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Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1

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Title: Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1
Author(s): Velpula, Kiran Kumar; Dasari, Venkata Ramesh; Tsung, Andrew J.; Gondi, Christopher S.; Klopfenstein, Jeffrey D.; Mohanam, Sanjeeva; Rao, Jasti S.
Subject(s): beta catenin dependent kinase breast cancer brain tumors gene therapy bone marrow
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 G1 phase. Methodology/Principal Findings: In the present study, human umbilical cord blood stem cells (hUCBSC) in co-cultures with glioblastoma cells (U251 and 5310) not only induced G0-G1 phase arrest, but also reduced the number of cells at S and G2-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, b-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 G0-G1 phase despite the reduction of G0-G1 regulatory proteins cyclin D1 and Cdk 4. We found that this reduction of G0-G1 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/Significance: 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 G0-G1 phase.
Issue Date: 2011-03-24
Publisher: Public Library of Science
Citation Info: Velpula, K. K., Dasari, V. R., Tsung, A. J., Gondi, C. S., Klopfenstein, J. D., Mohanam, S., & Rao, J. S. 2011. Regulation of Glioblastoma Progression by Cord Blood Stem Cells Is Mediated by Downregulation of Cyclin D1. PLoS One., 6(3): e18017. DOI: 10.1371/journal.pone.0018017
Type: Article
Description: © 2011 Velpula et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The original version is available through the Public Library of Science at DOI: 10.1371/journal.pone.0018017.
ISSN: 1932-6203
Sponsor: The project was supported by Award Number NS057529 (J.S.R.) from the National Institute of Neurological Disorders and Stroke (NINDS).
Date Available in INDIGO: 2011-05-26

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