title: NuMA is required for the selective induction of p53 target genes.
abstract: The p53 tumor suppressor protein is a transcription factor controlling various outcomes, such as growth arrest and apoptosis, through the regulation of different sets of target genes. The nuclear mitotic apparatus protein (NuMA) plays important roles in spindle pole organization during mitosis and in chromatin regulation in the nucleus during interphase. Although NuMA has been shown to colocalize with several nuclear proteins, including high-mobility-group proteins I and Y and GAS41, the role of NuMA during interphase remains unclear. Here we report that NuMA binds to p53 to modulate p53-mediated transcription. Acute and partial ablation of NuMA attenuates the induction of the proarrested p21 gene following DNA damage, subsequently causing impaired cell cycle arrest. Interestingly, NuMA knockdown had little effect on the induction of the p53-dependent proapoptotic PUMA gene. Furthermore, NuMA is required for the recruitment of cyclin-dependent kinase 8 (Cdk8), a component of the Mediator complex and a promoter of p53-mediated p21 gene function. These data demonstrate that NuMA is critical for the target selectivity of p53-mediated transcription.
authors.affiliation: Division of Cancer Differentiation, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohata
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Otomo
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsushima-Hibiya
authors.forename: Chihiro
authors.initials: C
authors.lastname: Otsubo
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagase
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Arakawa
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.forename: Masato
authors.initials: M
authors.lastname: Enari
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C050045:NUMA1 protein, human; D034521:Nuclear Matrix-Associated Proteins; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D056850:Cyclin-Dependent Kinase 8