Roles of N-Myc and STAT interactor in cancer: From initiation to dissemination

Pruitt, Hawley C.; Devine, Daniel J.; Samant, Rajeev S.

In addition to the NMI-Tip60 interaction, NMI also interacts with another important player in the DNA damage response pathway, ARF. 14 ARF responds to DNA damageinducing oncogenic stress from hyper-proliferative genes like c-Myc. 15 Synchronizing DNA damage repair pathways with cellular response requires complex signaling crosstalk converging at the tumor suppressor p53. Both Tip60 and ARF block MDM2-mediated degradation of p53, and therefore control the p53/MDM2 checkpoint leading to cell cycle arrest or apoptosis. 16, 17 Decreased NMI expression, a phenomenon seen in late stage breast tumors, may potentially destabilize ARF as experimental observations showed that NMI inhibits proteasomal degradation of ARF by displacing ULF, the ubiquitin ligase that catalyzes ARF ubiquitination. 14 Furthermore, NMI interacts with ARF after cells are stressed with DNA damaging agents such as IFNa, cisplatin or methylmethanosulfate. To summarize these findings, loss of NMI expression in cancer leads to down-regulation of ARF, destabilization of p53 and subsequent desensitization of cells to DNA damageinduced cell cycle arrest or cell death. In corroboration with these findings, NMI overexpression also induced CHK2 activation and G2/M cell cycle arrest downstream of p53, particularly after DNA damage. 14 Eymin et al. identified a novel p53 independent pathway in response to genotoxic stress. In this pathway, Tip60 and ARF activate ATM to induce G2 cell cycle arrest after DNA damage. 18 Moreover, Tip60 and ARF were identified as binding partners that accumulated after treatment with DNA alkylating agents. As NMI binds both Tip60 and ARF, it is plausible that NMI also has a role in this p53-independent mode of DNA damage sensing and cell cycle arrest, but this idea remains to be tested.