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Published on: January 31, 2018
DNA damage induces MDMX nuclear translocation by p53-dependent and -independent mechanisms
Changgong Li1, Lihong Chen, Jiandong Chen
1Molecular Oncology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Abstract:
The MDM2 homolog MDMX is an important regulator of p53 activity during embryonic development. MDMX inactivation in mice results in embryonic lethality in a p53-dependent fashion. The expression level of MDMX is not induced by DNA damage, and its role in stress response is unclear. We show here that ectopically expressed MDMX is mainly localized in the cytoplasm. DNA damage promotes nuclear translocation of MDMX in cells with or without p53. Coexpression of MDM2 or p53 is sufficient to induce MDMX nuclear translocation, suggesting that activation of p53 and induction of MDM2 expression can contribute to this process. Stable transfection of MDMX into U2OS cells does not alter p53 level but results in reduced p53 DNA-binding activity and reduced MDM2 expression. The ability of ARF (alternate reading frame of INK4a) to activate p53 is also significantly inhibited by expression of MDMX. These results suggest that MDMX function may be regulated by DNA damage. Furthermore, MDMX may complement MDM2 in regulating p53 during embryonic development due to its ability to inhibit p53 in the presence of ARF.
Insights
MDMX protein, a regulator of p53, translocates to the nucleus upon DNA damage, inhibiting p53 activity. This suggests MDMX plays a role in cellular stress response and embryonic development.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- MDMX (MDM2 homolog) is crucial for p53 regulation during embryonic development.
- MDMX inactivation leads to p53-dependent embryonic lethality.
- MDMX's role in stress response and its regulation by DNA damage are not well understood.
Purpose of the Study:
- To investigate the regulation and function of MDMX in response to DNA damage.
- To elucidate the mechanism of MDMX-mediated p53 inhibition.
Main Methods:
- Ectopic expression of MDMX in cell lines (U2OS).
- Induction of DNA damage and observation of MDMX localization.
- Coexpression studies with p53 and MDM2.
- Assessment of p53 DNA-binding activity and MDM2 expression levels.
Main Results:
- Ectopically expressed MDMX is primarily cytoplasmic but translocates to the nucleus upon DNA damage.
- p53 or MDM2 coexpression induces MDMX nuclear translocation.
- MDMX expression reduces p53 DNA-binding activity and MDM2 expression.
- MDMX inhibits p53 activation by ARF (alternate reading frame of INK4a).
Conclusions:
- MDMX function is likely regulated by DNA damage, impacting its role in cellular stress.
- MDMX may complement MDM2 in regulating p53 during embryonic development by inhibiting p53 activity, especially in the presence of ARF.
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