title: A positive feedback loop between Pim-1 kinase and HBP1 transcription factor contributes to hydrogen peroxide-induced premature senescence and apoptosis.
abstract: Oxidative stress can induce cell dysfunction and lead to a broad range of degenerative alterations, including carcinogenesis, aging, and other oxidative stress-related conditions. To avoid undergoing carcinogenesis in response to oxidative stress, cells trigger a succession of checkpoint responses, including premature senescence and apoptosis. Increasing evidence indicates that H2O2, an important cause of oxidative stress, functions as an important physiological regulator of intracellular signaling pathways that participate in regulation of cell premature senescence and apoptosis. However, the precise mechanisms underlying this process remain to be studied extensively. In this study, we describe the importance of Pim-1 kinase in this checkpoint response to oxidative stress. Pim-1 binds to and phosphorylates the transcription factor high mobility group box transcription factor 1 (HBP1), activating it. H2O2enhances the interaction between Pim-1 and HBP1 and promotes HBP1 accumulation. In turn, HBP1 rapidly and selectively up-regulates Pim-1 expression in H2O2-stimulated cells, thereby creating a Pim-1-HBP1 positive feedback loop that regulates H2O2-induced premature senescence and apoptosis. Furthermore, the Pim-1-HBP1 positive feedback loop exerts its effect by regulating the senescence markers DNMT1 and p16 and the apoptosis marker Bax. The Pim-1-HBP1 axis thus constitutes a novel checkpoint pathway critical for the inhibition of tumorigenesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Shuya
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Zhengyi
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, China. Electronic address: xiaoweizhang@bjmu.edu.cn.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1 / Q000096:biosynthesis* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C486328:HBP1 protein, human; D006609:High Mobility Group Proteins; D012097:Repressor Proteins; D006861:Hydrogen Peroxide; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1
keywords: HBP1; Pim-1; apoptosis; cellular senescence; gene transcription; hydrogen peroxide; phosphorylation; positive feedback loop