Oncogene Proteins c-mdm2 - analysis
Proto-Oncogene Proteins c-mdm2 - metabolism
TATA Box Binding Protein-Like Proteins - analysis
TATA Box Binding Protein-Like Proteins - metabolism
Tumor Suppressor Protein p53 - analysis
Tumor Suppressor Protein p53 - metabolism
Ubiquitination
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Stress-induced activation of p53 is an essential cellular response to prevent aberrant cell proliferation and cancer development. The ubiquitin ligase MDM2 promotes p53 degradation and limits the duration of p53 activation. It remains unclear, however, how p53 persistently escapes MDM2-mediated negative control for making appropriate cell fate decisions. Here we report that TBP-like protein (TLP), a member of the TBP family, is a new regulatory factor for the p53-MDM2 interplay and thus for p53 activation. We found that TLP acts to stabilize p53 protein to ensure long-lasting p53 activation, leading to potentiation of p53-induced apoptosis and senescence after genotoxic stress. Mechanistically, TLP interferes with MDM2 binding and ubiquitination of p53. Moreover, single cell imaging analysis shows that TLP depletion accelerates MDM2-mediated nuclear export of p53. We further show that a cervical cancer-derived TLP mutant has less p53 binding ability and lacks a proliferation-repressive function. Our findings uncover a role of TLP as a competitive MDM2 blocker, proposing a novel mechanism by which p53 escapes the p53-MDM2 negative feedback loop to modulate cell fate decisions.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.763318