Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4

Collins, Loretta L.; Lee, Yi Fen; Heinlein, Cynthia A.; Liu, Ning Chun; Chen, Yei Tsung; Shyr, Chih Rong; Meshul, Charles K.; Uno, Hideo; Platt, Kenneth A.; Chang, Chawnshang

doi:10.1073/pnas.0405700101

Cited by 88 publications

(116 citation statements)

References 45 publications

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“…The TR4 −/− mice showed several important phenotypes including defects in motor coordination and aberrant cerebellar developments with increased neuronal apoptosis [13]. Furthermore, we found that loss of TR4 resulted in delayed adhesion and growth retardation of mouse embryonic fibroblast (MEF) cells in this study.…”

Section: Introductionmentioning

confidence: 52%

TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression

Kim

Lung

Lin

et al. 2007

Biochemical and Biophysical Research Communications

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While Bcl-2 plays an important role in cell apoptosis, its relationship to the orphan nuclear receptors remains unclear. Here we report that mouse embryonic fibroblast (MEF) cells prepared from TR4-deficient (TR4 −/− ) mice are more susceptible to UV-irradiation mediated apoptosis compared to TR4-Wildtype (TR4 +/− ) littermates. Substantial increasing TR4 −/− MEF apoptosis to UV-irradiation was correlated to the down-regulation of Bcl-2 RNA and protein expression and collaterally increased caspase-3 activity. Furthermore, this TR4-induced Bcl-2 gene expression can be suppressed by cotransfection with TR4 coregulators, such as androgen receptor (AR) and receptor-interacting protein 140 (RIP140) in a dose-dependent manner. Together, our results demonstrate that TR4 might function as an apoptosis modulator through induction of Bcl-2 gene expression.

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Section: Introductionmentioning

confidence: 52%

TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression

Kim

Lung

Lin

et al. 2007

Biochemical and Biophysical Research Communications

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“…TR4KO mice were obtained from Lexicon Genetics Incorporated and were generated and genotyped as described previously [12]. Animals were maintained and experimental procedures on animals were conducted in accordance with guidelines outlined by the Guide for the Care and Use of Laboratory Animals following the legal requirement of the United States and approved by the University Committee of Animal Resources.…”

Section: Methodsmentioning

confidence: 99%

“…Mice lacking Tr4 ( TR4KO ) have high rates of early postnatal mortality, show significant growth retardation [12], display reproductive defects in both genders [12, 13], abnormalities in spermatogenesis [14], reduced lipoprotein metabolism [15, 16], and reduced gluconeogenesis [17], as well as defects in cerebella development [18]. Furthermore, the premature aging phenotype of TR4KO mouse led to the finding of TR4’s role in defending oxidative stress and DNA damage response [19].…”

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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“…Recent studies with TR4 gene knock-out mice (TR4 Ϫ/Ϫ ) have revealed that TR4 is essential for normal spermatogenesis, cerebellum development, glucose metabolism, and insulin resistance (3)(4)(5)(6)(7). Mouse embryonic fibroblasts (MEFs) from TR4 Ϫ/Ϫ mice display a higher rate of apoptosis compared with wild-type MEFs when exposed to a high dose of UV irradiation (8).…”

Section: Testicular Nuclear Receptor 4 (Tr4)mentioning

confidence: 99%

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

Liu

Yan

Lee

et al. 2011

Journal of Biological Chemistry

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Background: CSB, a member of the TC-NER pathway, is essential for UV light-induced DNA damage repair. Results: CSB expression is reduced in TR4-deficient tissues/cells, and restored CSB expression rescues UV hypersensitivity of TR4-deficient cells. Conclusion: TR4 modulates UV sensitivity via promoting the TC-NER DNA repair pathway through transcriptional regulation of CSB. Significance: Our findings may provide new information for the treatment of UV light-sensitive syndromes, skin cancer, and aging.

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Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4

Cited by 88 publications

References 45 publications

TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression

TR4 orphan nuclear receptor functions as an apoptosis modulator via regulation of Bcl-2 gene expression

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

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

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