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A p18 Mutant Defective in CDK6 Binding in Human Breast Cancer Cells¹

Laboratory of Molecular Endocrinology, CHUL Research Center and Laval University, 2705 Laurier Boulevard, Ste-Foy, Quebec G1V 4G2, Canada

Progression from G₁ to the S-phase of the cell cycle is controlled by a family of low molecular weight cyclin-dependent kinase (CDK) inhibitors. The importance of these proteins in cell growth control is underscored by the observation that some members of this family are deleted or mutated in human cancers. For example, the gene encoding the CDK inhibitor p18 is located on a segment of chromosome 1 that is often abnormal in human breast tumors. We have identified an alanine to proline substitution at codon 72 of the p18 gene in BT-20 human breast cancer cells. This mutation abrogates the ability of p18 to interact with CDK6 and renders p18 deficient in suppressing cell growth in a colony formation assay. Our results suggest that p18 inactivation by point mutations may contribute to deregulated growth control in certain cell lines and/or tumors.

¹ This work was supported by a grant from the Canadian Breast Cancer Research Initiative to C. L. and a scholarship from the Fonds de la Recherche en Santé du Québec to C. L. Additional financial support was provided by Endorecherche. J. L. was supported in part by the Fonds de la Recherche en Santé du Québec.

² To whom requests for reprints should be addressed. Phone: (418) 654-2296; Fax: (418) 654-2761; E-mail: Claude.Labrie@crchul.ulaval.ca.

Received 7/11/96. Accepted 8/29/96.

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