Signal Transduction: The Ras superfamily G-proteins function as a molecular switch to regulate signaling pathways. Currently, we are investigating a unique subfamily called Rheb G-protein. Initially, Rheb was found in brain, but was later found to be ubiquitously expressed. We have identified Rheb homologues in a number of organisms including fruit fly and yeasts, and defined unique features of this family of G-protein. Genetic studies using fission yeast as well as Drosophila showed that Rheb plays critical roles in cell growth and regulation of cell cycle at the G1/S boundary. In addition, yeast Rheb regulates amino acid uptake. The effect of Rheb on cell growth is mediated by its role in the activation of the TOR/S6K signaling pathway. Rheb is downregulated by Tsc1/Tsc2 complex that acts as a GTPase activating protein (GAP) for Rheb. Mutations in the Tsc1 or Tsc2 gene leads to genetic disorder called tuberous sclerosis that is associated with the appearance of benign tumors at multiple sites in the body. Our current effort is aimed at defining proteins involved in the Rheb signaling pathway.
Nanodelivery of anticancer drugs: Another research interest of our lab is utilization of silica nanoparticles for controllable drug delivery system for cancer therapy. One of the major problems in clinical use of anti-cancer drugs is that many of them are hydrophobic, which poses a critical obstacle for cancer therapy. We have used mesoporous silica nanoparticles prepared in the presence of surfactants. These nanoparticles have the diameter of approximately 130 nm and contain thousands of pores whose diameter is about 3 nm. We incorporated different hydrophobic anticancer drugs, such as camptothecin (CPT) and taxol, into the pores of the mesoporous silica nanoparticles and delivered the drug to a variety of human cancer cells. This caused cell death. We are also exploring ways to use molecular valves to carry out controlled release of anti-cancer drugs with the mesoporous silica nanoparticles. One approach is to use molecules that change conformation by light exposure to accomplishcontrolled delivery. Targeting to cancer by attaching ligands specific to cancer cells is currently being investigatedin our lab.
Protein lipidation and prenyltransferase inhibitors: Protein prenylation is aposttranslational modification of proteins involving the addition of isoprenoids, intermediates in cholesterol biosynthesis. Two types of modification, farnesylation and geranylgeranylation, occur with a variety of proteins. Farnesylation is of particular interest, since many of these farnesylated proteins are involved in signal transduction. Farnesylated proteins include Ras superfamily G-proteins as well as tyrosine phosphatases. Farnesylation is catalyzed by protein farnesyltransferase which recognizes the CysAAX motif at the C-termini of substrate proteins and transfers a farnesyl group forming a thioether bond. This heterodimeric enzyme is conserved from yeast to human, and their genes have been identified in a variety of organisms. Small molecule inhibitors of protein farnesyltransferase have been studied. These inhibitors, called FTIs, block anchorage-independent growth of a wide variety of human cancer cells. A number of animal studies have shown that FTIs inhibit the growth of tumors or even regress tumor growth and clinical trials of FTIs are ongoing. Our study focuses on the mechanism how FTI affects human cancer cells. More recently, we have also identified small molecule inhibitors of protein geranylgeranyltransferase I. These compounds are identified from a novel library of allenoate derived compounds. Our GGTIs inhibit proliferation of human cancer cell lines causing G1 cell cycle arrest.