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

• Autorzy: Yan S.-J. , Lee Y.-F. , Ting H.-J. , Liu N.-C. , Liu S. , Lin S.-J. , Yeh S.-D. , Li G. , Chang C.
• Języki publikacji: EN

Abstrakty

EN

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.

Słowa kluczowe

EN

deficiency; TR4 nuclear receptor; biological activity; oxidative stress; Gadd45a gene; gene expression; cytotoxicity; ionizing radiation; embryonic fibroblast; mouse; mice; genotoxic stress; TR4 response element

• Wydawca: -
• Czasopismo: Cellular and Molecular Biology Letters
• Rocznik: 2012
• Tom: 17
• Numer: 2
• Opis fizyczny: p.309-322,fig.,ref.

Twórcy

autor

Yan S.-J.

• George Whipple Lab for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14642

autor

Lee Y.-F.

autor

Ting H.-J.

autor

Liu N.-C.

autor

Liu S.

autor

Lin S.-J.

autor

Yeh S.-D.

autor

Li G.

autor

Chang C.

Bibliografia

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