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Cowden’s Disease and PTEN

Cowden’s Disease and PTEN. Cowden’s Disease (CD). A rare autosomal dominant disease similar to Lehrmitte-Duclos Disease (LDD) and Bannayan-Zonana Syndrome (BZS)

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Cowden’s Disease and PTEN

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  1. Cowden’s Disease and PTEN

  2. Cowden’s Disease (CD) • A rare autosomal dominant disease similar to Lehrmitte-Duclos Disease (LDD) and Bannayan-Zonana Syndrome (BZS) • Common features: (i) benign tumors (usually hamartomas) in various tissues, (ii) increased hand and foot size, (iii) a predisposition to cancer

  3. Cowden’s Disease – continued…

  4. Cowden’s Disease – continued… • More than 80% of patients with CD, LDD, or BZS show germline mutations in PTEN • Based on these symptoms, PTEN is probably involved in regulating… • Growth!

  5. PTEN – The Basics • Phosphatase and tensin homolog on chromosome ten

  6. PTEN Crystal Structure

  7. PTEN Biochemistry • A protein and lipid tyrosine phosphatase in vitro • In the cell its primary substrate is the lipid phosphatidylinositol (3, 4, 5) triposphate (a.k.a. PIP3). • It acts as an antagonist of PI3kinase (a.k.a. PI3K), which phosphorylates PIP2.

  8. PTEN Pathway – The Short Version

  9. PTEN Pathway – Introducing AKT

  10. PTEN and Cancer • Inactivation of one allele creates an environment conducive to tumor growth. • Tumor Suppressor • Next comes LOH, which is seen in 25 – 50% of all primary tumors. • Mutations of both alleles are found in most types of cancer. • Only p53 is mutated more frequently

  11. PTEN and Cancer – continued… • PTEN loss of function mutations occur often in glioblastoma, late stage prostate cancer, and endometrial cancer. • For other cancers complete loss of PTEN function usually occurs in late stage tumors.

  12. PTEN and Cancer – continued…

  13. Model Organisms • PTEN -/- is embryonic lethal in mice • PTEN +/- mice, including ES chimeras, displayed intestinal polyps and increased skin thickness, similar to symptoms of CD, LDD, and ZBS. • Malignant tumors were also found in several PTEN +/- mice at a young age

  14. Model Organisms – continued…

  15. Model Organisms – continued…

  16. PTEN – Additional Effects • So far we’ve focused on growth, but there’s more… • “PTEN has been shown to influence growth, survival, cell cycle progression, cell motility and migration and angiogenesis…”

  17. PTEN – Additional Effects

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