Open Access

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

  • Shian-Jang Yan1,
  • Yi-Fen Lee1,
  • Huei-Ju Ting1,
  • Ning-Chun Liu1,
  • Su Liu1,
  • Shin-Jen Lin1,
  • Shauh-Der Yeh2,
  • Gonghui Li1 and
  • Chawnshang Chang1, 3Email author
Cellular & Molecular Biology LettersAn International Journal201217:12

DOI: 10.2478/s11658-012-0012-9

Received: 24 August 2011

Accepted: 27 February 2012

Published: 7 March 2012

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.

Key words

TR4 GADD45A Ionizing radiation Mouse embryonic fibroblast Genotoxic stress TR4 response element

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