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Adenomatous polyposis coli is down-regulated by the ubiquitin-proteasome pathway in a process facilitated by Axin

Jongkyu Choi1, Sun Young Park, Frank Costantini

  • 1Laboratory of Ophthalmology and Visual Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul, 137-701, Korea.

The Journal of Biological Chemistry
|September 10, 2004
PubMed

Insights

Adenomatous polyposis coli (APC) protein levels are controlled by the ubiquitin-proteasome pathway. Wnt signaling inhibits this process, revealing a new regulatory mechanism for APC in colorectal tumor development.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • Adenomatous polyposis coli (APC) protein and Axin form a complex crucial for down-regulating beta-catenin, a key Wnt signaling effector.
  • Truncated APC mutations cause colorectal tumors by disrupting beta-catenin down-regulation, but APC regulation itself is poorly understood.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling Adenomatous polyposis coli (APC) protein levels.
  • To elucidate the role of the ubiquitin-proteasome pathway and Wnt signaling in APC regulation.

Main Methods:

  • Ubiquitin-proteasome pathway assays
  • Identification of APC ubiquitination domains
  • Axin oligomerization studies
  • Wnt signaling modulation

Main Results:

  • APC protein levels are regulated by the ubiquitin-proteasome pathway.
  • Wnt signaling was found to inhibit the ubiquitin-proteasome-mediated down-regulation of APC.
  • A specific domain responsible for APC down-regulation and ubiquitination was identified.
  • Axin facilitates APC down-regulation through oligomerization, independent of its role in beta-catenin regulation.

Conclusions:

  • APC protein levels are subject to ubiquitin-proteasome-mediated degradation.
  • Wnt signaling provides negative feedback by inhibiting APC degradation.
  • Axin plays a novel role in promoting APC degradation, adding complexity to Wnt pathway regulation.

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