hCDC4 gene mutations in endometrial cancer

Area of Science:

• Cell Cycle Regulation
• Cancer Genetics
• Molecular Biology

Background:

• Cyclin E/cyclin-dependent kinase 2 (CDK2) controls DNA replication initiation and S phase progression.
• Cyclin E protein levels are tightly regulated by periodic transcription and SCF(hCdc4)-mediated proteolysis.
• Elevated and deregulated cyclin E protein is observed in many human tumors, but the underlying mechanism is unclear.

Purpose of the Study:

• To investigate the mechanism of cyclin E deregulation in human tumors.
• To determine the role of the F-box protein hCdc4 in tumor development.
• To identify mutations in the hCDC4 gene in human cancers.

Main Methods:

• Analysis of hCDC4 gene mutations in human endometrial tumors.
• Mutation screening in the substrate-binding domain and amino terminus of hCdc4.
• Assessment of loss of heterozygosity and correlation with disease aggressiveness.
• Chromosomal localization of the hCDC4 gene.

Main Results:

• Mutations in the hCDC4 gene were identified in at least 16% of human endometrial tumors.
• Mutations occurred in critical regions of hCdc4, including the substrate-binding domain and amino terminus.
• hCDC4 gene mutations were associated with loss of heterozygosity and more aggressive disease.
• The hCDC4 gene is located on chromosome 4q32, a region frequently deleted in tumors.

Conclusions:

• The hCDC4 gene is frequently mutated in primary human tumors.
• Mutations in hCDC4 disrupt the degradation of cyclin E, contributing to its deregulation.
• hCDC4 functions as a tumor suppressor, and its inactivation plays a role in the genesis of various human cancers.