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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 - PowerPoint PPT Presentation
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TSC2 GENE ENCODES FOR TUBERIN By May Doan
Content
Disease: Tuberous SclerosisTSC2 Gene DiscoveredGeneral Roles within the Organism
Molecular Roles within the CellMutations and CancerPossible TreatmentsSummary
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 OrganismAbnormalities Observed in TSC pathology
Implied Role of TSC2
Picture
Cell size Cell growth
Cell number Cell proliferation
Morphology Differentiation
Location Migration
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
Possible Treatment: Rapamycin
DAY 4: reduction in tumor size
WEEK 2: extensive tumor cell death
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 up-regulation in TSC pathology.
WNT/Beta-Catenin Pathway
Hypothesis: The level of B-catenin is correspondingly up-regulated by increased protein stability Aka: if B-catenin is not degraded, it is overly stable, producing more
than normal CyclinD Known
TSC1/TSC2 act downstream of DSH and upstream of B-catenin. Conclusion
This places the function of the tuberin at the level of the B-catenin degradation complex.
Experiment 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