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Unformatted text preview: Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease Aristotelis Astrinidis 1 and Elizabeth P Henske* ,1 1 Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA The most exciting advances in the tuberous sclerosis complex (TSC) field occurred in 1993 and 1997 with the cloning of the TSC2 and TSC1 genes, respectively, and in 2003 with the identification of Rheb as the target of tuberins (TSC2) GTPase activating protein (GAP) domain. Rheb has a dual role: it activates mTOR and inactivates B-Raf. Activation of mTOR leads to increased protein synthesis through phosphorylation of p70S6K and 4E-BP1. Upon insulin or growth factor stimulation, tuberin is phosphorylated by several kinases, including AKT/PKB, thereby suppressing its GAP activity and activating mTOR. Phosphorylation of hamartin (TSC1) by CDK1 also negatively regulates the activity of the hamartin/tuberin complex. Despite these biochemical advances, exactly how mutations in TSC1 or TSC2 lead to the clinical manifestations of TSC is far from being understood. Two of the most unusual phenotypes in TSC are the apparent metastasis of benign cells carrying TSC1 and TSC2 mutations, resulting in pulmonary lymphangio- myomatosis, and the ability of cells with TSC1 or TSC2 mutations to differentiate into the separate components of renal angiomyolipomas (vessels, smooth muscle and fat). We will discuss how the TSC signaling pathways are affected by mutations in TSC1 or TSC2 , focusing on how these mutations may lead to the renal and pulmonary manifestations of TSC. Oncogene (2005) 24, 74757481. doi:10.1038/sj.onc.1209090 Keywords: tuberous sclerosis complex; lymphangio- myomatosis; mammalian target of Rapamycin; Rheb; AKT/PKB Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome with a wide spectrum of clinical manifestations, many of which are age-related. It often manifests in early age with infantile seizures and benign cerebral cortical tubers, and patients may have mental retardation and autism. Other brain lesions include subependymal nodules, subependymal giant cell astro- cytomas (SEGAs) and retinal hamartomas. Patients often develop skin lesions, including facial angiofibro- mas, hypomelanotic macules, ungual fibromas and shagreen patches. In the kidney, benign angiomyolipo- mas and cysts occur frequently, and malignant angio- myolipomas and renal cell carcinomas are less common. The brain, skin, and renal manifestations are hallmarks of TSC and can be used as the basis for differential diagnosis. Brain and renal lesions cause the highest mor- bidity and mortality among TSC patients. Heart rhabdo- myomas, often observed in infancy, spontaneously regress. A particularly striking manifestation of TSC is pulmonary lymphangiomyomatosis (LAM). It is observed exclusively in female TSC patients. LAM can also occur in women who do not have TSC (sporadic LAM). LAM is characterized by benign smooth muscle cell proliferation in the lungs, which thicken the alveolar...
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