Comparison of p53 and the PDZ domain containing protein MAGI-3 regulation by the E6 protein from high-risk human papillomaviruses.
Central to cellular transformation caused by human papillomaviruses (HPVs) is the ability of E6 proteins to target cellular p53 and proteins containing PDZ domains, including MAGI-3, for degradation. The aim of this study was to compare E6-mediated degradation of p53 and MAGI-3 under parallel experimental conditions and further with respect to the involvement of proteasomes and ubiquitination. We also compared the degradation of p53 and MAGI-3 by E6 from several HPV types including different variants from HPV-33. All of the E6 genes from different HPV types displayed similar abilities to mediate the degradation of both p53 and MAGI-3 although there may be subtle differences observed with the different 33E6 variants. There were however differences in E6 mediated degradation of p53 and MAGI-3. Proteasome inhibition assays partially protected p53 from E6 mediated degradation, but did not protect MAGI-3. In addition, under conditions where p53 was ubiquitinated by E6 and MDM2 in vivo, ubiquitination of MAGI-3 was not detected. These results imply that although both p53 and MAGI-3 represent effective targets for oncogenic E6, the mechanisms by which E6 mediates p53 and MAGI-3 degradation are distinct with respect to the involvement of ubiquitination prior to proteasomal degradation.
Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada. j.ainsworth22@gmail.com
Julia
J
Ainsworth
Miranda
M
Thomas
Lawrence
L
Banks
Francois
F
Coutlee
Greg
G
Matlashewski
D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D027383:Papillomaviridae / Q000502:physiology*; D011110:Polymorphism, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination; D014759:Viral Envelope Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; C524477:E6 protein, HPV-33; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C496469:MAGI3 protein, human; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D061988:Proteasome Inhibitors; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D014759:Viral Envelope Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex