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Carol Lim

Associate Professor of Pharmaceutics and Pharmaceutical Chemistry

B.S. Purdue University

Ph.D. University of California, San Francisco

Research

References

carol.lim@pharm.utah.edu

Carol Lim's Lab Page

Carol Lim's PubMed Literature Search

Research

Subcellular Subcellular mislocalization of proteins constitutes a serious clinical problem that results in diseases that range from metabolic disorders to cancer. Two distinct opportunities are afforded by addressing this clinical need: 1) understanding why protein mislocalization occurs, and 2) establishing therapeutic methodologies to address the consequences. Deliberately changing the subcellular localization of signal transducing proteins involved in disease is a novel approach for therapeutic intervention. Mislocalized proteins are evolving as an important new class of drug targets for treating many diseases, particularly cancer. Mislocalization of proteins such as tumor suppressors and cell cycle regulators result in aberrant functioning of these proteins, leading to disease. Our lab is using signal sequences (both constitutively active, and also "protein switches" regulated by ligand) to control the subcellular location of proteins involved in disease, or to direct a protein to an organelle where it causes cell death. Our current targets involve proteins involved in cancer (either oncogenes or tumor suppressors), where the altered location of these proteins leads to change in function (typically inducing apoptosis), thus representing a new type of therapeutic intervention.

Chronic Myelogenous Leukemia: Change in location of Bcr-Abl from cytoplasm to nucleus converts it from an oncogene to an apoptotic factor: Bcr-Abl is the causative agent of chronic myelogenous leukemia (CML). When Bcr-Abl is found in the cytoplasm of cells, it behaves as an oncogene, but if forced to the nucleus, it becomes an apoptotic factor. CML is a myeloproliferative disorder characterized by increased proliferation of granulocytes and their immature precursors. While Gleevec® (imatinib mesylate), a tyrosine kinase inhibitor that binds to the ATP-binding site of Bcr-Abl is regarded as the first line of treatment, about a third of chronic-phase patients treated with Gleevec® develop resistance to it. Resistance in some cases is the result of point mutations in Bcr-Abl which render Gleevec® unable to bind. Our lab exploring alternative strategies to treat CML, including our ligand responsive "protein switch" constructs to control the subcellular location of Bcr-Abl, and convert Bcr-Abl from an oncogene to an apoptotic factor. Depletion of Bcr-Abl from the cytoplasm by nuclear entrapment of Bcr-Abl can result in apoptosis. If Bcr-Abl can be specifically directed to the nucleus, it can be converted from an oncogene to an apoptotic factor, producing a new treatment modality for CML. Since Bcr-Abl oligomerizes with itself to form active tetramers, nuclear trapping could be achieved by introducing exogenous localization-controllable Bcr-Abl in specific disease producing cells. Upon ligand induction, localization controllable Bcr-Abl will oligomerize with wt Bcr-Abl and will undergo transport to the nucleus, followed by cellular apoptosis. We are also exploring the use of the teramerization motif (coiled-coil domain) as a means to block the activity of Bcr-Abl. Alternative strategies such as these to block Bcr-Abl may prove to be useful therapies for CML.

Simultaneous Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy: The p53 protein plays a pivotal role in suppression of most cancers. Half of all tumors have mutant p53, while inactivity of p53 defines the majority of the remaining cancer cases. Additionally, the apoptotic pathways of p53 have now been clearly delineated. Nuclear accumulation of p53 is essential for its transcriptional activities leading to induction of proteins involved in both the intrinsic and extrinsic apoptotic pathways. Also, p53 triggers a non-transcriptionally mediated intrinsic apoptotic response if delivered to the mitochondria. Indeed, p53 has emerged as a "master switch" for cancer prevention and is being actively pursued as the ultimate cancer therapeutic target. We propose to investigate an improved mechanism for p53 cancer therapy by utilizing a novel dual gene (2-gene) therapy—employing simultaneous nuclear and mitochondrial targeting of p53-- to achieve therapeutically relevant apoptosis in breast cancer cells.

Proteasomal Degradation of Cancer-Causing Proteins: This project focuses on a novel approach to targeting disease-causing proteins, and how they may be specifically degraded intracellularly. These disease causing proteins will be targeted with a system capable of controlled proteasomal degradation. This system is composed of two main components: a domain that interacts with the proteasome degradation pathway and a domain that will specifically and efficiently bind the disease-causing protein. The result will be elimination of the target protein, and the cell will be thus rescued from its deleterious effects. Our first target protein is survivin, a 16.7kDa member of the inhibitor of apoptosis (IAP) family, and is a promising, nearly universal target for cancer. Survivin promotes cancer by inhibiting apoptosis, promoting cell proliferation and enhancing angiogenesis. Survivin is overexpressed in most solid and hematopoietic tumors, but is undetectable in differentiated tissues. With this technology, survivin can be specifically degraded, and normal apoptotic processes will proceed. Removal of an anti-apoptotic protein from cancer cells will result in apoptosis, and thus could be exploited as therapy.

References