Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner.

Abstract

WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Nerve injury-induced protein 1 (Ninj1) is a target of p53 and forms a feedback loop with p53 by repressing p53 mRNA translation. Here, we show that loss of <i>Ninj1</i> increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of <i>Ninj1</i> inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of <i>Ninj1</i>-deficient mice and found that <i>Ninj1</i>^<i>+/-</i> mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of <i>Ninj1</i> altered the tumor susceptibility in both mutant <i>p53</i> and <i>p53</i>-null background. Specifically, in a mutant p53(R270H) background, <i>Ninj1</i> deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a <i>p53</i>-null background, <i>Ninj1</i> deficiency significantly increased the incidence of T-lymphoblastic lymphoma. Taken together, our data suggest that depending on p53 genetic status, Ninj1 has two opposing functions in tumorigenesis and that the Ninj1-p53 loop may be targeted to manage inflammatory diseases and cancer.