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Molecular and Cellular Biology, April 2003, p. 2859-2870, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2859-2870.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Abolition of Cyclin-Dependent Kinase Inhibitor p16Ink4a and p21Cip1/Waf1 Functions Permits Ras-Induced Anchorage-Independent Growth in Telomerase-Immortalized Human Fibroblasts

Wenyi Wei,1,{dagger} Wendy A. Jobling,1 Wen Chen,2 William C. Hahn,2 and John M. Sedivy1*

Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02912,1 Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 021152

Received 20 September 2002/ Returned for modification 29 October 2002/ Accepted 28 January 2003

Human cells are more resistant to both immortalization and malignant transformation than rodent cells. Recent studies have established the basic genetic requirements for the transformation of human cells, but much of this work relied on the expression of transforming proteins derived from DNA tumor viruses. We constructed an isogenic panel of human fibroblast cell lines using a combination of gene targeting and ectopic expression of dominantly acting mutants of cellular genes. Abolition of p21Cip1/Waf1 and p16Ink4a functions prevented oncogenically activated Ras from inducing growth arrest and was sufficient for limited anchorage-independent growth but not tumorigenesis. Deletion of the tumor suppressor p53 combined with abolition of p16Ink4a function failed to mimic the introduction of simian virus 40 large T antigen, indicating that large T antigen may target additional cellular functions. Ha-Ras and Myc cooperated only to a limited extent, but in the absence of Ras, Myc cooperated strongly with the simian virus 40 small t antigen to elicit aggressive anchorage-independent growth. The experiments reported here further define specific components of human transformation pathways.

* Corresponding author. Mailing address: Department of Molecular Biology, Cell Biology and Biochemistry, J. W. Wilson Laboratory, 69 Brown St., Brown University, Providence, RI 02912. Phone: (401) 863-7631. Fax: (401) 863-9653. E-mail: john_sedivy{at}brown.edu.

{dagger} Present address: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.

Molecular and Cellular Biology, April 2003, p. 2859-2870, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2859-2870.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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