hCDC4 gene mutations in endometrial cancer.
Cyclin-dependent kinase 2 activated by cyclin E is involved in the initiation of 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 SCF(hCdc4). 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.
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Charles H
CH
Spruck
Heimo
H
Strohmaier
Olle
O
Sangfelt
Hannes M
HM
Müller
Michael
M
Hubalek
Elisabeth
E
Müller-Holzner
Christian
C
Marth
Martin
M
Widschwendter
Steven I
SI
Reed
D000230:Adenocarcinoma / Q000235:genetics*; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000235:genetics*; D019927:Cyclin E / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics*; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases
D018797:Cell Cycle Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044767:Ubiquitin-Protein Ligases