Loss of the PTEN tumor suppressor is frequently associated with the malignant progression of brain tumors. This lipid phosphatase plays a key role in regulating PI3K/Akt signaling which, through TSC2, activates the mTOR/S6K pathway. We recently identified the TSC2 tumor suppressor as a GAP (GTPase activating protein; off switch) for the Ras-like GTPase, Rheb, and demonstrated that Rheb activates the mTOR/ S6K pathway. This suggested that upon PTEN or TSC2 loss, Rheb will become constitutively activated. Indeed, we find Rheb-GTP levels are halved upon re-expression of PTEN in PTEN-deficient glioblastoma cells. Interestingly, Rheb is farnesylated and its biological activity is inhibited by the farnesyl transferase inhibitors (FTIs) previously designed to block Ras action. Our central hypothesis is that deregulated Rheb activity, resulting from PTEN loss, promotes abnormal cell growth that contributes to tumor progression. We further propose that this transforming activity can be attenuated by FTIs. To test this hypothesis, in Aim 1, we will demonstrate that dominant inhibitory Rheb mutants, Rheb RNAi and FTIs can inhibit S6 kinase activation and the proliferation of human glioma cells.
In Aim 2, we will use xenograft and intracranial mouse tumor models to determine the ability of these approaches to inhibit tumor growth.
In Aim 3, we will use our established assays to identify the guanine nucleotide exchange factor (GEF) responsible for turning Rheb on. Identification of this GEF and the pathway that regulates it will provide a better understanding of Rheb's cellular function and identify additional avenues to disrupt its activity. We will also determine if the Rheb-related GTPase, Rheb2, is similarly regulated by TSC2 and GEFs and if it functions in a similar manner to Rheb. Together these studies will provide valuable new information on the mechanisms of Rheb activation and its role in cell growth regulation/ tumorigenesis. They will address the molecular basis of non-Ras action of FTIs and demonstrate the value of targeting Rheb in cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108647-02
Application #
7052093
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Ault, Grace S
Project Start
2005-04-11
Project End
2010-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$231,339
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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