TY - JOUR
T1 - Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner
AU - Yang, Hee Jung
AU - Zhang, Jin
AU - Yan, Wensheng
AU - Cho, Seong Jun
AU - Lucchesi, Christopher
AU - Chen, Mingyi
AU - Huang, Eric C.
AU - Scoumanne, Ariane
AU - Zhang, Weici
AU - Chen, Xinbin
N1 - Funding Information:
ACKNOWLEDGMENTS. This work is supported in part by American Cancer Society Institutional Research Grant IRG-95-125-13 (to J.Z.) and by NIH Grant CA076069 (to X.C.).
PY - 2017/10/24
Y1 - 2017/10/24
N2 - 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 Ninj1 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of Ninj1 inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1,we generated a cohort of Ninj1-deficient mice and found that Ninj1+/- mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of Ninj1 altered the tumor susceptibility in both mutant p53 and p53-null background. Specifically, in a mutant p53(R270H) background, Ninj1 deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a p53-null background, Ninj1 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.
AB - 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 Ninj1 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of Ninj1 inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1,we generated a cohort of Ninj1-deficient mice and found that Ninj1+/- mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of Ninj1 altered the tumor susceptibility in both mutant p53 and p53-null background. Specifically, in a mutant p53(R270H) background, Ninj1 deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a p53-null background, Ninj1 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.
KW - Cell adhesion
KW - Inflammation
KW - Mutant p53
KW - Ninjurin 1
KW - P53
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U2 - 10.1073/pnas.1711814114
DO - 10.1073/pnas.1711814114
M3 - Article
C2 - 29073078
AN - SCOPUS:85032212314
SN - 0027-8424
VL - 114
SP - 11500
EP - 11505
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
ER -