A sequence element of p53 that determines its susceptibility to viral oncoprotein-targeted degradation.
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.
Gu
J
J
Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts, MA 02115, USA.
Rubin
R M
RM
Yuan
Z M
ZM
D000818:Animals; D001665:Binding Sites; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016158:Genes, p53; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
C068651:E6 protein, Human papillomavirus type 16; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D011505:Protein-Tyrosine Kinases