Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download TSC2 GENE ENCODES FOR TUBERIN
Document related concepts
no text concepts found
Transcript
TSC2 GENE ENCODES FOR TUBERIN By May Doan Content Disease: Tuberous Sclerosis TSC2 Gene Discovered General Roles within the Organism Molecular Roles within the Cell Mutations and Cancer Possible Treatments Summary Disease: Tuberous Sclerosis Autosomal dominant Rare, multisystem disorder Loci assigned at chromosomes 9 and 16 Characterized by: Cortical lesions called tubers Benign tumors called hamartomas arising from the brain, heart, lungs, and kidneys Intractable epilepsy Mental retardation Autism What causes tuberous sclerosis? TSC2 Gene Discovered PFGE: 5 TSC-related deletions were IDed at Chromosome 16. Positional Cloning: These deletions were mapped to a 120kb “candidate region” in which four genes were isolated. One gene, now TSC2, was interrupted in all five deletions. Northen blot analysis identified either shortened transcript or reduced expression in TSC patients. This confirmed that TSC2 (5.5 kb) is the chromosome 16 TSC gene. So what is TSC2? TSC2 is a Tumor Supressor Gene Follows Knudson’s “two-hit” hypothesis Loss of Heterozygosity through various mutations: Germline insertions De novo deletions TSC2 is NOT TSC1 Similarities Differences What does TSC2 do within the organism? General Roles within the Organism Abnormalities Observed in TSC pathology Implied Role of TSC2 Cell size Cell growth Cell number Cell proliferation Morphology Differentiation Location Migration Picture How does TSC-2 function molecularly? What are the mechanisms in which it executes all these roles? TSC2 is a Kinase and Molecular Switch Regulate many biological processes=Participates in many signaling pathways mTOR WNT/B-catenin TSC2tuberin (kinase domain and GAP domain) mTOR Pathway TSC2 a Rheb-GTPase that suppresses mTOR signaling suspends the phosphorylation of p70S6K and 4E-BP1 thereby regulates cell proliferation TSC2 MutationsCancer Mutations on TSC2 gene Tuberin lossof-function Constitutively Active Rheb Hamartomas (as in Tuberous Sclerosis) Uncontrolled Cell Proliferation Activates mTOR Cascade Possible Treatment: Rapamycin Mutations on TSC2 gene Tuberin lossof-function Constitutively Active Rheb Harmatomas (as in Tuberous Sclerosis) Uncontrolled Cell Proliferation Activates mTOR Cascade WEEK 2: extensive tumor cell death DAY 4: reduction in tumor size Additional Comments Have not documented a consistent complete pathologic response to long-term rapamycin treatment. In fact, after two months, there was evidence of active kidney disease. Only short-term clinical efficacy with minimal toxocity. Still issues to be worked out optimal dosing schedule duration of responses potential resistance WNT/B-Catenin Pathway Observations/Correlations CyclinD gene promoter is responsive to the effects of WNT/B-catenin stimulation. CyclinD mRNA is elevated in cortical tumors like hamartomas. inhibition of TSC2 expression by anti-sense oligos was accompanied by increased cyclin D1 protein Conclusion May be a link between the TSC2 and the B-catenin signaling pathway as a possible mechanism of cyclin D1 upregulation in TSC pathology. WNT/Beta-Catenin Pathway Hypothesis: The level of B-catenin is correspondingly up-regulated by increased protein stability Known This places the function of the tuberin at the level of the B-catenin degradation complex. Experiment TSC1/TSC2 act downstream of DSH and upstream of B-catenin. Conclusion Aka: if B-catenin is not degraded, it is overly stable, producing more than normal CyclinD Co-immunoprecipitation analyses showed interaction between TSC2 and GSK3/Akin amount of endogenous GSK3 associated with tuberin in 293 cells was reduced by Wnt stimulation. Conclusion TSC2 binds the GSK3/Axin complex and promotes B-catenin degradation. Upon Wnt stimulation, DSH destabilizes the degradation complex and increases the free B-catenin pool. Summary Tuberous Sclerosis is an autosomal dominant disease characterized by skin lesions and hamartomas. TSC2 was discovered in 1993 through positional cloning. TSC2 regulates many biological processes. TSC2’s protein product, tuberin, is a kinase and molecular switch that participates in many pathways Pathway related to cell proliferation: mTOR Rapamycin has had positive clinical results to treat TSC in rats. Pathway related to cell fate determination and migration: WNT/B-catenin
