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Molecular and Cellular Biology, April 2003, p. 2530-2542, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2530-2542.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Dissecting the Contribution of p16INK4A and the Rb Family to the Ras Transformed Phenotype

Philip J. Mitchell, Elena Perez-Nadales, Denise S. Malcolm, and Alison C. Lloyd*

MRC Laboratory for Molecular Cell Biology and Department of Biochemistry, University College London, London WC1E 6BT, United Kingdom,

Received 18 July 2002/ Returned for modification 11 September 2002/ Accepted 19 December 2002

Although oncogenic Ras commonly contributes to the development of cancer, in normal primary cells it induces cell cycle arrest rather than transformation. Here we analyze the additional genetic changes required for Ras to promote cell cycle progression rather than arrest. We show that loss of p53 is sufficient for oncogenic Ras to stimulate proliferation in the absence of extrinsic mitogens in attached cells. However, surprisingly, we find that p53 loss is not sufficient for Ras to overcome anchorage dependence or contact inhibition. In contrast, expression of simian virus 40 (SV40) large T antigen (LT) allows Ras to overcome these additional cell cycle controls. Mutational analysis of SV40 LT shows that this action of SV40 LT depends on its ability to inactivate the retinoblastoma (Rb) family of proteins, in concert with the loss of p53. Importantly, we show that inactivation of the Rb family of proteins can be mimicked by loss of the cyclin-dependent kinase inhibitor p16INK4A. p16INK4A is commonly lost in human tumors, but its contribution to the transformed phenotype is unknown. We demonstrate here a role for p16INK4A in the loss of cell cycle controls required for tumorigenesis and show how accumulating genetic changes cooperate and contribute to the transformed phenotype.

* Corresponding author. Mailing address: MRC Laboratory for Molecular Cell Biology and Department of Biochemistry, University College London, Gower Street, London WC1E 6BT, United Kingdom. Phone: 44-207-679-2240. Fax: 44-207-679-7805. E-mail: alison.lloyd{at}ucl.ac.uk.

Molecular and Cellular Biology, April 2003, p. 2530-2542, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2530-2542.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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