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Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037 [C. H. S., H. S., O. S., S. I. R.]; Department of Obstetrics and Gynecology, University of Innsbruck, A-6020 Innsbruck, Austria [H. M. M., M. H., E. M-H., C. M., M. W.]; and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089 [M. W.]
Cyclin-dependent kinase 2 activated by cyclin E is involved in the initiationof DNA replication and other S phase functions. Consistent with this role, cyclin E protein accumulates at the G1-S phase transition and declines during early S phase. This profile of expression is the result of periodic transcription and ubiquitin-mediated proteolysis directed by SCFhCdc4. However, in many types of human tumors cyclin E protein is elevated and deregulated relative to the cell cycle by an unknown mechanism. Here, we show that the F-box protein hCdc4 that targets cyclin E to the SCF (Skp1-Cull-F-box) protein ubiquitin ligase is mutated in at least 16% of human endometrial tumors. Mutations were found either in the substrate-binding domain of the protein or at the amino terminus, suggesting a critical role for the region of hCdc4 upstream of the F-box. hCDC4 gene mutations were accompanied by loss of heterozygosity and correlated with aggressive disease. The hCDC4 gene is localized to chromosome region 4q32, which is deleted in over 30% of human tumors. Our results show that the hCDC4 gene is mutated in primary human tumors and suggest that it may function as a tumor suppressor in the genesis of many human cancers.
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