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RET and MEN2

RET and MEN2. This presentation brought to you by Meredith Stewart. The Disease:. MEN = Multiple endocrine neoplasia. MEN 2 Cancers. F amilial M edullary T hyroid C arcinoma MEN 2A MEN 2B. Medullary thyroid carcinoma (C cells) Pheochromocytoma (adrenal tumors) Parathyroid hyperplasia.

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RET and MEN2

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  1. RET and MEN2 This presentation brought to you by Meredith Stewart

  2. The Disease: MEN = Multiple endocrine neoplasia

  3. MEN 2 Cancers • Familial Medullary Thyroid Carcinoma • MEN 2A • MEN 2B • Medullary thyroid carcinoma (C cells) • Pheochromocytoma (adrenal tumors) • Parathyroid hyperplasia

  4. MEN 2 Cancer, con’t: • Autosomal dominant inheritance • Nearly 100 % penetrance • 1 case out of 30,000 – 50,000 people • Treatment options: • Remove the thyroid • Inhibit malfunctioning protein’s action

  5. RET = The Bad Guy(Rearranged during Transfection) • Proto-oncogene • Receptor tyrosine kinase

  6. RET = The Bad Guy(Rearranged during Transfection) • Proto-oncogene • Receptor tyrosine kinase • One of pathways is in fact Ras  MAPK

  7. Many paths to follow…

  8. Many paths to follow…

  9. A less detailed view • Coreceptor = GFRα family • Ligand = GFL family • Cysteine region autophosphorylates when bound by ligand • Phosphorylates other substrates

  10. Normal RET Function? “The activation of the RET pathway results in increased cell motility, dissociation of cell adhesion, and the migration towards a localized source of GDNF. Cellular responses to RET include the formation of lamellipodia, filopodia, and reorganization of the actin cytoskeleton.” -Tang, Worley, Sanicola and Dressler, 1998

  11. Normal RET Function? Homozygous knockouts have no kidneys!!! Knockout Mice

  12. Normal RET Function? Homozygous knockouts have no kidneys!!! Knockout Mice

  13. Normal RET Function? “The activation of the RET pathway results in increased cell motility, dissociation of cell adhesion, and the migration towards a localized source of GDNF.” -Tang, Worley, Sanicola and Dressler, 1998 …such as a ureteric bud growing towards some mesenchymal cells to form kidneys…

  14. Normal RET Function? • RET expressed at different points of development of organism (and differently in organism)

  15. What goes wrong in cancer? • Proto-oncogene  constituvely active

  16. What goes wrong in cancer? • Proto-oncogene  constituvely active • FMTC: cysteine mutation (extracellular domain) • MEN 2A: cysteine mutation at codon 634

  17. What goes wrong in cancer? • Proto-oncogene  constituvely active • FMTC: cysteine mutation (extracellular domain) • MEN 2A: cysteine mutation at codon 634 • MEN 2B: kinase mutation at codon 918

  18. When RET goes bad… • Loss of function RET leads to Hirschsprung disease (recessive) • Overactive RET can also lead to papillary thryoid cancer

  19. BUT LOOK!!! Normal RET Too much RET Too much RET + zd6474 Washington University School of Medicine performed this experiment: The third eye shown was treated during development with kinase inhibitor zd6474 and mostly rescued

  20. Works Referenced • L. Alberti, C. Carniti, C. Miranda, E. Roccatto, and M. Pierotti. “RET and NRTK1 Proto-Oncogenes in Human Diseases.” Journal of Cellular Physiology 195 (2003): 168—186. • J. Hansford and L. Mulligan. “Multiple endocrine neoplasia type 2 and RET: from neoplasia and neurogenesis.” Journal of Medical Genetics 37 (2003): 817—827. • Hofstra, Robert M.W. “The RET gene and its associated diseases.” Diss. Department of Medical Genetics, University of Groningen. Netherlands: 1995. 15—19. Accessed at http://dissertations.ub.rug.nl/FILES/faculties/medicine/1995/r.m.w.hofstra/thesis.pdf • M. Ichihara, Y. Murakumo, and M. Takahashi. “RET and neuroendocrine tumors.” Cancer Letters 204 (2004): 197—211. • S. Manie, M. Santoro, A. Fusco and M. Billaud. “The RET receptor: function in development and dysfunction in congenital malformation.” TRENDS in Genetics 17 (2001): 580—589. • M. Tang, D. Worley, M. Sanicola, and G. Dressler. “The RET-Glial Cell-derived Neurotrophic Factor (GDNF) Pathway Stimulates Migration and Chemoattraction of Epithelial Cells.” The Journal of Cell Biology 142 (1998): 1337—1345. • M. Vidal, S. Wells, R. Anderson, and R. Cagan. “ZD6474 Suppresses Oncogenic RET Isoforms in a Drosophila Model for Type 2 Multiple Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma.” Cancer Research 65 (2005): 3538—3541. • (Basic information about different types of cancer was searched for at www.emedicine.com)

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