Although abrogation of p16ink4A function is the most common alteration that may lead to bypass the anti-proliferative control in MM [48], we showed here that in the absence of the p16ink4A gene, as in our melanoma cell model, MAPK can induce a secondary mechanism of feedback protection that might go through p21cip1 up-regulation, which directly blocks MM cells at the S-phase checkpoint, as supported by previous evidence [33, 34]. This evidence concerns the gene CDKN1A and Miyoshi myopathy.