Several diverse mechanisms of p53 inactivation in melanoma have been proposed, including mutations of CDKN2A (CDKN2A encodes for both p16INK4A and p14ARF), upregulation of MDM2 (an E3 ubiquitin ligase that controls p53 expression and function) or MDM4 (negative regulator of p53) overexpression, activation of iASPP (inhibitor of apoptosis stimulating protein of p53) or deubiquitinase USP5, and silencing of the TP53 gene by epigenetic mechanisms [55,59,60,61,62]. The gene discussed is MDM4; the disease is melanoma.