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TSC1/Hamartin and Facial Angiofibromas

TSC1/Hamartin and Facial Angiofibromas. Biology 169 Ann Hau. Overview. Tuberous Sclerosis Complex (TSC) & facial angiofibromas Gene: TSC1 Protein: Hamartin TSC1 mutation and cancer. X. Truncated hamartin TUMOR GROWTH. TSC1 Hamartin. Mutation. Tuberous Sclerosis Complex (TSC).

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TSC1/Hamartin and Facial Angiofibromas

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  1. TSC1/Hamartin and Facial Angiofibromas Biology 169 Ann Hau

  2. Overview • Tuberous Sclerosis Complex (TSC) & facial angiofibromas • Gene: TSC1 • Protein: Hamartin • TSC1 mutation and cancer X Truncated hamartin TUMOR GROWTH TSC1Hamartin Mutation

  3. Tuberous Sclerosis Complex (TSC) • Bourneville’s Disease • Development of multiple hamartomas • Tumor growth in skin, kidneys, brain, heart, eyes, lungs, teeth • Seizures, autism, mental retardation

  4. Tuberous Sclerosis Complex (TSC) • Variable phenotypic manifestations • 1 in 6,000 live births; 1 million people worldwide; 50,000 Americans

  5. Facial Angiofibromas • Manifestation of TSC in skin • Benign tumors of the face • Treat with laser treatment or dermabrasion www.schoolscience.co.uk/.../ mrc/15/page4.html

  6. Mild facial angiofibroma Severe facialangiofibroma www.schoolscience.co.uk/.../ mrc/15/page4.html

  7. Genetics of TSC • Autosomal dominant disorder • Mutation via LOH in one of two known tumor suppressor genes • TSC2 on chromosome 16 • TSC1 on chromosome 9 • Transmittance • Genetic inheritance (1/3 of cases) • Spontaneous genetic mutation (2/3 of cases)

  8. TSC1 and RB: Similar LOH at Locus Hereditary TSC: 1/3 of cases Sporadic TSC: 2/3 of cases Lodish, et al. Molecular Cell Biology, 4th ed.

  9. TSC1 Gene • Identification by positional cloning • Location at 9q34 • 23 exons • Encodes hamartin • Homolog of TSC1 transcript in yeast S. pombe van Slegtenhorst, M., et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277: 805-808, 1997.

  10. Hamartin Protein • 1,164 amino acids; 130 kD • Hydrophilic • Transmembrane domain • Coiled-coil region

  11. TSC1/Hamartin: Normal function • Tumor suppressor • Forms a functional complex with TSC2/tuberin in multiple signaling cascades • Regulates growth, proliferation, migration, and differentiation

  12. TSC1/Hamartin: Normal function • Hamartin-tubulin interaction • Hamartin binds to tuberin via coiled-coil domain, inhibits tuberin ubiquitination (Benvenuto et al., 2000) • Hamartin protein expression and hamartin-tubulin interaction detected throughout entire cell cycle (Miloloza, et al. 2000) • Phosphorylation may be key regulatory mechanism controlling TSC1-TSC2 function (Aicher, et al. 2001)

  13. Tee, et al. 2002. Tuberin-hamartin complex and mTOR pathway

  14. TSC:GENES GONE WILD!

  15. Mutations of TSC1 • 32 distinct mutations identified • 30 truncating, 1 missense, 1 splice site mutation • Small deletions, insertions, point mutations • No genomic deletions or genomic rearrangements • Mutated in sporadic bladder tumors (Hornigold, et al. 1999)

  16. TSC Lesions • Shared characteristics • Abnormalities in cell size, number, morphology, and location • Suggests role of TSC genes in proliferation, growth, migration, differentiation

  17. EXPERIMENTALEVIDENCE

  18. What happens when there is no TSC1? • Mutants of TSC1 homolog in S. pombe • Defective uptake of nutrients from environment (van Slegtenhorst, et al. 2004) • Mutants of TSC1 homolog in Drosophila • “Gigas” phenotype: increased cell and organ size; relatively normal differentiation and morphology (Ito, et al. 1999)

  19. Ito, et al. gigas, a Drosophila Homolog of Tuberous Sclerosis Gene Product-2, Regulates the Cell Cycle Cell. Vol 96, 529-539, 19 February 1999

  20. Mouse Models • TSC1 knockout mice via gene targeting (Kobayashi et al. 2001) • TSC1 -/- mutants died around embryonic days 10.5-11.5; growth failure, anaemia • TSC1 +/- mutants developed renal and extrarenal tumors that have a loss of wildtype TSC1 allele

  21. Kobayashi, et al. A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proc. Nat. Acad. Sci. 98: 8762-8767, 2001.

  22. Mouse Models • TSC1 and TSC2 knockouts • Similar phenotypes suggest that a common pathway for TSC1/2 products exists • Heterozygous TSC1 and TSC2 mice have increased astrocyte proliferation: hamartin and tuberin are important growth regulators for astrocytes Uhlmann, E., et al. Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2 +/- cells. Oncogene 21: 4050-4059, 2002.

  23. Summary • TSC pathology implies role of TSC1 in regulating growth, proliferation, differentiation, and migration • TSC1 -/- mice phenotype indicates role in embryonic development of brain • TSC1-TSC2 complex acts as a tumor suppression in the mTOR-S6K pathway

  24. Summary • TSC1 is a negative regulator of growth • TSC1 mutation causes cells to grow faster: increased translation through constitutively active mTOR pathway • Overgrowth of cells leads to growths of TSC; cells are growing when they shouldn’t be!

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