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Molecular and Cellular Biology, April 2002, p. 2703-2715, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2703-2715.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Scatter Factor/Hepatocyte Growth Factor Stimulation of Glioblastoma Cell Cycle Progression through G1 Is c-Myc Dependent and Independent of p27 Suppression, Cdk2 Activation, or E2F1-Dependent Transcription

Kevin A. Walter,1 Mir Ahamed Hossain,2,3 Carey Luddy,2 Nidhi Goel,3 Thomas E. Reznik,2 and John Laterra2,3,4,5*

Departments of Neurosurgery,1 Neurology,3 Neuroscience,4 Oncology, The Johns Hopkins University School of Medicine,5 The Kennedy Krieger Institute, Baltimore, Maryland 212052

Received 12 June 2001/ Returned for modification 23 July 2001/ Accepted 3 January 2002

Scatter factor/hepatocyte growth factor (SF/HGF) expression has been linked to malignant progression in glial neoplasms. Using two glioma cell lines, U373MG and SNB-19, we have demonstrated that SF/HGF stimulation allows cells to escape G1/G0 arrest induced by contact inhibition or serum withdrawal. SF/HGF induced effects on two mechanisms of cell cycle regulation: suppression of the cyclin-dependent kinase inhibitor p27 and induction of the transcription factor c-Myc. Regulation of p27 by SF/HGF was posttranslational and is associated with p27 nuclear export. Transient transfections of U373MG and SNB-19 with wild-type p27 and a degradation-resistant p27T187A mutant were insufficient to induce cell cycle arrest, and SF/HGF downregulation of p27 was not necessary for cell cycle reentry. Analysis of Cdk2 kinase activity and p27 binding to cyclin E complexes in the presence of exogenous wild-type p27 or p27T187A demonstrated that Cdk2 activity was not necessary for SF/HGF-mediated G1/S transition. Similarly, overexpression of dominant-negative forms of Cdk2 did not block SF/HGF-triggered cell cycle progression. In contrast, SF/HGF transcriptionally upregulated c-Myc, and overexpression of c-Myc was able to prevent G1/G0 arrest in the absence of SF/HGF. Transient overexpression of MadMyc, a dominant-negative chimera for c-Myc, caused G1/G0 arrest in logarithmically growing cells and blocked SF/HGF-mediated G1/S transition. c-Myc did not exert its effects through p27 downregulation in these cell lines. SF/HGF induced E2F1-dependent transcription, the inhibition of which did not block SF/HGF-induced cell cycle progression. We conclude that SF/HGF prevents G1/G0 arrest in glioma cell lines by a c-myc-dependent mechanism that is independent of p27, Cdk2, or E2F1.

* Corresponding author. Mailing address: Kennedy Krieger Institute, Room 400, 707 N. Broadway, Baltimore, MD 21205. Phone: (443) 923-2679. Fax: (443) 923-2695. E-mail: Laterra{at}kennedykrieger.org.

Molecular and Cellular Biology, April 2002, p. 2703-2715, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2703-2715.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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