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Journal of Virology, June 2004, p. 5720-5727, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5720-5727.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

IGFBP-3, a Marker of Cellular Senescence, Is Overexpressed in Human Papillomavirus-Immortalized Cervical Cells and Enhances IGF-1-Induced Mitogenesis

Astrid C. Baege, Gary L. Disbrow, and Richard Schlegel*

Department of Pathology, Georgetown University Medical Center, Washington, D.C.

Received 26 November 2003/ Accepted 23 January 2004

Human ectocervical cells, following retroviral transduction with the human papillomavirus type 16 E6/E7 oncogenes, are altered in their array of transcribed cellular genes, including increased mRNA for the insulin-like growth factor binding protein 3 (IGFBP-3). IGFBP-3 expression is associated with cellular senescence, and its addition to many cell types inhibits growth or induces apoptosis. By immunoblotting and enzyme-linked immunosorbent assay methods, we demonstrate that late-passage, immortalized E6/E7-transduced cells secrete high levels of IGFBP-3 (25 ng/ml), which represent a 500-fold increase compared to levels in early-passage, nonimmortalized transduced cells (<0.05 ng/ml). Concomitantly, these late-passage cervical cells exhibit an increase in sensitivity to IGF-1, including enhanced phosphorylation of the IGF receptor (IGF-R) and insulin receptor substrate as well as increased DNA synthesis (5-fold) and cell proliferation (3.7-fold). However, there was no change in the level of IGF-R in these cells (surface or total), and the cells did not synthesize IGF-1, indicating that these arms of the IGF pathway were independently regulated and not responsible for the augmented signaling. Consistent with a causal relationship between IGFBP-3 expression and enhanced IGF-1 responses, we found that early-passage cells could be converted to the late-passage, IGF-1-responsive phenotype by preincubation with IGFBP-3. Thus, in contrast to findings with some cell types, IGFBP-3 expression in cervical cells is associated with augmented IGF-1 signaling and cell proliferation and correlates with the timing of cellular immortalization.

* Corresponding author. Mailing address: Department of Pathology, Georgetown University Medical Center, 3900 Reservoir Rd. NW, Washington DC 20057. Phone: (202) 687-7733. Fax: (202) 687-8934. E-mail: schleger{at}georgetown.edu.

Journal of Virology, June 2004, p. 5720-5727, Vol. 78, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.11.5720-5727.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Disbrow, G. L., Baege, A. C., Kierpiec, K. A., Yuan, H., Centeno, J. A., Thibodeaux, C. A., Hartmann, D., Schlegel, R. (2005). Dihydroartemisinin Is Cytotoxic to Papillomavirus-Expressing Epithelial Cells In vitro and In vivo. Cancer Res. 65: 10854-10861 [Abstract] [Full Text]  


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