title: Two ZNF509 (ZBTB49) isoforms induce cell-cycle arrest by activating transcription of p21/CDKN1A and RB upon exposure to genotoxic stress.
abstract: ZNF509 is unique among POK family proteins in that four isoforms are generated by alternative splicing. Short ZNF509 (ZNF509S1, -S2 and -S3) isoforms contain one or two out of the seven zinc-fingers contained in long ZNF509 (ZNF509L). Here, we investigated the functions of ZNF509 isoforms in response to DNA damage, showing isoforms to be induced by p53. Intriguingly, to inhibit proliferation of HCT116 and HEK293 cells, we found that ZNF509L activates p21/CDKN1A transcription, while ZNF509S1 induces RB. ZNF509L binds to the p21/CDKN1A promoter either alone or by interacting with MIZ-1 to recruit the co-activator p300 to activate p21/CDKN1A transcription. In contrast, ZNF509S1 binds to the distal RB promoter to interact and interfere with the MIZF repressor, resulting in derepression and transcription of RB. Immunohistochemical analysis revealed that ZNF509 is highly expressed in normal epithelial cells, but was completely repressed in tumor tissues of the colon, lung and skin, indicating a possible role as a tumor suppressor.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Bu-Nam
authors.initials: BN
authors.lastname: Jeon
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Min-Kyeong
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Jae-Hyeon
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Haemin
authors.initials: H
authors.lastname: An
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Noh
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea.
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Koh
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Plus Project for Medical Science, Severance Biomedical Research Institute, Yonsei University School of Medicine, 50-1, Yonsei-Ro, SeoDaeMun-Gu, Seoul 120-752, Korea mwhur2@yuhs.ac.
authors.forename: Man-Wook
authors.initials: MW
authors.lastname: Hur
mesh_terms: D059447:Cell Cycle Checkpoints; D002460:Cell Line; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D016335:Zinc Fingers; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D020033:Protein Isoforms; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C107961:ZBTB17 protein, human; C000594511:ZBTB49 protein, human