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Molecular and Cellular Biology, April 2002, p. 2111-2123, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2111-2123.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Enumeration of the Simian Virus 40 Early Region Elements Necessary for Human Cell Transformation

William C. Hahn,1,2 Scott K. Dessain,1,3 Mary W. Brooks,1 Jessie E. King,1 Brian Elenbaas,1,{dagger} David M. Sabatini,1 James A. DeCaprio,2 and Robert A. Weinberg1,4*

Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142,1 Department of Adult Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,2 Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114,3 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 021394

Received 23 October 2001/ Returned for modification 29 November 2001/ Accepted 7 January 2002

While it is clear that cancer arises from the accumulation of genetic mutations that endow the malignant cell with the properties of uncontrolled growth and proliferation, the precise combinations of mutations that program human tumor cell growth remain unknown. The study of the transforming proteins derived from DNA tumor viruses in experimental models of transformation has provided fundamental insights into the process of cell transformation. We recently reported that coexpression of the simian virus 40 (SV40) early region (ER), the gene encoding the telomerase catalytic subunit (hTERT), and an oncogenic allele of the H-ras gene in normal human fibroblast, kidney epithelial, and mammary epithelial cells converted these cells to a tumorigenic state. Here we show that the SV40 ER contributes to tumorigenic transformation in the presence of hTERT and oncogenic H-ras by perturbing three intracellular pathways through the actions of the SV40 large T antigen (LT) and the SV40 small t antigen (ST). LT simultaneously disables the retinoblastoma (pRB) and p53 tumor suppressor pathways; however, complete transformation of human cells requires the additional perturbation of protein phosphatase 2A by ST. Expression of ST in this setting stimulates cell proliferation, permits anchorage-independent growth, and confers increased resistance to nutrient deprivation. Taken together, these observations define the elements of the SV40 ER required for the transformation of human cells and begin to delineate a set of intracellular pathways whose disruption, in aggregate, appears to be necessary to generate tumorigenic human cells.

* Corresponding author. Mailing address: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142. Phone: (617) 258-5159. Fax: (617) 258-5213. E-mail: weinberg{at}wi.mit.edu.

{dagger} Present address: Biogen, Cambridge, MA 02142.

Molecular and Cellular Biology, April 2002, p. 2111-2123, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2111-2123.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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