Oligomerisation of full length p53 contributes to the interaction with mdm2 but not HPV E6.
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.
Marston
N J
NJ
Ludwig Institute for Cancer Research, St Mary's Hospital Medical School, London.
Jenkins
J R
JR
Vousden
K H
KH
D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012097:Repressor Proteins; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2