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 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of -deficient mice and found that mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of altered the tumor susceptibility in both mutant and -null background. Specifically, in a mutant p53(R270H) background, deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a -null background, 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.

Detrimental Role of Nerve Injury-Induced Protein 1 in Myeloid Cells under Intestinal Inflammatory Conditions

“…Similar to the previous paper that analyzed the role of Ninj1 in colon cancer, several reports have demonstrated that Ninj1 mediates migration of cells in inflammatory conditions [2][3][4][41][42][43]. Thus, it was surprising that during colitis development, Ninj1 did not alter the migration capacity of macrophages, which is seen only in lung fibrosis.…”

Disruption of the Rbm38-eIF4E Complex with a Synthetic Peptide Pep8 Increases p53 Expression

“…Next, the cells were incubated for 1 hour in methionine-free DMEM before being labeled with 100 mCi/mL 35 S for 30 minutes. The amount of 35 S incorporation was measured by TCA precipitation and scintillation counting. Equal amounts of 35 S-labeled lysates (3.7 Â 10 6 cpm) were incubated with 1.0 mg anti-p53 antibody and Protein G agarose beads (25 mL bed volume).…”

“…The amount of 35 S incorporation was measured by TCA precipitation and scintillation counting. Equal amounts of 35 S-labeled lysates (3.7 Â 10 6 cpm) were incubated with 1.0 mg anti-p53 antibody and Protein G agarose beads (25 mL bed volume). The immunocomplexes were resolved on an 8% SDS-PAGE gel and subjected to autoradiography.…”

“…Colony formation assays were performed as previously described (35). Briefly, 1,000 cells were plated in 6-well plates.…”

“…Xenograft tumors were fixed in 10% (wt/vol) neutral-buffered formalin, routinely processed, and embedded in paraffin blocks. H&E staining and IHC were performed on xenograft tissue sections (5 mm) as previously described (35).…”