TP53inp1 Gene Is Implicated in Early Radiation Response in Human Fibroblast Cells

Abstract

Tumor protein 53-induced nuclear protein-1 (TP53inp1) is expressed by activation via p53 and p73. The purpose of our study was to investigate the role of TP53inp1 in response of fibroblasts to ionizing radiation. γ-Ray radiation dose-dependently induces the expression of TP53inp1 in human immortalized fibroblast (F11hT) cells. Stable silencing of TP53inp1 was done via lentiviral transfection of shRNA in F11hT cells. After irradiation the clonogenic survival of TP53inp1 knockdown (F11hT-shTP) cells was compared to cells transfected with non-targeting (NT) shRNA. Radiation-induced senescence was measured by SA-β-Gal staining and autophagy was detected by Acridine Orange dye and microtubule-associated protein-1 light chain 3 (LC3B) immunostaining. The expression of TP53inp1, GDF-15, and CDKN1A and alterations in radiation induced mitochondrial DNA deletions were evaluated by qPCR. TP53inp1 was required for radiation (IR) induced maximal elevation of CDKN1A and GDF-15 expressions. Mitochondrial DNA deletions were increased and autophagy was deregulated following irradiation in the absence of TP53inp1. Finally, we showed that silencing of TP53inp1 enhances the radiation sensitivity of fibroblast cells. These data suggest functional roles for TP53inp1 in radiation-induced autophagy and survival. Taken together, we suppose that silencing of TP53inp1 leads radiation induced autophagy impairment and induces accumulation of damaged mitochondria in primary human fibroblasts.

Linking Alzheimer's disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach

“…Our results, along with previous studies, have indicated that both TP53INP1 and TOMM40 were related to AD [69,70] and T2D [50,63], whereas C8orf38 was identified as a novel gene for T2D. The TP53INP1 encodes a protein for mediating autophagy-dependent cell death through apoptosis and regulating cellular-extracellular matrix adhesion and cell migration [77], and was expressed by activation via p53, which regulated the oxidative damage response [78]. A study with mice genetically engineered knockout for TP53INP1 demonstrated that the impaired mitophagy of dysfunctional mitochondria is the main source of the chronic oxidative stress, and may cause insulin resistance and promote the predisposition to T2D [79].…”

Delivery of Sonic Hedgehog Gene Repressed Irradiation-induced Cellular Senescence in Salivary Glands by Promoting DNA Repair and Reducing Oxidative Stress

“…How Hh signaling regulates GDF15 expression is unclear. The expression of GDF15 is regulated by p53 pathway 33 , and Trp53inp1 was required for IR-induced maximal elevation of GDF15 expression in human fibroblasts 34 . Since transient Hh activation did not repress the upregulation of Trp53inp1 and other p53 target genes including p21 and Mdm2 by IR on day 7 (Fig.…”

Genomic footprints of dryland stress adaptation in Egyptian fat-tail sheep and their divergence from East African and western Asia cohorts

“…We found several genes involved in the development of the nervous system and eliciting response to stress, indicating the importance of the neuroendocrine system in activating stress response in the candidate regions. One of the genes, DMBX1 is involved in brain and sensory organ development 49 , 50 while TP53INP1 is a key cell stress response protein with antioxidant function 51 , 52 . Through its interaction with the ERK1 and p38 mitogen-activated protein kinases, MKNK1 may play a role in responding to environmental stress and control cytokine production and delayed apoptosis 53 , 54 .…”