Ectopic expression of p53 mutant R282W in H1299 and SaOS2 cells significantly upregulated CYP3A4 mRNA and protein levels, and cancer cell lines bearing mortality-associated p53 mutations display higher CYP3A4 expression and resistance to several CYP3A4-metabolized chemotherapeutic drugs.
The effects of the mutations were rationalized based on homology modeling of the Dmp53 DNA-binding domain, suggesting that the drastically different effects of a cancer mutation in the loop-sheet-helix motif (R282W in Hp53 and R268W in Dmp53) on stability and DNA binding affinity of the two proteins are related to conformational differences in the L1 loop adjacent to the mutation site.