title: 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 radiation-induced 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.
authors.affiliation: Comparative Oncology Laboratory, University of California, Davis, CA 95616, USA.
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Cho
authors.forename: Andrea
authors.initials: A
authors.lastname: Rossi
authors.forename: Yong-Sam
authors.initials: YS
authors.lastname: Jung
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yan
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology* / Q000528:radiation effects; D016922:Cellular Senescence / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D003114:Colony-Forming Units Assay; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D008156:Luciferases; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013462:Sulfur Radioisotopes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D017931:DNA Primers; D009414:Nerve Growth Factors; C484439:Ninj1 protein, mouse; D013462:Sulfur Radioisotopes; D016159:Tumor Suppressor Protein p53; D008156:Luciferases
keywords: cellular senescence; radiosensitivity