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TSC1 Tuberous Sclerosis 1. Where is TSC1?. TSC1 Pathway. Is a tumor suppressor Part of complex that promotes -growth & proliferation -differentiation -migration. CGM http://www.cgm.cnrsgif.fr/montagne/index_en.html. What’s TSC1/Hamartin?. Localizes TSC2/tuberin
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TSC1 Pathway • Is a tumor suppressor • Part of complex that promotes • -growth & proliferation • -differentiation • -migration CGM http://www.cgm.cnrsgif.fr/montagne/index_en.html
What’s TSC1/Hamartin? • Localizes TSC2/tuberin • In the cytoplasm- peripheral membrane protein • Phosphorylated by… 1. CDK1 2. GSK3β Oncogene 2005 Nature Publishing Group
What’s TSC2/Tuberin? • Regulated through phosphorylation • Forms a heterodimer with TSC1/hemartin • Also located in the Golgi apparatus & nucleus Oncogene 2005 Nature Publishing Group
TSC1/TSC2 complex CGM http://www.cgm.cnrsgif.fr/montagne/index_en.html Oncogene 2005 Nature Publishing Group
What’s Rheb? • Ras homolog enriched in brain • Heterotrimeric G-protein • Activates mTOR by GTP http://www.nature.com/nrd/journal/v4/n12/images/nrd1902-f3.jpg
Rheb in the Pathway CGM http://www.cgm.cnrsgif.fr/montagne/index_en.html Oncogene 2005 Nature Publishing Group
Background on Tuberous Sclerosis the Disease • Germline mutation • Inherited in an autosomal dominant fashion • Highly penetrant • Manifested in early age • Autism or Retardation • Tumors are mostly benign
2.Facial angiofibromas 1. Angiomyolipoma (AML) 3.Brain and skin lesions
TSC1 gone wrong • Nonsense or frameshift mutations • LOH • No response to amino acid starvation • Targets are more phosphorylated • Increased expression of 1. Cyclin D1 2. β-catenin Aberrant migration
How did we know this? • TSC1 mouse knockout • Mutagenesis screens in Drosophila • Biochemical data • In vivo studies with Rapamycin http://www.bio.davidson.edu/Courses/genomics/method/homoimplant.jpg CGM http://www.cgm.cnrsgif.fr/montagne/index_en.html
Some possible treatments • Rapamycin CGM http://www.cgm.cnrsgif.fr/montagne/index_en.html http://www.merckbiosciences.co.uk/sharedimages/calbiochem/spotlights/mTOR_fig2.gif
Unanswered Questions? • How dRHeb regulates Tor-dependent nutrient sensing. • Whether Rheb inhibits other members of the Raf family. • Whether hamartin is important for the function of tuberin as a GAP protein. • Whether differences in the subcellular localization of hamartin/tuberin reflect 1.cell type 2.cell-specific differential localization 3.antibody nonspecificity