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C-terminal ubiquitination of p53 contributes to nuclear export
M A Lohrum1, D B Woods, R L Ludwig
1Regulation of Cell Growth Laboratory, National Cancer Institute at Frederick, Building 5460, Rm. 22-96, 1050 Boyles St., Frederick, MD 21702-1201, USA.
Abstract:
The growth inhibitory functions of p53 are controlled in unstressed cells by rapid degradation of the p53 protein. One of the principal regulators of p53 stability is MDM2, a RING finger protein that functions as an E3 ligase to ubiquitinate p53. MDM2 promotes p53 nuclear export, and in this study, we show that ubiquitination of the C terminus of p53 by MDM2 contributes to the efficient export of p53 from the nucleus to the cytoplasm. In contrast, MDM2 did not promote nuclear export of the p53-related protein, p73. p53 nuclear export was enhanced by overexpression of the export receptor CRM1, although no significant relocalization of MDM2 was seen in response to CRM1. However, nuclear export driven by CRM1 overexpression did not result in the degradation of p53, and nuclear export was not essential for p53 degradation. These results indicate that MDM2 mediated ubiquitination of p53 contributes to both nuclear export and degradation of p53 but that these activities are not absolutely dependent on each other.
Insights
MDM2-mediated ubiquitination of p53 protein drives its nuclear export and degradation. However, these processes are not strictly dependent on each other for controlling cell growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The tumor suppressor protein p53's growth inhibitory functions are regulated by its degradation in unstressed cells.
- MDM2, an E3 ligase, is a key regulator of p53 stability, ubiquinating p53 and promoting its degradation.
- MDM2 also facilitates p53 nuclear export, a critical step in regulating p53 activity.
Purpose of the Study:
- To investigate the role of MDM2-mediated ubiquitination in p53 nuclear export.
- To determine the relationship between p53 nuclear export and degradation.
- To compare the effect of MDM2 on p53 and the related protein p73.
Main Methods:
- Studied the ubiquitination of p53 by MDM2.
- Investigated the impact of MDM2 on p53 localization between the nucleus and cytoplasm.
- Examined the role of the export receptor CRM1 in p53 nuclear export.
- Assessed the effect of nuclear export on p53 degradation.
Main Results:
- MDM2-mediated ubiquitination of p53's C-terminus promotes its efficient export from the nucleus to the cytoplasm.
- MDM2 did not induce nuclear export of the p53-related protein p73.
- Overexpression of CRM1 enhanced p53 nuclear export but did not lead to p53 degradation.
- Nuclear export was not essential for p53 degradation, and degradation could occur independently of export.
Conclusions:
- MDM2-mediated ubiquitination of p53 contributes to both its nuclear export and degradation.
- These two processes, nuclear export and degradation, are linked but not absolutely dependent on each other.
- Understanding this regulatory mechanism is crucial for cancer research and therapeutic development.