RGD Reference Report - Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. - Rat Genome Database

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Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling.

Authors: Leung, Janet Y  Kolligs, Frank T  Wu, Rong  Zhai, Yali  Kuick, Rork  Hanash, Samir  Cho, Kathleen R  Fearon, Eric R 
Citation: Leung JY, etal., J Biol Chem. 2002 Jun 14;277(24):21657-65. Epub 2002 Apr 8.
RGD ID: 13432156
Pubmed: PMID:11940574   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M200139200   (Journal Full-text)

The Wnt pathway regulates cell fate, proliferation, and apoptosis, and defects in the pathway play a key role in many cancers. Although Wnts act to stabilize beta-catenin levels in the cytosol and nucleus, a multiprotein complex containing adenomatous polyposis coli, glycogen synthase kinase 3beta, and Axin1 or its homolog Axin2/Axil/conductin promotes beta-catenin phosphorylation and subsequent proteasomal degradation. We found that the rat Axil gene was strongly induced upon neoplastic transformation of RK3E cells by mutant beta-catenin or gamma-catenin or after ligand-induced activation of a beta-catenin-estrogen receptor fusion protein. Expression of Wnt1 in murine breast epithelial cells activated the conductin gene, and human cancers with defective beta-catenin regulation had elevated AXIN2 gene and protein expression. Expression of AXIN2/Axil was strongly repressed in cancer cells by restoration of wild type adenomatous polyposis coli function or expression of a dominant negative form of T cell factor (TCF)-4. TCF binding sites in the AXIN2 promoter played a key role in the ability of beta-catenin to activate AXIN2 transcription. In contrast to AXIN2/Axil, expression of human or rat Axin1 homologs was nominally affected by beta-catenin-TCF. Because Axin2 can inhibit beta-catenin abundance and function, the data implicate AXIN2 in a negative feedback pathway regulating Wnt signaling. Additionally, although Axin1 and Axin2 have been thought to have comparable functions, the observation that Wnt pathway activation elevates AXIN2 but not AXIN1 expression suggests that there may be potentially significant functional differences between the two proteins.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
endometrial adenocarcinoma  IGICTNNB1 (Homo sapiens)13432156 RGD 
endometrial adenocarcinoma  ISOAXIN2 (Homo sapiens)13432156; 13432156 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Axin2  (axin 2)

Genes (Mus musculus)
Axin2  (axin 2)

Genes (Homo sapiens)
AXIN2  (axin 2)


Additional Information