This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Walter, K. A. Articles by Laterra, J. Search for Related Content PubMed PubMed Citation Articles by Walter, K. A. Articles by Laterra, J.

 Previous Article  |  Next Article 

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

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.

This article has been cited by other articles:

• Reznik, T. E., Sang, Y., Ma, Y., Abounader, R., Rosen, E. M., Xia, S., Laterra, J. (2008). Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor. Mol Cancer Res 6: 139-150 [Abstract] [Full Text]  
• Xia, S., Li, Y., Rosen, E. M., Laterra, J. (2007). Ribotoxic Stress Sensitizes Glioblastoma Cells to Death Receptor Induced Apoptosis: Requirements for c-Jun NH2-Terminal Kinase and Bim. Mol Cancer Res 5: 783-792 [Abstract] [Full Text]  
• Li, Y., Lal, B., Kwon, S., Fan, X., Saldanha, U., Reznik, T. E., Kuchner, E. B., Eberhart, C., Laterra, J., Abounader, R. (2005). The Scatter Factor/Hepatocyte Growth Factor: c-Met Pathway in Human Embryonal Central Nervous System Tumor Malignancy. Cancer Res. 65: 9355-9362 [Abstract] [Full Text]  
• Abounader, R., Laterra, J. (2005). Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro Oncol 7: 436-451 [Abstract]  
• Gao, C.-F., Xie, Q., Su, Y.-L., Koeman, J., Khoo, S. K., Gustafson, M., Knudsen, B. S., Hay, R., Shinomiya, N., Woude, G. F. V. (2005). Proliferation and invasion: Plasticity in tumor cells. Proc. Natl. Acad. Sci. USA 102: 10528-10533 [Abstract] [Full Text]  
• Lal, B., Xia, S., Abounader, R., Laterra, J. (2005). Targeting the c-Met Pathway Potentiates Glioblastoma Responses to {gamma}-Radiation. Clin. Cancer Res. 11: 4479-4486 [Abstract] [Full Text]  
• Hossain, M. A., Russell, J. C., O'Brien, R., Laterra, J. (2004). Neuronal Pentraxin 1: A Novel Mediator of Hypoxic-Ischemic Injury in Neonatal Brain. J. Neurosci. 24: 4187-4196 [Abstract] [Full Text]  
• Bhowmick, N. A., Chytil, A., Plieth, D., Gorska, A. E., Dumont, N., Shappell, S., Washington, M. K., Neilson, E. G., Moses, H. L. (2004). TGF-{beta} Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia. Science 303: 848-851 [Abstract] [Full Text]