title: CUL4B impedes stress-induced cellular senescence by dampening a p53-reactive oxygen species positive feedback loop.
abstract: Tumor suppressor p53 is known to regulate the level of intracellular reactive oxygen species (ROS). It can either alleviate oxidative stress under physiological and mildly stressed conditions or exacerbate oxidative stress under highly stressed conditions. We here report that a p53-ROS positive feedback loop drives a senescence program in normal human fibroblasts (NHFs) and this senescence-driving loop is negatively regulated by CUL4B. CUL4B, which can assemble various ubiquitin E3 ligases, was found to be downregulated in stress-induced senescent cells, but not in replicative senescent cells. We observed that p53-dependent ROS production was significantly augmented and stress-induced senescence was greatly enhanced when CUL4B was absent or depleted. Ectopic expression of CUL4B, on the other hand, blunted p53 activation, reduced ROS production, and attenuated cellular senescence in cells treated with H2O2. CUL4B was shown to promote p53 ubiquitination and proteosomal degradation in NHFs exposed to oxidative stress, thus dampening the p53-dependent cellular senescence. Together, our results established a critical role of CUL4B in negatively regulating the p53-ROS positive feedback loop that drives cellular senescence.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Zhaojian
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Xiyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education/Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Genetics/Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: shaochangshun@sdu.edu.cn.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
mesh_terms: D000818:Animals; D016922:Cellular Senescence / Q000502:physiology*; D044842:Cullin Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000008:administration & dosage; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C517832:CUL4B protein, human; D044842:Cullin Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide
keywords: CUL4B; Feedback loop; Reactive oxygen species; Senescence; Ubiquitination; p53