- TSC-FoxO Signaling Network in Kidney Cancer Development
- The Role of Plk1 in Tuberous Sclerosis Complex
Tuberous Sclerosis Complex (TSC) Syndrome is an autosomal dominant genetic disease characterized by the development of benign tumors, called hamartomas, in multiple organs. Renal complications are a frequent cause of death in patients with TSC. The renal manifestations in TSC patients include the development of renal angiomyolipomas (AMLs), renal cell carcinomas (RCCs), and polycystic kidney disease (PKD). Although great progress has been made in the last decade in the field of TSC, little is known about TSC’s role in renal cancer development, and the cooperative events in TSC-mediated renal tumorigenesis. With funding from an FY09 Career Transition Award, Dr. Boyi Gan aims to elucidate the molecular pathogenesis of TSC-related renal tumorigenesis and to provide novel insights of targeted therapies against renal complications in TSC patients. Dr. Gan’s central hypothesis is that FoxO transcriptional factors play a key role in the molecular pathogenesis of TSC-related renal tumorigenesis. Dr. Gan proposes to (1) determine the mechanism and role of FoxO activation in TSC-deficient cells and renal tumors, (2) investigate the underlying mechanisms by which FoxOs cooperate with the TSC1-TSC2 complex to inhibit mTORC1 signaling, and (3) identify direct FoxO transcriptional targets that contribute to TSC-mediated renal tumorigenesis. Dr. Gan’s research has the potential to advance the understanding of TSC-mediated renal tumorigenesis and to expand drug development for those TSC patients with renal complications.
Tuberous Sclerosis Complex (TSC) is an inherited disorder characterized by seizures, mental retardation, and benign tumors in multiple organs including the brain, kidney, heart, and skin. Worldwide, there are approximately 900,000 patients with TSC, 40,000 of whom are in the United States. TSC is caused by mutations in two genes: TSC1 and TSC2. The rare disorder Lymphangioleiomyomatosis (LAM), which manifests primarily in the lungs and affects exclusively women, is another disease caused by TSC1 and TSC2 mutations.
Loss of TSC1 or TSC2 function leads to uncontrolled cell growth via activation of mTOR, a protein that is sensitive to the antibiotic rapamycin. Clinical trials are underway to determine rapamycin�s potential for the treatment of TSC and LAM. Targeting multiple proteins in the TSC/mTOR pathway may provide additional TSC and LAM treatment options. Plk1, a protein regulating several aspects of cell division, including cytokinesis (the final stage of cell division) may serve as another protein target in TSC and LAM. Recent investigations in the laboratory of Dr. Aristotelis Astrinidis have identified Plk1 to be a new interacting partner of TSC1. His research team has also found that mTOR is activated by Plk1, that cells lacking TSC1 have abnormal cytokinesis, and that Plk1 expression is increased in cells without TSC1 or TSC2 and in samples from LAM patients. With funding from an FY09 Tuberous Sclerosis Research Program Idea Development Award, Dr. Astrinidis proposes to (1) define the pathway leading to mTOR activation by Plk1, (2) investigate the consequences of TSC1 or TSC2 loss in cell division, more specifically cytokinesis, and (3) determine whether targeting Plk1 by specific inhibitors causes death in cells without TSC1 or TSC2. This project will potentially lead to a new preclinical model for TSC treatment.