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Published on: May 17, 2016
Mdm2-mediated NEDD8 modification of TAp73 regulates its transactivation function
Ian R Watson1, Alvaro Blanch, Dan C C Lin
1Cancer Research Program and Division of Haematology-Oncology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
The Journal of Biological Chemistry
|September 19, 2006
Summary
The study reveals that the tumor suppressor TAp73 is covalently modified by NEDD8, a process dependent on Mdm2. This modification, NEDDylation, impacts TAp73
Area of Science:
- Oncology
- Molecular Biology
- Post-translational Modifications
Background:
- Mutations in p73 are uncommon in cancer, but isoform expression is implicated in tumorigenesis.
- p73 exists as full-length (TA) and N-terminally truncated (deltaN) isoforms with opposing functions.
- TAp73 is pro-apoptotic, while deltaNp73 is anti-apoptotic and inhibits TAp73 and p53.
Purpose of the Study:
- To investigate the post-translational modifications of p73 isoforms.
- To determine the role of NEDD8 modification in TAp73 function and regulation.
- To elucidate the involvement of Mdm2 in the regulation of TAp73.
Main Methods:
- Investigated covalent modification of p73 isoforms using Western blotting and co-immunoprecipitation.
- Assessed the effect of NEDD8 pathway modulation (NEDP1 co-expression, pathway blockage) on TAp73 activity.
- Determined subcellular localization of modified TAp73 species via immunofluorescence.
Main Results:
- TAp73, but not deltaNp73, undergoes covalent modification by NEDD8 under physiological conditions.
- This NEDD8 conjugation of TAp73 is dependent on Mdm2.
- NEDD8 modification of TAp73 leads to its preferential cytoplasmic localization and attenuates its transactivation function.
Conclusions:
- Mdm2-dependent NEDD8 modification is a novel mechanism regulating TAp73.
- NEDDylation of TAp73 promotes cytoplasmic localization, attenuating its tumor-suppressive activity.
- This study identifies a specific post-translational modification targeting TAp73 isoforms.
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