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Subcellular distribution of p53 and p73 are differentially regulated by MDM2
1Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Abstract:
The binding of MDM2 targets p53, but not p73, for degradation, whereas it suppresses the transactivation function of both proteins. MDM2 also mediates p53 nuclear export, but its role in the regulation of p73 distribution is unknown at the present time. We show here that, in sharp contrast to p53, MDM2 induces p73 to form nuclear aggregates that colocalize with MDM2 but are distinct from the promyelocytic leukemia dots. The MDM2 ring-domain that is necessary for mediating p53 nuclear export is not required for the induction of the p73 nuclear aggregates. Using a domain-swapping approach, we demonstrate that the inability of p73 to nuclear-export is attributable to its nonfunctional nuclear-export sequence.
Insights
MDM2 targets p53 for degradation but suppresses both p53 and p73 protein function. Unlike p53, MDM2 induces p73 to form nuclear aggregates, revealing distinct regulatory mechanisms for these tumor suppressors.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- MDM2 is a key regulator of the p53 tumor suppressor protein.
- MDM2 targets p53 for degradation and mediates its nuclear export.
- The interaction between MDM2 and the related p73 protein is less understood, particularly regarding p73 localization.
Purpose of the Study:
- To investigate the effect of MDM2 on p73 cellular distribution.
- To compare the regulatory mechanisms of MDM2 on p53 and p73.
- To identify the domains of MDM2 and p73 involved in their interaction and localization.
Main Methods:
- Co-immunoprecipitation assays to study protein interactions.
- Immunofluorescence microscopy to visualize protein localization and aggregate formation.
- Domain-swapping experiments between p53 and p73 to map functional regions.
Main Results:
- MDM2 binding suppresses the transactivation of both p53 and p73.
- In contrast to p53, MDM2 induces the formation of nuclear aggregates of p73.
- These p73 aggregates colocalize with MDM2 but are distinct from PML bodies.
- The MDM2 ring-domain, essential for p53 nuclear export, is not required for p73 aggregate formation.
- p73's inability to be exported from the nucleus is due to a nonfunctional nuclear-export sequence.
Conclusions:
- MDM2 regulates p53 and p73 through distinct mechanisms.
- MDM2 induces p73 nuclear aggregation, a novel regulatory pathway.
- The differential regulation of p73 localization by MDM2 involves specific sequence elements within p73.