Using wt TP53 cell lines and DNA-modified siRNAs specific to MDM2 and MDM4, we demonstrated here for the first time that knockdown of either MDM4 or MDM2 alone can reactivate the TP53 pathway in cancer cells with high MDM4 expression, whereas knockdown of MDM2, but not MDM4, can reactivate wt TP53 in the low MDM4 cancer cells. The gene discussed is TP53; the disease is cancer.