tsc2 gene encodes for tuberin n.
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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

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Presentation Transcript
content
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
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
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
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
General Roles within the Organism

How does TSC-2 function molecularly? What are the mechanisms in which it executes all these roles?

tsc2 is a kinase and molecular switch
TSC2 is a Kinase and Molecular Switch
  • Regulate many biological processes=Participates in many signaling pathways
    • mTOR
    • WNT/B-catenin
  • TSC2tuberin (kinase domain and GAP domain)
mtor pathway
mTOR Pathway
  • TSC2
    • a Rheb-GTPase that suppresses mTOR signaling
    • suspends the phosphorylation of p70S6K and 4E-BP1
    • thereby regulates cell proliferation
possible treatment rapamycin
Possible Treatment: Rapamycin

WEEK 2: extensive tumor cell death

DAY 4: reduction in tumor size

additional comments
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
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
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
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