Several mechanisms of p53 impairment in melanoma have been proposed, including mutations in the CDKN2A gene (encoding for both p16INK4A and p14ARF, the latter of which relieves p53 from the negative regulation of MDM2 and its inactivation promotes the inhibition of p53 by MDM2) and the over-expression of MDM2, MDMX/MDM4 (an additional negative regulator of p53), or the inhibitor of apoptosis-stimulating protein of p53 (iASPP) and anti-apoptotic proteins such as BCL-2, which allow melanoma cells to become highly resistant to apoptosis [11,12]. Here, MDM4 is linked to melanoma.