p53 and merlin tumor suppressors: Two of a kind

In EBioMedicine, Chen and colleagues [1] showed that more than 85% of sporadic vestibular schwannomas have at least one somatic mutation affecting the NF2 gene and that the “two-hits” NF2 gene status is associated with larger tumor size and with loss of merlin protein expression. This situation is associated with a significant decrease of p53 protein level and functions, due to enhanced nuclear accumulation of MDM2 and consequent nuclear export of p53 for degradation. The authors correlate this discovery with the relevant role of MDM2 as mediator of merlin and p53 interaction: in the normal Schwann cells they are both regularly present and reciprocally stabilized, while in Schwannoma p53 is rapidly degraded because of a higher presence of MDM2 in the absence of merlin expression. Importantly, the authors demonstrated that the combined inhibition of MDM2 and proteasome by the two drugs Nutlin-3 and MG-132 was able to restoring p53 and merlin normal level and normal biological activity (apoptosis induction and cell cycle blockade) and to efficiently reduce the growth of schwannoma in vivo. Their findings offer new opportunities both for preclinical and clinical research.