title: As a novel p53 direct target, bidirectional gene HspB2/αB-crystallin regulates the ROS level and Warburg effect.
abstract: Many mammalian genes are composed of bidirectional gene pairs with the two genes separated by less than 1.0kb. The transcriptional regulation and function of these bidirectional genes remain largely unclear. Here, we report that bidirectional gene pair HspB2/αB-crystallin, both of which are members of the small heat shock protein gene family, is a novel direct target gene of p53. Two potential binding sites of p53 are present in the intergenic region of HspB2/αB-crystallin. p53 up-regulated the bidirectional promoter activities of HspB2/αB-crystallin. Actinomycin D (ActD), an activator of p53, induces the promoter and protein activities of HspB2/αB-crystallin. p53 binds to two p53 binding sites in the intergenic region of HspB2/αB-crystallin in vitro and in vivo. Moreover, the products of bidirectional gene pair HspB2/αB-crystallin regulate glucose metabolism, intracellular reactive oxygen species (ROS) level and the Warburg effect by affecting metabolic genes, including the synthesis of cytochrome c oxidase 2 (SCO2), hexokinase II (HK2), and TP53-induced glycolysis and apoptosis regulator (TIGAR). The ROS level and the Warburg effect are affected after the depletion of p53, HspB2 and αB-crystallin respectively. Finally, we show that both HspB2 and αB-crystallin are linked with human renal carcinogenesis. These findings provide novel insights into the role of p53 as a regulator of bidirectional gene pair HspB2/αB-crystallin-mediated ROS and the Warburg effect.
authors.affiliation: Center for Medicine Research, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.affiliation: Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Center for Molecular Imaging, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan 410078, China; Key Laboratory of Carcinogenesis, Ministry of Health, Hunan 410078, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yan
authors.affiliation: Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Center for Molecular Imaging, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan 410078, China; Key Laboratory of Carcinogenesis, Ministry of Health, Hunan 410078, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Lai
authors.affiliation: Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Center for Molecular Imaging, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan 410078, China; Key Laboratory of Carcinogenesis, Ministry of Health, Hunan 410078, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892 USA.
authors.forename: Sichuan
authors.initials: S
authors.lastname: Xi
authors.affiliation: Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Center for Molecular Imaging, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan 410078, China; Key Laboratory of Carcinogenesis, Ministry of Health, Hunan 410078, China.
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Center for Molecular Imaging, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan 410078, China; Key Laboratory of Carcinogenesis, Ministry of Health, Hunan 410078, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 4010078, China.
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Center for Molecular Imaging, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan 410078, China; Key Laboratory of Carcinogenesis, Ministry of Health, Hunan 410078, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Cancer Research Institute, Central South University, Changsha, Hunan 410078, China; Center for Molecular Imaging, Central South University, Changsha, Hunan 410078, China; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan 410078, China; Key Laboratory of Carcinogenesis, Ministry of Health, Hunan 410078, China. Electronic address: taoyong@csu.edu.cn.
authors.forename: Yongguang
authors.initials: Y
authors.lastname: Tao
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000235:genetics* / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; C442250:HSPB2 protein, human; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D038203:alpha-Crystallin B Chain
keywords: Bidirectional promoter; HspB2; Renal cell carcinoma; Warburg effect; p53; αB-crystallin