PPM1D controls nucleolar formation by up-regulating phosphorylation of nucleophosmin.
An increase of nucleolar number and size has made nucleoli essential markers for cytology and tumour development. However, the underlying basis for their structural integrity and abundance remains unclear. Protein phosphatase PPM1D was found to be up-regulated in different carcinomas including breast cancers. Here, we demonstrate for the first time that PPM1D regulates nucleolar formation via inducing an increased phosphorylation of the nucleolar protein NPM. We show that PPM1D overexpression induces an increase in the nucleolar number regardless of p53 status. We also demonstrated that specific sequential phosphorylation of NPM is important for nucleolar formation and that PPM1D is a novel upstream regulator of this phosphorylation pathway. These results enhance our understanding of the molecular mechanisms that govern nucleoli formation by demonstrating that PPM1D regulates nucleolar formation by regulating NPM phosphorylation status through a novel signalling pathway, PPM1D-CDC25C-CDK1-PLK1.
Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan.
Yuuki
Y
Kozakai
Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan.
Rui
R
Kamada
Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan.
Junya
J
Furuta
Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan.
Yuhei
Y
Kiyota
Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan.
Yoshiro
Y
Chuman
Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Japan.
Kazuyasu
K
Sakaguchi
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016203:CDC2 Protein Kinase / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002466:Cell Nucleolus / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D020687:cdc25 Phosphatases / Q000235:genetics; D000097869:Polo-Like Kinase 1
D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D020687:cdc25 Phosphatases; D000097869:Polo-Like Kinase 1; C000716967:NPM1 protein, human; C495901:TP53 protein, human; C528899:CDK1 protein, human; C000607458:PPM1D protein, human; C517009:CDC25C protein, human