Dissecting the Dual Role of cyclin C in Tumor Suppression

Abstract

Cyclin C has conically been known as a regulator of transcription through its interaction with the CDK8 kinase module (CKM) and the Mediator complex. In response to reactive oxygen species, cyclin C takes on a mitochondrial role, stimulating mitochondrial fission and apoptosis, through its interactions with DRP1 and Bax, respectively. Prior work in our laboratory has identified cyclin C as a tumor suppressor in two murine models of cancer (Thyroid and Pancreatic). In addition, the genomic loci containing cyclin C is lost in many late‐stage cancers. The extent to which the nuclear and mitochondrial roles play in tumor suppression however is unknown. To better understand the significance of these functions on tumor suppression, a system was devised to identify point mutations that separated the transcriptional and mitochondrial function of cyclin C. Using the Sleeping Beauty transposon system, stable cell lines were created by inserting Ccnc variants into Ccnc‐/‐ immortalized mouse embryonic fibroblasts. Cyclin C expression and function were found to be dependent on both promoter choice as well as UTR elements in Ccnc cDNA. Using this expression system, key mutations were found in cyclin C that disabled its transcriptional activity. Going forward these results will be used to address the in‐vivo effects of loss of cyclin C transcriptional activity as it relates to tumor suppression as well as other cellular mechanisms associated with the CKM such as development.