Apc1638T: A mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development

Ron Smits, Menno F. Kielman, Cor Breukel, Chris Zurcher, Kristi Neufeld, Shantie Jagmohan-Changur, Nandy Hofland, Jaap Van Dijk, Ray White, Winfried Edelmann, Raju Kucherlapati, P. Meera Khan, Riccardo Fodde

Research output: Contribution to journalArticle

177 Citations (Scopus)

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 Apc mutations 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.

Original languageEnglish (US)
Pages (from-to)1309-1321
Number of pages13
JournalGenes and Development
Volume13
Issue number10
StatePublished - May 15 1999

Fingerprint

Adenomatous Polyposis Coli Protein
Catenins
Carcinogenesis
Adenomatous Polyposis Coli
Mutation
APC Genes
Amino Acids
Neoplasms
Proteins
Nipples
Mutant Proteins
Codon
Embryonic Development
Cysts
Colorectal Neoplasms
Homeostasis
Down-Regulation
Maintenance
Growth
Genes

Keywords

  • β-catenin
  • Apc
  • Development
  • SAMP
  • Tumorigenesis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Smits, R., Kielman, M. F., 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 and Development, 13(10), 1309-1321.

Apc1638T : A mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. / Smits, Ron; Kielman, Menno F.; Breukel, Cor; Zurcher, Chris; Neufeld, Kristi; Jagmohan-Changur, Shantie; Hofland, Nandy; Van Dijk, Jaap; White, Ray; Edelmann, Winfried; Kucherlapati, Raju; Meera Khan, P.; Fodde, Riccardo.

In: Genes and Development, Vol. 13, No. 10, 15.05.1999, p. 1309-1321.

Research output: Contribution to journalArticle

Smits, R, Kielman, MF, Breukel, C, Zurcher, C, Neufeld, K, Jagmohan-Changur, S, Hofland, N, Van Dijk, J, White, R, Edelmann, W, Kucherlapati, R, Meera Khan, P & Fodde, R 1999, 'Apc1638T: A mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development', Genes and Development, vol. 13, no. 10, pp. 1309-1321.
Smits R, Kielman MF, Breukel C, Zurcher C, Neufeld K, Jagmohan-Changur S et al. Apc1638T: A mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. Genes and Development. 1999 May 15;13(10):1309-1321.
Smits, Ron ; Kielman, Menno F. ; Breukel, Cor ; Zurcher, Chris ; Neufeld, Kristi ; Jagmohan-Changur, Shantie ; Hofland, Nandy ; Van Dijk, Jaap ; White, Ray ; Edelmann, Winfried ; Kucherlapati, Raju ; Meera Khan, P. ; Fodde, Riccardo. / Apc1638T : A mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development. In: Genes and Development. 1999 ; Vol. 13, No. 10. pp. 1309-1321.
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