Sequence variants of the axin gene in breast, colon, and other cancers: An analysis of mutations that interfere with GSK3 binding
✍ Scribed by Marie-Therese Webster; Magdalena Rozycka; Elizabeth Sara; Elaine Davis; Matthew Smalley; Neville Young; Trevor C. Dale; Richard Wooster
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 164 KB
- Volume
- 28
- Category
- Article
- ISSN
- 1045-2257
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✦ Synopsis
Axin is a recently discovered component of a multiprotein complex containing APC, -catenin, GSK3, and PP2A, which functions in the degradation of the -catenin protein. As part of WNT signal transduction, the function of the Axin complex is inhibited, leading to the accumulation of -catenin. The inappropriate stabilization of -catenin has been implicated in a range of human tumors. Two oncogenic mechanisms leading to -catenin stabilization are the loss of the APC tumor suppressor protein and the mutational activation of -catenin, such that the Axin/APC complex can no longer regulate it. Studies in Drosophila and mammalian tissue culture showed loss of Axin function interfered with -catenin turnover and activated -catenin/TCF-dependent transcription. Based on these observations, Axin was screened for mutations in a range of human tumor cell lines and primary breast tumor samples. We identified two sequence variants causing amino acid substitutions in four colon cancer cell lines, a Ser-to-Leu at residue 215 in LS513 and a Leu-to-Met at residue 396 in HCT-8, HCT-15, and DLD-1. The Axin L396M mutation was selected for further study since it lay within a region that was shown to interact with glycogen synthase kinase-3. Biochemical and functional studies showed that the L396M change interfered with Axin's ability to bind GSK3. Interestingly, this mutation and a neighboring L392M change differentially altered Axin's ability to interfere with two upstream activators of TCF-dependent transcription, Frat1 and Disheveled.