title: BMI1, a new target of CK2α.
abstract: The polycomb group protein, BMI1 plays important roles in chromatin modification, stem cell function, DNA damage repair and mitochondrial bioenergetics. Such diverse cellular functions of BMI1 could be, in part, due to post-translational modifications, especially phosphorylation. To date, AKT has been reported as a kinase that by site specific phosphorylation of BMI1 modulates its oncogenic functions.
  
  
  
  Immunoprecipitation in conjunction with kinase assay and mass spectrometry was used to determine association with and site specific phosphorylation of BMI1 by CK2α. Functional implications of the BMI1/CK2α axis was examined in cancer cells utilizing siRNA and exogenous gene expression followed by biochemical and phenotypic studies. Correlations between expression of CK2α and BMI1 were determined from cell lines and formalin fixed paraffin embedded tissues representing the normal fallopian tube epithelium and high grade serous ovarian cancer samples.
  
  
  
  Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. In ovarian cancer cell lines, expression of CK2α correlated with the phospho-species, as well as basal BMI1 levels. Preventing phosphorylation of BMI1 at Serine 110 significantly decreased half-life and stability of the protein. Additionally, re-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function. Clinically, compared to normal fallopian tube epithelial tissues, the expression of both BMI1 and CK2α were significantly higher in tumor tissues obtained from high-grade serous ovarian cancer patients. Among tumor samples, the expression of BMI1 and CK2α positively correlated (Spearman coefficient = 0.62, P = 0.0021) with each other.
  
  
  
  Taken together, our findings establish an important regulatory role of CK2α on BMI1 phosphorylation and stability and implicate the CK2α/BMI1 axis in ovarian cancer.
authors.affiliation: Peggy and Charles Stephenson Cancer Center (OUHSC), University of Oklahoma Health Science Center, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK, 73104, USA.|Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors.forename: Soumyajit
authors.initials: S
authors.lastname: Banerjee Mustafi
authors.affiliation: Peggy and Charles Stephenson Cancer Center (OUHSC), University of Oklahoma Health Science Center, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK, 73104, USA.|Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors.forename: Prabir Kumar
authors.initials: PK
authors.lastname: Chakraborty
authors.affiliation: Peggy and Charles Stephenson Cancer Center (OUHSC), University of Oklahoma Health Science Center, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK, 73104, USA.|Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors.forename: Shailendra Kumar Dhar
authors.initials: SK
authors.lastname: Dwivedi
authors.affiliation: Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ding
authors.affiliation: Peggy and Charles Stephenson Cancer Center (OUHSC), University of Oklahoma Health Science Center, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK, 73104, USA.|Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Moxley
authors.affiliation: Peggy and Charles Stephenson Cancer Center (OUHSC), University of Oklahoma Health Science Center, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK, 73104, USA.|Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
authors.forename: Priyabrata
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: Peggy and Charles Stephenson Cancer Center (OUHSC), University of Oklahoma Health Science Center, 975 NE 10th Street, BRC-1409B, Oklahoma City, OK, 73104, USA. Resham-Bhattacharya@ouhsc.edu.|Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA. Resham-Bhattacharya@ouhsc.edu.|Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA. Resham-Bhattacharya@ouhsc.edu.
authors.forename: Resham
authors.initials: R
authors.lastname: Bhattacharya
mesh_terms: D047390:Casein Kinase II / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D015398:Signal Transduction
chemical_list: C069077:BMI1 protein, human; D063150:Polycomb Repressive Complex 1; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; D048054:Mitogen-Activated Protein Kinase 7
keywords: Clonal growth; Fallopian tube epithelial (FTE) cells; Formalin fixed paraffin embedded tissues (FFPE); High-grade serous ovarian cancer; Kinase assay; Phosphorylation; Post translational modification; Protein stability