Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality

Abstract

The tumor suppressor protein p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest, apoptosis, and senescence. The nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a homophilic adhesion molecule and involved in nerve regeneration. Interestingly, Ninj1 is found to be overexpressed in human cancer, but its role in tumorigenesis is not clear. Here, we found that Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage in a p53-dependent manner. We also found that knockout or knockdown of Ninj1 increases p53 expression potentially through enhanced p53 mRNA translation. In addition, we found that Ninj1 deficiency suppresses cell proliferation but enhances apoptosis and premature senescence in a p53-dependent manner. Consistent with this, we found that mice heterozygous in ninj1 are hypersensitive to ionizing radiation-induced lethality, along with increased expression of p53 in thymus. Taken together, we provided evidence that Ninj1 is a p53 target and modulates p53 mRNA translation and p53-dependent premature senescence, cell proliferation, apoptosis, and radiationinduced mortality in vitro and in vivo. Thus, we postulate that as a membrane adhesion molecule, Ninj1 is an ideal target to regulate p53 activity via the p53-Ninj1 loop. cellular senescence | radiosensitivity

AP-1 Is a Key Regulator of Proinflammatory Cytokine TNFα-mediated Triple-negative Breast Cancer Progression

“…4F). Together, these findings indicate that Ninj1 is a potential oncogene that increases malignant characteristics of TNBC cells, in agreement with previous findings in colon cancer cells (24). To determine the role of Ninj1 in apoptosis and invasion downstream of c-Jun, we examined whether simultaneous c-Jun knockdown and Ninj1 overexpression would rescue cells from the effects of c-Jun depletion.…”

“…In line with this, up-regulation of Ninj1 expression was observed in hepatocellular carcinoma (38) and acute lymphoblastic leukemia (39). Cho et al reported that knockdown of Ninj1 suppresses cell proliferation and enhances apoptosis in human RKO colon cancer cells (24). They further demonstrated that silencing of Ninj1 increases p53 expression through modulating p53 mRNA translation in RKO cells that express wild-type p53.…”

“…4A). Recently, it has been reported that lack of Ninj1 leads to growth suppression in colon cancer cells, implying that Ninj1 has potential oncogenic functions (24). However, its role in breast tumor growth and progression has not been studied.…”

Ninjurin1 Deficiency Attenuates Susceptibility of Experimental Autoimmune Encephalomyelitis in Mice

“…However, a recent paper indicated that Ninjurin1 KO mice died prematurely (21). Consistent with this result, we also observed developmental defects in some of the Ninjurin1 KO mice.…”

“…A recent study showed that Ninjurin1 depletion promotes cell apoptosis and senescence in a p53-dependent manner (21). Although the hemogram between WT and Ninjurin1 KO mice did not differ under normal conditions (Table 1), the inflammatory EAE induction may alter the homeostatic functions of leukocytes in Ninjurin1 KO mice.…”