p27Kip1 and cyclin D1 are necessary for focal adhesion kinase regulation of cell cycle progression in glioblastoma cells propagated in vitro and in vivo in the scid mouse brain

Qiang Ding, J. Robert Grammer, Mark A. Nelson, Jun Lin Guan, Jerry E. Stewart, Candece L. Gladson

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

We have reported previously that the expression of focal adhesion kinase (FAK) is elevated in glioblastomas and that expression of FAK promotes the proliferation of glioblastoma cells propagated in either soft agar or in the C.B.17 severe combined immunodeficiency (scid) mouse brain. We therefore determined the effect of FAK on cell cycle progression in these cells. We found that overexpression of wild-type FAK promoted exit from G1 in monolayer cultures of glioblastoma cells cefls, enhanced the expression of cyclins D1 and E while reducing the expression of p27Kip1 and p21Waf1, and enhanced the kinase activity of the cyclin D1-cyclin-dependent kinase-4 (cdk4) complex. Transfection of the monolayers with a FAK molecule in which the autophosphorylation site is mutated (FAK397F) inhibited exit from G1 and reduced the expression of cyclins D1 and E while enhancing the expression of p27Kip1 and p21Waf1. Small interfering RNA (siRNA)-mediated down-regulation of cyclin D1 inhibited the enhancement of cell cycle progression observed on expression of wild-type FAK, whereas siRNA-mediated down-regulation of cyclin E had no effect. siRNA-mediated down-regulation of p27Kip1 overcame the inhibition of cell cycle progression observed on expression of FAK397F, whereas down-regulation of p21Waf1 had no effect. These results were confirmed in vivo in the scid mouse brain xenograft model in which propagation of glioblastoma cells expressing FAK397F resulted in a 50% inhibition of tumor growth and inhibited exit from G1. Taken together, our results indicate that FAK promotes proliferation of glioblastoma cells by enhancing exit from G1 through a mechanism that involves cyclin D1 and p27 Kip1.

Original languageEnglish (US)
Pages (from-to)6802-6815
Number of pages14
JournalJournal of Biological Chemistry
Volume280
Issue number8
DOIs
StatePublished - Feb 25 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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