A sequence element of p53 that determines its susceptibility to viral oncoprotein-targeted degradation

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.