title: Premature aging with impaired oxidative stress defense in mice lacking TR4.
abstract: Early studies suggest that TR4 nuclear receptor is a key transcriptional factor regulating various biological activities, including reproduction, cerebella development, and metabolism. Here we report that mice lacking TR4 (TR4(-/-)) exhibited increasing genome instability and defective oxidative stress defense, which are associated with premature aging phenotypes. At the cellular level, we observed rapid cellular growth arrest and less resistance to oxidative stress and DNA damage in TR4(-/-) mouse embryonic fibroblasts (MEFs) in vitro. Restoring TR4 or supplying the antioxidant N-acetyl-l-cysteine (NAC) to TR4(-/-) MEFs reduced the DNA damage and slowed down cellular growth arrest. Focused qPCR array revealed alteration of gene profiles in the DNA damage response (DDR) and anti-reactive oxygen species (ROS) pathways in TR4(-/-) MEFs, which further supports the hypothesis that the premature aging in TR4(-/-) mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Together, our finding identifies a novel role of TR4 in mediating the interplay between oxidative stress defense and aging.
authors.affiliation: George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Orthopaedics, University of Rochester Medical Center, Rochester, New York 14620, USA. chang@urmc.rochester.edu
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lee
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.forename: Ning-Chun
authors.initials: NC
authors.lastname: Liu
authors.forename: Ruey-Sheng
authors.initials: RS
authors.lastname: Wang
authors.forename: Lu-Min
authors.initials: LM
authors.lastname: Chen
authors.forename: Wen-Jye
authors.initials: WJ
authors.lastname: Lin
authors.forename: Huei-Ju
authors.initials: HJ
authors.lastname: Ting
authors.forename: Hsin-Chiu
authors.initials: HC
authors.lastname: Ho
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Puzas
authors.forename: Qiao
authors.initials: Q
authors.lastname: Wu
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000235:genetics / Q000502:physiology; D005260:Female; D042822:Genomic Instability / Q000235:genetics; D007107:Immune System / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*
chemical_list: D000975:Antioxidants; C490514:Nr2c2 protein, mouse; D017382:Reactive Oxygen Species; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone