Regulation and Function of the Mitotic Checkpoint Protein CHFR.

[摘要] Regulation of mitosis through mitotic checkpoints is critical to prevent propagation of DNA damage and to ensure proper DNA content of the resulting daughter cells.Loss of these checkpoint functions may lead to neoplasias or cancers.The protein checkpoint with forkhead associated and RING domains (CHFR) has been implicated as a tumor suppressor in a multitude of cancers.Originally identified as a major component of the antephase checkpoint, CHFR has recently been associated with the spindle assembly checkpoint through its interaction with MAD2.To further understand the role of CHFR in this checkpoint, we deleted key functional domains from the CHFR protein and investigated the effects on MAD2 binding and function.We found that the C-terminal cysteine-rich domain of CHFR is required for the CHFR/MAD2 interaction.In addition, this domain is important for MAD2 localization, interaction with CDC20, and prevention of chromosome segregation defects.These data indicate an important role for CHFR in the function of MAD2 and the spindle assembly checkpoint.CHFR loss is observed in a wide array of cancers, supporting its role as a tumor suppressor.Most often, CHFR is lost via hypermethylation of the CHFRgene promoter.However hypermethylation is not observed in the majority of breast cancers.Using a panel of breast cancer lines we explored the role ofmicroRNA in reducing CHFR levels.We found a correlation between expression of miR-26 and decreased transcription of CHFR, suggesting that this miRNAcould target the CHFR mRNA to reduce protein levels.These data suggest that miR-26 could be useful in the future as a biomarker indicating CHFR protein loss.

[发布机构] University of Michigan

[效力级别] Mitotic Checkpoint

[关键词] CHFR;Mitotic Checkpoint;Breast Cancer;Genetics;Molecular;Cellular and Developmental Biology;Health Sciences;Cell and Developmental Biology