Testicular Nuclear Receptor 4 (TR4) Regulates UV Light-induced Responses via Cockayne Syndrome B Protein-mediated Transcription-coupled DNA Repair

Liu, Su; Yan, Shian Jang; Lee, Yi Fen; Liu, Ning Chun; Ting, Huei-Ju; Li, Gonghui; Wu, Qiao; Chen, Lu Min; Chang, Chawnshang

doi:10.1074/jbc.m111.259523

Cited by 12 publications

(11 citation statements)

References 43 publications

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“…In addition, the γ H2AX assay is good for quantitation of DNA rejoining, but it does not cover DNA misrepair, which also account for cell killing. However, preliminary study found that TR4 could also modulate DNA repair through the nucleotide excision repair pathway . Our results support the conclusion that TR4 might modulate the DNA repair system demonstrated by previous study, although the detail mechanism of how TR4 affects the HRR or NHEJ repair pathways still needs further investigation.…”

Section: Discussionsupporting

confidence: 89%

Testicular orphan nuclear receptor 4 is associated with the radio-sensitivity of prostate cancer

Wang

Ding

et al. 2015

Prostate

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Section: Discussionsupporting

confidence: 89%

Testicular orphan nuclear receptor 4 is associated with the radio-sensitivity of prostate cancer

Wang

Ding

et al. 2015

Prostate

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“…4 As an important transcription factor, TR4 can interact with several nuclear receptors and influence intracellular reactive oxygen species (ROS), oxidative stress resistance 5,6 and DNA damage reparation via its various down stream target genes. 7,8 In vivo studies of TR4 gene knockout mice (TR4 − / − ) demonstrated that they display impaired oxidative stress defense, 5 subfertility 9 and premature aging. 6 However, the linkage between TR4 and PCa docetaxel resistance remains unclear.…”

Section: Introductionmentioning

confidence: 99%

The role of testicular nuclear receptor 4 in chemo-resistance of docetaxel in castration-resistant prostate cancer

Chen

Ding

et al. 2014

Cancer Gene Ther

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Docetaxel-based therapy is one of the first-line options for castration-resistant prostate cancer (CRPC). However, a large proportion of CRPC patients show different extents of docetaxel resistance. The current study aims to investigate the role of testicular nuclear receptor 4 (TR4) in docetaxel resistance in CRPC. TR4 expression level in prostate biopsy samples from CRPC patients treated with docetaxel was measured by immunohistochemistry (IHC). Alternation of TR4 expression in prostate cancer (PCa) cell line PC3 was applied to find out the influence of TR4 on half-maximal inhibitory concentration (IC50), cell viability and cell apoptosis. Patients who failed to achieve prostate-specific antigen (PSA) response (<50% PSA reduction from baseline) after docetaxel-based chemotherapy had a comparatively higher TR4 expression than those who achieved PSA response (⩾50% PSA reduction from baseline). Knocking down TR4 in PC3 cells led to a lower IC50 dose, poorer cell viability and more cell apoptosis when treated with docetaxel, whereas overexpression of TR4 in PC3 led to a higher IC50 dose, better cell viability and less cell apoptosis. TR4 enhances the chemo-resistance of docetaxel in CRPC. It may serve as a biomarker to determine the prognosis of docetaxel-based therapy and as a potential therapy target to combine with docetaxel to better suppress CRPC.

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“…TR4 also protects cells from ultraviolet radiation via regulating transcription-coupled DNA repair protein, Cockayne syndrome B [21]. Following these discoveries, the protective mechanism of TR4 in cells facing stress was further explored.…”

Section: Introductionmentioning

confidence: 99%

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

Yan

Lee

Ting

et al. 2012

Cellular and Molecular Biology Letters

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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.

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Testicular Nuclear Receptor 4 (TR4) Regulates UV Light-induced Responses via Cockayne Syndrome B Protein-mediated Transcription-coupled DNA Repair

Cited by 12 publications

References 43 publications

Testicular orphan nuclear receptor 4 is associated with the radio-sensitivity of prostate cancer

Testicular orphan nuclear receptor 4 is associated with the radio-sensitivity of prostate cancer

The role of testicular nuclear receptor 4 in chemo-resistance of docetaxel in castration-resistant prostate cancer

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

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