Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation

Abstract

The testicular receptor 4 (TR4) is a member of the nuclear receptor superfamily that controls various biological activities. A protective role of TR4 against oxidative stress has recently been discovered. We here examined the protective role of TR4 against ionizing radiation (IR) and found that small hairpin RNA mediated TR4 knockdown cells were highly sensitive to IR-induced cell death. IR exposure increased the expression of TR4 in scramble control small hairpin RNA expressing cells but not in TR4 knockdown cells. Examination of IR-responsive molecules found that the expression of Gadd45a, the growth arrest and DNA damage response gene, was dramatically decreased in Tr4 deficient (TR4KO) mice tissues and could not respond to IR stimulation in TR4KO mouse embryonic fibroblast cells. This TR4 regulation of GADD45A was at the transcriptional level. Promoter analysis identified four potential TR4 response elements located in intron 3 and exon 4 of the GADD45A gene. Reporter and chromatin immunoprecipitation (ChIP) assays provided evidence indicating that TR4 regulated the GADD45A expression through TR4 response elements located in intron 3 of the GADD45A gene. Together, we find that TR4 is essential in protecting cells from IR stress. Upon IR challenges, TR4 expression is increased, thereafter inducing GADD45A through transcriptional regulation. As GADD45A is directly involved in the DNA repair pathway, this suggests that TR4 senses genotoxic stress and up-regulates GADD45A expression to protect cells from IR-induced genotoxicity.

Correlation between the aberrant human testicular germ-cell gene expression and disruption of spermatogenesis leading to male infertility

“…Correspondingly, the levels of Cyclin-B are also depleted in these patients. Further, GADD45A-null cells show higher sensitivity to apoptosis under conditions of stress 52 indicating its role as an anti-apoptotic factor and supports lack of apoptosis seen in the diploid arrested patients ( Figure 3A).…”

Increased Chemosensitivity via Targeting Testicular Nuclear Receptor 4 (TR4)-Oct4-Interleukin 1 Receptor Antagonist (IL1Ra) Axis in Prostate Cancer CD133+ Stem/Progenitor Cells to Battle Prostate Cancer

“…It has been known to modulate many signaling pathways by interacting with the thyroid receptor, androgen receptor, retinoic acid receptor/retinoid X receptor, and estrogen receptor (24 -26). TR4 knockout mouse studies have shown that TR4 knockout results in defects in development and abnormalities in spermatogenesis and reproductive systems in both genders, which indicates that TR4 might play important roles in stem/progenitor cell differentiation (24). On the other hand, TR4 was also shown to play protective roles against oxidative stress-and ionizing radiationinduced damage (27).…”

TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth

“…Early studies suggested that TR4 might play important roles to alter several key signaling pathways via interacting with selective nuclear receptors including thyroid receptor, androgen receptor, retinoic acid receptor/retinoid X receptor, and estrogen receptor [7–9]. TR4 could influence oxidative stress- and ionizing radiation-induced damage [10], and altered TR4 led to change the chemo-resistance of PCa stem/progenitor cells [11].…”