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RET

RET. Multiple Endocrine Neoplasia Type 2 (MEN2). Brooke Martin 3/20/08. History of RET. Discovered in 1985 by the transfection of NIH3T3 cells with DNA from T cell lymphoma cells RET stands for re arranged during t ransfection

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RET

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  1. RET Multiple Endocrine Neoplasia Type 2 (MEN2) Brooke Martin 3/20/08

  2. History of RET • Discovered in 1985 by the transfection of NIH3T3 cells with DNA from T cell lymphoma cells • RET stands for • rearranged during transfection • Can have either loss of function or gain of function mutations

  3. RET Properties • Transmembrane protein and RTK • Mainly found in precursors of the urogenital system and neural crest • Has 3 isoforms • short (RET9), middle(RET43), and long (RET51) • Homodimer • Also pairs with GFR (growth factor receptor)α 1, 2, 3, and 4 • Ligands • GDNF (glial-derived neurotrophic factor), neurturin (NTN), persephin (PSP), and artemin

  4. GDNF Family with Receptors SIGMA-ALDRICH

  5. RET Properties Continued • Gene found on long arm of chromosome 10 at 11.2 • Gene has 21 exons • Cadherin part must bind with Ca2+ in order for RET to work • 5 phosphotyrosine residues • 2 more in long isoform

  6. Protein Structures of RET Unphosphorylated Phosphorylated J. Biol. Chem. v281, p.33577-33587

  7. What Does RET Do Normally? • Helps with kidney development and enteric nervous system • Also implicated in cell differentiation and apoptosis

  8. Knockout Mice • Knockouts had no neurons in the gut, superior cervical ganglia, no kidneys at all or malformed and malfunctioning • RET null mutation die shortly after birth • No endocrine organs affected in MEN 2 • Heterozygotes have no apparent defects

  9. MEN 2-multiple endocrine neoplasia type 2 • Inherited form of cancer and very rare • First to be discovered in 1993 that MEN 2 was caused by germline mutations • Three subtypes • MEN 2A and MEN 2B • Familial medullary thyroid carcinoma (FMTC) • Autosomal dominant • RET constitutively active • Endocrine glands affected • Adrenal, parathyroid, and thyroid • Gain of function mutations

  10. MEN 2A

  11. MEN 2B

  12. FMTC • Have the same mutations as 2A in extracellular domain but also can be in TK domain at 768, 790, 791,(exon 13); 804, 844,(exon 14); or 891 (exon15) • Have mild C cell disease • Low transforming activity can predispose to FMTC rather than MEN 2A

  13. Treatment and Testing Thyroidectomy Before age 6 or 6-12 depending on mutation If MEN 2B, needed before a year old Have to take thyroid for the rest of life Chemotherapy not effective Microarray (best) Direct sequencing or single-strand conformational polymorphism Drugs being tested to disrupt RET kinase activity Needs a higher concentration though

  14. Questions?

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