2- cdc4 and cycE

2- cdc4 and cycE - Oncogene (2004) 23, 41874192 & 2004...

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Cyclin E dysregulation and chromosomal instability in endometrial cancer Michael M Hubalek 1,6 , Andreas Widschwendter 1,6 , Martin Erdel 2 , Andreas Gschwendtner 3 , Heidi M Fiegl 1 , Hannes M Mu ¨ ller 1 , Georg Goebel 4 , Elisabeth Mueller-Holzner 1 , Christian Marth 1 , Charles H Spruck 5,7 , Steven I Reed 5 and Martin Widschwendter* ,1 1 Department of Obstetrics and Gynecology, Innsbruck University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria; 2 Institut for Medical Biology and Human Genetics, University of Innsbruck, A-6020 Innsbruck, Austria; 3 Department for Pathology, University of Innsbruck, A-6020 Innsbruck, Austria; 4 Department of Biostatistics and Documentation, University of Innsbruck, A-6020 Innsbruck, Austria; 5 Department for Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA Deregulation of cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), has been associated with a broad spectrum of human malignancies. Yet the mechanism linking abnormal cyclin E expression to carcinogenesis is largely unknown. The gene encoding the F-box protein hCdc4, a key component of the molecular machinery that targets cyclin E for degradation, is frequently mutated in endometrial cancer, leading to deregulation of cyclin E expression. Here we show that hCDC4 gene mutation and hyperphosphorylation of cyclin E, a parameter that usually correlates with hCDC4 mutation, have a strong statistically signi±cant association with polypoidy and aneuploidy in endometrial cancer. On the contrary, elevated expression of cyclin E by itself was not signi±cantly correlated with polyploidy or aneuploidy when tumors of similar grade are evaluated. These data suggest that impairment of cell cycle regulated proteolysis of cyclin E may be linked to carcinogenesis by promoting genomic instability. Oncogene (2004) 23, 4187–4192. doi:10.1038/sj.onc.1207560 Published online 29 March 2004 Keywords: cyclin E; dysregulation; chromosomal in- stability; endometrial cancer Cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), is a critical regulator of the G 1 –S phase transition in mammalian cells. Although the substrates of cyclin E/Cdk2 are not well de±ned, the kinase complex has been shown to regulate a number of important S phase processes such as pRb phosphoryla- tion, histone biosynthesis, and pre-replication complex assembly (Reed, 1996; Ekholm and Reed, 2000). In normal cells, cyclin E protein levels are periodic, peaking at the G 1 /S phase boundary and declining once an S phase program is initiated. The decline of cyclin E protein level occurs through a combination of down- regulation of cyclin E transcription and ubiquitin- mediated proteolysis of cyclin E protein (Clurman et al ., 1996; Won and Reed, 1996; Reed, 1997). Proteolysis is initiated by auto-phosphorylation of either residue Thr62 or Thr380 by its catalytic partner Cdk2 (Strohmaier et al ., 2001). Phosphorylated cyclin E is then targeted for ubiquitylation by a ligase belonging to the SCF family. SCF ligases are composed of an invariable core of Skp1, Cul1 (Cdc53), and Roc1, bound to one of several F-box proteins that provide substrate speci±city. Recently, the F-box protein that targets
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2- cdc4 and cycE - Oncogene (2004) 23, 41874192 & 2004...

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