title: Regulation of glioblastoma progression by cord blood stem cells is mediated by downregulation of cyclin D1.
abstract: BACKGROUND
  The normal progression of the cell cycle requires sequential expression of cyclins. Rapid induction of cyclin D1 and its associated binding with cyclin-dependent kinases, in the presence or absence of mitogenic signals, often is considered a rate-limiting step during cell cycle progression through the G(1) phase.
  
  
  RESULTS
  In the present study, human umbilical cord blood stem cells (hUCBSC) in co-cultures with glioblastoma cells (U251 and 5310) not only induced G(0)-G(1) phase arrest, but also reduced the number of cells at S and G(2)-M phases of cell cycle. Cell cycle regulatory proteins showed decreased expression levels upon treatment with hUCBSC as revealed by Western and FACS analyses. Inhibition of cyclin D1 activity by hUCBSC treatment is sufficient to abolish the expression levels of Cdk 4, Cdk 6, cyclin B1, β-Catenin levels. Our immuno precipitation experiments present evidence that, treatment of glioma cells with hUCBSC leads to the arrest of cell-cycle progression through inactivation of both cyclin D1/Cdk 4 and cyclin D1/Cdk 6 complexes. It is observed that hUCBSC, when co-cultured with glioma cells, caused an increased G(0)-G(1) phase despite the reduction of G(0)-G(1) regulatory proteins cyclin D1 and Cdk 4. We found that this reduction of G(0)-G(1) regulatory proteins, cyclin D1 and Cdk 4 may be in part compensated by the expression of cyclin E1, when co-cultured with hUCBSC. Co-localization experiments under in vivo conditions in nude mice brain xenografts with cyclin D1 and CD81 antibodies demonstrated, decreased expression of cyclin D1 in the presence of hUCBSC.
  
  
  CONCLUSIONS
  This paper elucidates a model to regulate glioma cell cycle progression in which hUCBSC acts to control cyclin D1 induction and in concert its partner kinases, Cdk 4 and Cdk 6 by mediating cell cycle arrest at G(0)-G(1) phase.
authors: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois, United States of America.
authors: Kiran Kumar
authors: KK
authors: Velpula
authors: Venkata Ramesh
authors: VR
authors: Dasari
authors: Andrew J
authors: AJ
authors: Tsung
authors: Christopher S
authors: CS
authors: Gondi
authors: Jeffrey D
authors: JD
authors: Klopfenstein
authors: Sanjeeva
authors: S
authors: Mohanam
authors: Jasti S
authors: JS
authors: Rao
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D056744:Cyclin B1 / Q000235:genetics; D019938:Cyclin D1 / Q000378:metabolism*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: C534699:CCNB1 protein, human; C475820:CCNE1 protein, human; D056744:Cyclin B1; D019927:Cyclin E; D015513:Oncogene Proteins; D019938:Cyclin D1; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6