APC in Cell Cycle and Cancer

  

Anaphase-promoting complex (APC/C), a large multi-subunit enzyme, is a master regulator of cell cycle progression that functions as an ubiquitin E3 ligase for protein destruction by adding ubiquitin to the targeted substrates. The activity of APC fluctuates during the cell cycle, which is controlled by Cdc20 and Cdh1. The major role of APC is to control sister-chromatid separation in mitosis by ungluing the pairs of chromatids through the destruction of securin. Deregulation of sister-chromatid separation usually results in aneuploidy, a hallmark for many types of cancer. In addition, APC in association with Cdh1 regulates G1/S transition by targeting Skp2 for degradation, therefore, preventing premature entry into S phase by orchestrating p27 levels. To thoroughly understand how APC activity is controlled during the cell cycle, we are utilizing FPLC-based protein fractionation approach in combination with Tandem Affinity Purification (TAP) strategy to study the regulation of APC.

Epigenetic studies strongly suggest the role of APC in tumor formation. Mutation or dysfunction in APC subunits such as APC7, Cdc23, Cdc17 and its activator Cdh1 is implicated in breast cancer, colon carcinoma, leukemia as well as lymphoma. To address the underlying mechanism by which malfunction in APC results in tumorigenesis, we are using cancer xenograft mouse model system and tumor tissue arrays to analyze APC in cancer in collaboration with oncologists at the Hillman Cancer Center.