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A sequence element of p53 that determines its susceptibility to viral oncoprotein-targeted degradation
1Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts, MA 02115, USA.
Abstract:
The molecular basis that the viral oncoproteins, including HPV16 E6 and E1B55k/E4 34k complex, differentially target p53 but not its homolog p73 for degradation remains elusive. Using a series of p53/p73 chimeras, we demonstrated that despite binding to the different regions of p53, both HPV16 E6 and E1B55k/E4 34k required a very same p53 sequence, amino acid residues 92 to 112 [p53(aa.92-112)], previously identified as a necessity for Mdm2-mediated degradation, to target p53 for degradation. Removal of the p53(aa.92-112) by either substitution or deletion resulted in a p53 protein that was no longer degradable by the viral proteins. More significantly, swapping the oncoprotein-binding motif and the p53(aa.92-112) rendered p73 susceptible to oncoprotein-mediated degradation. Collectively, our data supports a model in which the p53(aa.92-112) functions as a determinant for p53 stability while the binding of the oncoproteins directs p53 into the specific pathway for proteolysis.
Insights
Viral oncoproteins HPV16 E6 and E1B55k/E4 34k target p53 for degradation via a shared sequence (aa.92-112). This crucial region determines p53 stability, and its manipulation affects viral protein targeting and p73 degradation susceptibility.
Area of Science:
- Molecular biology
- Virology
- Cancer research
Background:
- Viral oncoproteins like HPV16 E6 and E1B55k/E4 34k play roles in cancer by targeting tumor suppressors.
- The precise mechanisms by which these oncoproteins degrade p53, but not its homolog p73, are not fully understood.
Purpose of the Study:
- To elucidate the molecular basis for differential targeting of p53 by viral oncoproteins.
- To identify specific p53 sequences critical for oncoprotein-mediated degradation.
Main Methods:
- Utilized p53/p73 chimera constructs to map degradation domains.
- Performed sequence substitutions and deletions within p53 to assess the role of specific amino acid residues.
- Investigated the impact of swapping functional motifs between p53 and p73.
Main Results:
- Identified a common p53 sequence, amino acid residues 92 to 112 (p53(aa.92-112)), essential for degradation by both HPV16 E6 and E1B55k/E4 34k.
- Demonstrated that deletion or substitution of p53(aa.92-112) renders p53 resistant to viral oncoprotein-induced degradation.
- Showed that swapping the oncoprotein-binding motif and p53(aa.92-112) between p53 and p73 makes p73 susceptible to degradation.
Conclusions:
- The p53(aa.92-112) region acts as a critical determinant of p53 stability against viral oncoprotein-mediated proteolysis.
- Oncoprotein binding directs p53 towards a specific degradation pathway, with p53(aa.92-112) being a key component.
- Findings provide insights into viral oncogenesis and potential therapeutic strategies targeting p53 stability.