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Oligomerisation of full length p53 contributes to the interaction with mdm2 but not HPV E6
N J Marston1, J R Jenkins, K H Vousden
1Ludwig Institute for Cancer Research, St Mary's Hospital Medical School, London.
Abstract:
The tumour suppressor protein p53 normally functions as a tetramer in a defined conformational state. Mutations within p53 which contribute to cancer development frequently induce a conformational shift in the protein which correlates with loss of wild type growth suppressor functions. Both the cell encoded mdm2 protein and the human papillomavirus oncoprotein E6 can regulate p53 function and we have examined the interaction of these proteins with p53. The E6/p53 association is sensitive to conformational alterations in the p53 protein, although oligomerisation is not necessary for this interaction to occur. Analysis of C-terminal p53 truncations has indicated that the region between residues 327 and 347 may play a role in E6 binding. Since monomeric forms of p53 retain transcriptional and transformation suppressor activities, our results indicate that E6 targets p53 proteins which retain these wild type functions. Conversely, the interaction of p53 with mdm2 is not dependent on the conformation of the p53 protein but is significantly impaired by loss of quaternary structure. It is possible that mdm2 plays a role in mediating activities of p53 which, unlike transcriptional activation, depend on oligomerisation.
Insights
The tumor suppressor protein p53
Area of Science:
- Molecular Biology
- Cancer Research
- Protein Biochemistry
Background:
- The tumor suppressor protein p53 is crucial for preventing cancer and normally functions as a tetramer.
- Mutations in p53 can lead to cancer by altering its conformation and function.
- Cellular and viral proteins, such as mdm2 and human papillomavirus E6, regulate p53 activity.
Purpose of the Study:
- To investigate the interaction between p53 and its regulators, mdm2 and E6.
- To determine how protein conformation and oligomerization affect these interactions.
- To understand which p53 functions are targeted by the E6 oncoprotein.
Main Methods:
- Analysis of p53 protein interactions with mdm2 and E6.
- Examination of p53 conformational states and oligomerization.
- Study of C-terminal p53 truncations to identify binding regions.
Main Results:
- The E6/p53 interaction is conformation-dependent but does not require p53 oligomerization.
- A specific region (residues 327-347) in p53 may be involved in E6 binding.
- Monomeric p53 retains suppressor activities, indicating E6 targets functional p53.
- The p53/mdm2 interaction is conformation-independent but impaired by loss of quaternary structure.
Conclusions:
- The human papillomavirus E6 oncoprotein targets conformationally altered p53 proteins that retain wild-type functions.
- The mdm2 protein may mediate p53 activities dependent on oligomerization, distinct from transcriptional activation.