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PTEN (a.k.a. MMAC1 and TEP1)

“ P hosphatase and ten sin homolog on Chromosome ten ”. PTEN (a.k.a. MMAC1 and TEP1). and Cowden’s Disease. Multiple benign growths – hamartomas CD confers an increased susceptibility to malignant carcinomas Breast cancer, thyroid cancers and glioblastoma. Cowden Disease. GLIOBLASTOMA.

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PTEN (a.k.a. MMAC1 and TEP1)

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  1. “Phosphatase and tensin homolog on Chromosome ten” PTEN(a.k.a. MMAC1 and TEP1) and Cowden’s Disease

  2. Multiple benign growths – hamartomas CD confers an increased susceptibility to malignant carcinomas Breast cancer, thyroid cancers and glioblastoma Cowden Disease GLIOBLASTOMA http:www.ncbi.nlm.nih.gov

  3. Cowden Disease • 89% of females with CD get breast hamartomas • 74% develop malignant breast tumors (Schrager et al. 1998) • 50% - 75% of people with CD develop thyroid disease • Prostate Cancer • Loss of PTEN and p27

  4. Discovery of PTEN • In 1996 Cowden Syndrome was mapped to the 10q22-23 • This region is also commonly mutated in thyroid cancers

  5. Phosphatase and Tensin Homologue on Chromosome 10 • Either germline or sporadic mutation • 80% have a germline mutation • PTEN acts as classic tumor suppressor • Inherited as an autosomal dominant trait • Must lose both copies to be affected - Loss of Heterozygosity (LOH) Simpson and Parsons.(2001) Experimental Cell Research 264, 29-41

  6. PTEN is a Phosphatase • High degree of sequence homology with typical protein phosphatase • Postulated dual specificity as a protein and lipid phosphatase

  7. Component of the PIP3/PI3K/AKT pathway NEGATIVE REGULATOR of this pathway Antagonist of cell survival, cell growth, cell cycle and cell migration Phosphatase and Tensin Homologue on Chromosome 10 Waite and Eng.(2002) Am. J. Hum. Genet. 70:829-844

  8. Protein Protein Binding Domain Phosphatase Catalytic Domain Lipid Binding Domain Stability Biochemical Structure and Activity of PTEN N C 403 aa

  9. Biochemical Structure and Function of PTEN Active site of the phosphatase domain

  10. PTEN Intracellular role 1999. Coffee Break. PTEN and the Tumor Suppressor. 1-3

  11. Biochemical Structure and Activity of PTEN Found 8 different mutations in PTEN Protein Protein Binding Domain Phosphatase Catalytic Domain Lipid Binding Domain Stability 186 403 “Hot Spot” – 31% of all mutations G129E 43% of all mutations

  12. PTEN Intracellular role 1999. Coffee Break. PTEN and the Tumor Suppressor. 1-3

  13. Critical Role of Akt SUPPRESSES CELL DEATH!!! Cooper (2000) The CELL a Molecular Approach fig.15.3

  14. Biochemical structure and function of PTEN • Converts PIP3  PIP2 = INACTIVATED • PIP2 can NOT signal AKT = Suppression of GROWTH • Loss of PTEN results in hyper-accumulation of PIP3 • This leads to hyper-activation of AKT • Result = INCREASED GROWTH, DIVISION and the ability to EVADE APOPTOSIS Sulis and Parson(2003) TRENDS in Cell Biology Vol.13:9

  15. Cellular Role of PTEN • Cell Culture: • PTEN -/- mutants – showed a decreased sensitivity to apoptotic signals • These mutants could be rescued by reintroduction of PTEN • Mice Knockouts: • PTEN -/- mutant – LETHAL • PTEN -/+ mutants developed multiple tumors including endometrial, prostate, thyroid and colon Simpson and Parsons (2001) Experimental Cell Research 264, 29-41

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