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Otub1 stabilizes MDMX and promotes its proapoptotic function at the mitochondria
Yingxiao Chen1, Yue-Gang Wang1, Yuhuang Li1
1Department of Molecular and Medical Genetics, School of Medicine, and The OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Oncotarget
|December 31, 2016
Summary
Otub1 stabilizes MDMX protein, enhancing its mitochondrial localization and promoting p53 phosphorylation at S46. This pathway is crucial for apoptosis induction, particularly after UV irradiation.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Otub1 is known to regulate p53 stability by inhibiting UbcH5, a ubiquitin-conjugating enzyme crucial for MDM2.
- The effect of Otub1 on MDMX stability and function remained unclear.
Purpose of the Study:
- To investigate whether Otub1 regulates MDMX stability and activity.
- To elucidate the role of Otub1-mediated MDMX regulation in p53 activation and apoptosis.
Main Methods:
- Cell-based assays to assess MDMX ubiquitination and stability.
- In vitro ubiquitination assays.
- Mitochondrial localization studies of MDMX.
- Analysis of p53 phosphorylation at S46 (p53S46P) and apoptosis induction.
- UV irradiation experiments to study apoptosis pathways.
Main Results:
- Otub1 suppresses MDM2-mediated MDMX ubiquitination, independent of its deubiquitinating activity.
- Otub1 overexpression stabilizes MDMX, increasing its cellular levels.
- Otub1-induced MDMX localizes to mitochondria, enhancing p53S46P and promoting apoptosis.
- Knockdown of MDMX diminishes Otub1-induced p53S46P and apoptosis.
- Otub1 promotes UV-induced p53S46P and apoptosis, which is inhibited by MDMX depletion.
Conclusions:
- Otub1 stabilizes MDMX, contributing to p53S46P and mitochondria-mediated apoptosis.
- This represents an alternative mechanism for Otub1's role in apoptosis induction.
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