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The Ras-superfamily G-proteins play critical roles in cell growth and differentiation. Our research focuses on two members, Ras and Rheb. Ras is mutated in a wide range of human cancer including pancreatic, lung and colon cancers. This GTPase plays a central role in the growth factor signal transduction that is initiated by the activation of a receptor tyrosine kinase and results in the activation of multiple downstream pathways such as the Raf/Mek/Erk. Rheb is a novel and unique member of the Ras superfamily G-proteins. 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, regulation of cell cycle and nutrient uptake. Rheb is a component of the TSC/TOR/S6K signaling pathway and is a direct activator of TOR. 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 a 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. Both Ras and Rheb proteins are farnesylated, and the farnesylation is critical for their function. In particular, membrane association and transforming activity of Ras is dependent on its farnesylation. This led to the development of small molecule inhibitors of protein farnesyltransferase. These inhibitors, called FTIs, have recently been evaluated as anti-cancer drugs. FTIs block anchorage-independent growth of a wide variety of human cancer cells and animal studies have shown that FTIs inhibit the growth of tumors or even regress tumor growth. Our study focuses on the mechanism how FTI affects human cancer cells.
The Ras-superfamily G-proteins play critical roles in cell growth and differentiation. Our research focuses on two members, Ras and Rheb. Ras is mutated in a wide range of human cancer including pancreatic, lung and colon cancers. This GTPase plays a central role in the growth factor signal transduction that is initiated by the activation of a receptor tyrosine kinase and results in the activation of multiple downstream pathways such as the Raf/Mek/Erk. Rheb is a novel and unique member of the Ras superfamily G-proteins. 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, regulation of cell cycle and nutrient uptake. Rheb is a component of the TSC/TOR/S6K signaling pathway and is a direct activator of TOR. 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 a 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. Both Ras and Rheb proteins are farnesylated, and the farnesylation is critical for their function. In particular, membrane association and transforming activity of Ras is dependent on its farnesylation. This led to the development of small molecule inhibitors of protein farnesyltransferase. These inhibitors, called FTIs, have recently been evaluated as anti-cancer drugs. FTIs block anchorage-independent growth of a wide variety of human cancer cells and animal studies have shown that FTIs inhibit the growth of tumors or even regress tumor growth. Our study focuses on the mechanism how FTI affects human cancer cells.
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biorxiv(2023)
Nanoscale advancesno. 9 (2023): 2537-2546
crossref(2023)
crossref(2023)
John D. Short,Kevin D. Houston,Ruhee Dere,Sheng-Li Cai,Jinhee Kim, Charles L. Johnson,Russell R. Broaddus,Jianjun Shen, Susie Miyamoto,Fuyuhiko Tamanoi,David Kwiatkowski,Gordon B. Mills,
crossref(2023)
Impactno. 2 (2022): 15-17
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The Enzymes (2022): 1-10
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