Pilot Project Abstract - Gary Thomas, PhD

Gary Thomas, PhD, Senior Scientist of the Vollum Institute at OHSU: “Role of PACS-2 in colorectal cancer”

The long-range goal of this research is to determine the role of the novel sorting protein PACS-2 in regulating apoptosis and colorectal cancer, a leading cause of cancer death in the United States. Colorectal cancer results from genetic instability that stimulates tumorigenesis by dysregulating proliferative and apoptotic genes, but the molecular details of this transformation pathway remain elusive. We recently reported PACS-2 is a multifunctional protein that integrates endoplasmic reticulum (ER) trafficking with apoptotic pathways. PACS-2 function is lost in up to 40% of sporadic colorectal cancers. In healthy cells, PACS-2 regulates ER trafficking, but our preliminary data show that in response to apoptotic inducers, PACS-2 binds to proapoptotic Bcl2-family members and translocates them to mitochondria to trigger apoptosis. The goal of this proposal is to determine the extent to which the loss of PACS-2 contributes to the onset and severity of colorectal cancer. We hypothesize that the dysregulated expression of PACS-2 accelerates tumorigenesis in colorectal cancer. Studies in Aim 1 will determine when PACS-2 is lost during the adenoma-carcinoma sequence whereas studies in Aim 2 will determine the effect of targeted disruption of the mouse PACS-2 gene on the onset and severity of adenocarcinomas. Successful completion of our studies will illuminate how loss of PACS-2 contributes to colorectal cancer.

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