Proteasome-dependent Degradation of Transcription Factor Activating Enhancer-binding Protein 4 (TFAP4) Controls Mitotic Division

Background: TFAP4 is a transcription factor that controls cell proliferation, stemness and epithelial-mesenchymal transition and is up-regulated in colorectal cancer. Results: TFAP4 is targeted for degradation by the SCFTrCP ubiquitin ligase. Failure to degrade TFAP4 leads to aberrant mitosis. Conclusion: TFAP4 degradation is required for the fidelity of mitosis. Significance: Misregulation of TFAP4 might contribute to genomic instability and tumorigenesis. TFAP4, a basic helix-loop-helix transcription factor that regulates the expression of a multitude of genes involved in the regulation of cellular proliferation, stemness, and epithelial-mesenchymal transition, is up-regulated in colorectal cancer and a number of other human malignancies. We have found that, during the G(2) phase of the cell division cycle, TFAP4 is targeted for proteasome-dependent degradation by the SCFTrCP ubiquitin ligase. This event requires phosphorylation of TFAP4 on a conserved degron. Expression of a stable TFAP4 mutant unable to interact with TrCP results in a number of mitotic defects, including chromosome missegregation and multipolar spindles, which eventually lead to the activation of the DNA damage response. Our findings reveal that TrCP-dependent degradation of TFAP4 is required for the fidelity of mitotic division