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Colon cancer is the second leading cause of cancer deaths in the U.S.

Colon cancer is the second leading cause of cancer deaths in the U.S. Polyps, the first stage In tumor development. http://www.clevelandclinic.org/registries/inherited/fap.htm. Colorectal cancer. 150,000 cases diagnosed per year (i.e., your chances are 1/18)

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Colon cancer is the second leading cause of cancer deaths in the U.S.

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  1. Colon cancer is the second leading cause of cancer deaths in the U.S. Polyps, the first stage In tumor development http://www.clevelandclinic.org/registries/inherited/fap.htm

  2. Colorectal cancer 150,000 cases diagnosed per year (i.e., your chances are 1/18) > 50,000 deaths (2nd to lung cancer) Early detection key >90% 5 year survival with early detection 60% if it has spread locally <10% if it has metastasized Data from ACS

  3. Colorectal cancer treatment 1. Surgical removal of tumor This can be followed by either Radiation or chemotherapy (fluorouracil) 3. Chemotherapy also used to slow the progress of metastatic disease Data from ACS

  4. Colon cancer genetics 95% of cases sporadic (no genetic history) HNPCC 3% of all cases. Defects in mismatch repair. Familial adenomatous polyposis (FAP) 1% of all colon cancers Caused by mutation in a single gene = APC

  5. Familial Adenomatous Polyposis (FAP)

  6. Inheriting an APC mutation dramatically increases Your risk of developing colorectal cancer 300-1000 polyps by age 30 100% risk of colon cancer by age 40 www.myriadtests.com

  7. Until recently the only treatment Was to surgically remove the colon Treatment with an aspirin-like drug called celecoxib (a COX2 inhibitor) led to a 25% reduction in polyp number , and the remaining polyps shrank. Hope is this will allow doctors to Delay surgery till later in life Steinbeck et al. New England Journal of Medicine 342, 1946 (2000).

  8. Adenomatous Polyposis Coli (APC) tumor suppressor mutated in FAP and in 70% of sporadic cases of colon cancer colon polyps

  9. APC mutations are the earliest event in the development of the tumor

  10. To find clues to APC’s function they went fishing for partners APC Cell extract

  11. When they went fishing with APC, they pulled out Armadillo Armadillo APC (ß-catenin)

  12. Eric Wieschaus and Christiane Nüsslein-Volhard used genetics to identify proteins that set up the embryonic body plan

  13. The mighty fruit fly

  14. How is the body plan specified? Egg ---> animal in 24 hours!

  15. Wieschaus and Nüsslein-Volhard removed single genes and looked for effects on the body plan

  16. Wingless signaling specifies cell fates in the ventral epidermis wild type arm mutant

  17. Wingless signal influences the fates of neighboring cells

  18. Artist’s conception of an Armadillo

  19. Epithelial cells at work

  20. Elaine Fuch’s Hair Club for Men Rub ß-catenin here! Before After

  21. Wingless signaling modulates the stability of Armadillo protein Level of Wg signal Armadillo

  22. In the absence of APC, levels of Armadillo/ß-catenin rise dramatically APC mutant Wild-type

  23. Our current model for Wnt signaling

  24. Phosphorylation of Armadillo/ß-catenin By GSK3 creates a binding site for an E3 ubiquitin ligase

  25. APC is a complex protein 15 AA rpts 20 AA rpts Arm Repeats SAMP rpts Arm repeats protein-protein interaction motif also found in Arm !5 and 20 amino acids repeats bind to Arm SAMP repeats bind Axin

  26. Arm Repeats APC is a complex protein 15 AA rpts 20 AA rpts Arm Repeats SAMP rpts MCR All tumors carry one allele that makes A truncated APC protein And truncations almost always occur in the “mutation cluster region” (MCR)

  27. Activated Wnt signaling triggers colon cancer

  28. A branch in the Wnt pathway allows it to exert more diverse biological and cell biological effects

  29. APC interacts with the cytoskeleton Kinesin and Rac-GEF binding Microtubule Binding Arm Repeats EB1 directly binds microtubules in vitro colocalizes with microtubule ends binds EB1 binds a Kinesin motor and a Rac-GEF

  30. APC2 is localized to the cortex, where it could mediate interactions between mitotic spindles and cortical actin actin merged APC2 tubulin

  31. APC2 mutants have defects in spindle anchoring wild -type APC2 ∆S merged actin tubulin

  32. APC2 helps link spindles to cortical actin actin a-catenin Armadillo APC2 Protein X microtubules

  33. APC proteins may play several roles in genomic instability kinetochore APC spindle microtubules centromere Clevers, Fodde, Nathke & Sorger labs

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