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    APC1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development

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    NeufeldK_G&D_1999(13)1309.pdf (1.614Mb)
    Issue Date
    1999-04-01
    Author
    Neufeld, Kristi L.
    Smits, Ron
    Kielman, Menno F.
    Breukel, Cor
    Zurcher, Chris
    Jagmohan-Changur, Shantie
    Hofland, Nandy
    van Dijk, Jaap
    White, Ray
    Edelmann, Winfried
    Kucherlapati, Raju
    Khan, P. Meera
    Fodde, Riccardo
    Publisher
    Cold Spring Harbor Laboratory Press
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Metadata
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    Abstract
    The adenomatous polyposis coli (APC) gene is considered as the true gatekeeper of colonic epithelial proliferation: It is mutated in the majority of colorectal tumors, and mutations occur at early stages of tumor development in mouse and man. These mutant proteins lack most of the seven 20-amino-acid repeats and all SAMP motifs that have been associated with down-regulation of intracellular β-catenin levels. In addition, they lack the carboxy-terminal domains that bind to DLG, EB1, and microtubulin. APC also appears to be essential in development because homozygosity for mouse Apcmutations invariably results in early embryonic lethality. Here, we describe the generation of a mouse model carrying a targeted mutation at codon 1638 of the mouse Apc gene, Apc1638T, resulting in a truncated Apc protein encompassing three of the seven 20 amino acid repeats and one SAMP motif, but missing all of the carboxy-terminal domains thought to be associated with tumorigenesis. Surprisingly, homozygosity for the Apc1638T mutation is compatible with postnatal life. However, homozygous mutant animals are characterized by growth retardation, a reduced postnatal viability on the B6 genetic background, the absence of preputial glands, and the formation of nipple-associated cysts. Most importantly,Apc 1638T/1638T animals that survive to adulthood are tumor free. Although the full complement of Apc1638T is sufficient for proper β-catenin signaling, dosage reductions of the truncated protein result in increasingly severe defects in β-catenin regulation. The SAMP motif retained in Apc1638T also appears to be important for this function as shown by analysis of the Apc1572T protein in which its targeted deletion results in a further reduction in the ability of properly controlling β-catenin/Tcf signaling. These results indicate that the association with DLG, EB1, and microtubulin is less critical for the maintenance of homeostasis by APC than has been suggested previously, and that proper β-catenin regulation by APC appears to be required for normal embryonic development and tumor suppression.
    Description
    This is the publisher's version, also available electronically from "http://genesdev.cshlp.org".
    URI
    http://hdl.handle.net/1808/17452
    ISSN
    0890-9369
    Collections
    • Molecular Biosciences Scholarly Works [590]
    Citation
    Smits, R., Kielman, M., Breukel, C., Zurcher, C., Neufeld, K., Jagmohan-Changur, S., . . . Fodde, R. (1999). Apc1638T: A mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. GENES & DEVELOPMENT, 13, 1309-1321 http://genesdev.cshlp.org/content/13/10/1309.long

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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