title: HBP1-mediated Regulation of p21 Protein through the Mdm2/p53 and TCF4/EZH2 Pathways and Its Impact on Cell Senescence and Tumorigenesis.
abstract: The activity of the CDK inhibitor p21 is associated with diverse biological activities, including cell proliferation, senescence, and tumorigenesis. However, the mechanisms governing transcription of p21 need to be extensively studied. In this study, we demonstrate that the high-mobility group box-containing protein 1 (HBP1) transcription factor is a novel activator of p21 that works as part of a complex mechanism during senescence and tumorigenesis. We found that HBP1 activates the p21 gene through enhancing p53 stability by inhibiting Mdm2-mediated ubiquitination of p53, a well known positive regulator of p21. HBP1 was also found to enhance p21 transcription by inhibiting Wnt/β-catenin signaling. We identified histone methyltransferase EZH2, the catalytic subunit of polycomb repressive complex 2, as a target of Wnt/β-catenin signaling. HBP1-mediated repression of EZH2 through Wnt/β-catenin signaling decreased the level of trimethylation of histone H3 at lysine 27 of overall and specific histone on the p21 promoter, resulting in p21 transactivation. Although intricate, the reciprocal partnership of HBP1 and p21 has exceptional importance. HBP1-mediated elevation of p21 through the Mdm2/p53 and TCF4/EZH2 pathways contributes to both cellular senescence and tumor inhibition. Together, our results suggest that the HBP1 transcription factor orchestrates a complex regulation of key genes during cellular senescence and tumorigenesis with an impact on protein ubiquitination and overall histone methylation state.
authors.affiliation: From the 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 and.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the 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 and.
authors.forename: Kewu
authors.initials: K
authors.lastname: Pan
authors.affiliation: the Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Pingzhang
authors.initials: P
authors.lastname: Wang
authors.affiliation: From the 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 and.
authors.forename: Zhengyi
authors.initials: Z
authors.lastname: Cao
authors.affiliation: From the 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 and.
authors.forename: Weibin
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the 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 and.
authors.forename: Shuya
authors.initials: S
authors.lastname: Wang
authors.affiliation: From the 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 and.
authors.forename: Ningguang
authors.initials: N
authors.lastname: Hu
authors.affiliation: From the 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 and.
authors.forename: Junhui
authors.initials: J
authors.lastname: Xue
authors.affiliation: From the 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 and.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: From the 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 and.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: From the 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 and.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: From the 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 and. Electronic address: xiaoweizhang@bjmu.edu.cn.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006609:High Mobility Group Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050759:Cyclin-Dependent Kinase Inhibitor p21; C486328:HBP1 protein, human; D006609:High Mobility Group Proteins; D012097:Repressor Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: HBP1; Wnt signaling; histone methylation; p21; p53; senescence; tumorigenesis; ubiquitylation (ubiquitination)