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A knock-in mouse model reveals roles for nuclear Apc in cell proliferation, Wnt signal inhibition and tumor

M Zeineldin1, J Cunningham, W McGuinness

  • 1Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence, KS 66045, USA.

Oncogene
|October 15, 2011
PubMed

Insights

Nuclear adenomatous polyposis coli (APC) protein inhibits Wnt signaling and controls intestinal cell proliferation. Mutations inactivating nuclear APC in mice increase cell growth and polyp formation, highlighting nuclear APC

Area of Science:

  • Molecular biology
  • Cancer research
  • Genetics

Background:

  • Adenomatous polyposis coli (APC) mutations initiate most colorectal cancers.
  • APC normally inhibits the Wnt-signaling pathway by degrading β-catenin.
  • Nuclear APC is implicated in suppressing Wnt target gene expression.

Purpose of the Study:

  • To investigate the role of nuclear APC in vivo.
  • To generate and analyze a mouse model with inactivated nuclear localization signals (NLSs) of APC (Apc(mNLS)).

Main Methods:

  • Generated Apc(mNLS/mNLS) mice with mutations in APC's NLSs.
  • Fractionated mouse embryonic fibroblasts (MEFs) to assess nuclear APC levels.
  • Analyzed intestinal epithelial cell proliferation and Wnt target gene expression (c-Myc, axin-2, cyclin-D1, Hath-1).
  • Crossed Apc(mNLS) mice with Apc(Min/+) mice to study polyp formation.

Main Results:

  • Apc(mNLS/mNLS) mice showed reduced nuclear APC in MEFs.
  • No significant changes in total APC or β-catenin protein levels were observed.
  • Increased epithelial cell proliferation in the jejunum, ileum, and colon of Apc(mNLS/mNLS) mice.
  • Upregulation of Wnt target genes (c-Myc, axin-2, cyclin-D1) and downregulation of Hath-1 in Apc(mNLS/mNLS) mice.
  • Mice with both Apc(mNLS) and Apc(Min/+) alleles exhibited larger and more numerous polyps.

Conclusions:

  • Nuclear APC plays a crucial role in inhibiting canonical Wnt signaling in intestinal tissues.
  • Nuclear APC is essential for controlling intestinal epithelial cell proliferation.
  • Inactivation of nuclear APC contributes to polyp formation in the context of APC mutations.

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