Ninjurin 2, a Cell Adhesion Molecule and a Target of p53, Modulates Wild-Type p53 in Growth Suppression and Mutant p53 in Growth Promotion

Simple Summary The nerve injury-induced protein 2 (NINJ2) is a cell adhesion molecule, but its biological function remains largely unexplored. Here, we show that NINJ2 can be induced by tumor suppressor p53. Interestingly, we also found that Ninj2 can in turn modulate p53 expression via repressing both wild-type and mutant p53 mRNA translation. Consequently, we found that the loss of NINJ2 inhibits cell growth in wild-type p53-containing cells but promotes cell growth in mutant p53-containing cells. Together, our data reveal a novel feedback loop between NINJ2 and p53 and that NINJ2 exerts an opposing role in cell growth depending on the p53 status.Abstract The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. However, the biology of NINJ2 has not been well-explored. By using multiple in vitro cell lines and genetically engineered mouse embryo fibroblasts (MEFs), we showed that NINJ2 is induced by DNA damage in a p53-dependent manner. Moreover, we found that the loss of NINJ2 promotes p53 expression via mRNA translation and leads to growth suppression in wild-type p53-expressing MCF7 and Molt4 cells and premature senescence in MEFs in a wild-type p53-dependent manner. Interestingly, NINJ2 also regulates mutant p53 expression, and the loss of NINJ2 promotes cell growth and migration in mutant p53-expressing MIA-PaCa2 cells. Together, these data indicate that the mutual regulation between NINJ2 and p53 represents a negative feedback loop, and the NINJ2-p53 loop has opposing functions in wild-type p53-dependent growth suppression and mutant p53-dependent growth promotion.