Regulated Intramembrane Proteolysis
“Regulated Intramembrane proteolysis” (RIP) is a conserved, cellular signaling process whereby transmembrane proteins are cleaved within the membrane to generate cytosolic fragments that enter the nucleus to control gene transcription. This mechanism of cellular signaling regulation governs processes such as lipid metabolism, cellular differentiation, and response to unfolded proteins. Originally described for sterol regulatory element binding protein-1 (SREBP-1), the master transcription factor for adipogenesis, it has been found to also regulate notch and activating transcription factor-6 (ATF6), which regulate differentiation and the unfolded protein response (UPR). Interruption of the normal function of these processes can initiate two forms of programmed cell death, apoptosis and autophagy. Our laboratory has been studying approaches to inhibit this process through small molecules and siRNA, to understand the biological consequences in cancer.

Lipogenic Phenotype of Cancer
Sarcomas are a rare type of malignancy, accounting for less than 1% of all cancers. The most common type of soft-tissue sarcoma is liposarcoma, which develops from adipocytic tissue. This type of cancer is inherently resistant to chemotherapy. Importantly, development of a “lipogenic phenotype” in other more common types of cancer is now a recognized process whereby these tumors develop “fat-like” properties that are associated with progressive malignant characteristics as well as resistance to chemotherapy. The fatty acids and lipids generated by the “lipogenic phenotype” provide energy and molecules for membrane biosynthesis in these cancers. Interruption of RIP inhibits RIP and reverses this malignant phenotype. Our laboratory has been studying approaches to inhibit this process through small molecules and siRNA for therapeutic purposes.

High-Throughput Screening
We have begun collaborating with investigators at City of Hope to perform high-throughput screening for novel inhibitors of RIP based upon structure-based inhibitor design and ligand-based inhibitor design. These novel inhibitors will further our basic understanding of RIP, and may eventually serve a therapeutic purpose