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LKB1 Catalytically Deficient Mutants Enhance Cyclin D1 Expression

Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

Requests for reprints: Paola A. Marignani, Department of Biochemistry and Molecular Biology, Dalhousie University, Sir Charles Tupper Medical Building Room 9F1, Halifax, Nova Scotia, Canada B3H 1X5. Phone: 902-494-6033; Fax: 902-494-1355; E-mail: pmarigna{at}dal.ca.

Mutations in the serine-threonine tumor-suppressor kinase LKB1 are responsible for Peutz-Jeghers syndrome, characterized by hamartomatous proliferation and an increased risk of developing cancer. Mutations in lkb1 have also been identified in sporadic cancers, suggesting a wider role for LKB1 in cancer that is not limited to hamartomatous polyposis syndromes. Here, we show that LKB1 catalytically deficient mutants, when introduced into DLD1p21^–/–p53^–/– colorectal cancer cells, allowed for progression of cells through to S phase of cell cycle and elicited the expression of Rb, cyclin E, and cyclin A2 whereas the introduction of LKB1 lead to G₁ cell cycle arrest independent of p21^WAF/CIP1 and/or p53 expression. Furthermore, we show that LKB1 catalytically deficient mutants activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. In addition to compromising the tumor-suppressor function of LKB1, our findings highlight an emerging role for LKB1 catalytically deficient mutants, a gain of oncogenic properties. [Cancer Res 2007;67(12):5622–7]

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