Disease relevance of AXIN1

• AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1 [1].
• Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas [2].
• Mutations in the Wnt components AXIN1, AXIN2 and TCF4 have been found in microsatellite-unstable colon cancers, but it is not clear in every case whether these changes are functional [3].
• Identification of AXUD1, a novel human gene induced by AXIN1 and its reduced expression in human carcinomas of the lung, liver, colon and kidney [4].
• Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear beta-catenin expression [5].

High impact information on AXIN1

• P68 RNA Helicase Mediates PDGF-Induced Epithelial Mesenchymal Transition by Displacing Axin from beta-Catenin [6].
• Two novel Axin-1 interactions were validated experimentally, characterizing ANP32A and CRMP1 as modulators of Wnt signaling [7].
• Several interacting proteins, including Axin, APC, and the protein kinase GSK-3beta are implicated in regulating beta-catenin phosphorylation and its subsequent degradation [8].
• In the second group, demonstrating a chromosome instability, the most frequent allelic losses were on chromosome 1p, 4q, 6q, 9p, 13q, 16p, 16q, and 17p; Axin1 and p53 were frequently mutated [9].
• Axin also induces nuclear export of Smad7 [10].

Chemical compound and disease context of AXIN1

• A polyhistidine-tagged axin peptide (residues 419-672) was produced in Escherichia coli and either immobilized on Ni-NTA agarose beads or purified and immobilized on CNBr-activated Sepharose 4B [11].

Biological context of AXIN1

• Using single-strand conformation polymorphism analysis, screening for large deletions by reverse transcription-PCR, and sequencing analysis, a single somatic point mutation in exon 1 (Pro255Ser) and seven large deletions (12%) of AXIN1 were detected [2].
• This indicates that AXIN1 may function as a tumor suppressor gene in MBs [2].
• In the remaining 29 primary OEAs, unequivocal nuclear beta-catenin immunoreactivity was not observed, though a nonsense mutation in AXIN1 was observed in one tumor and a truncating frameshift mutation in AXIN2 was seen in another case [12].
• Loss of heterozygosity at the AXIN1 locus was present in four of five informative HCCs with AXIN1 mutations, suggesting a tumor suppressor function of this gene [13].
• The AXIN1 mutations included seven missense mutations, a 1 bp deletion, and a 12 bp insertion [13].

Anatomical context of AXIN1

• Among the 4 cell lines and 87 HCC5 in which we did not detect CTNNB1 mutations, we identified AXIN1 mutations in 3 cell lines and 6 mutations in 5 of the primary HCCs [1].
• Constitutive activation of the Wnt signaling pathway as a result of genetic alterations of APC, AXIN1, and CTNNB1 has been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach [14].
• Furthermore, Axin stimulated the degradation of beta-catenin in COS cells [15].
• Based on these observations, Axin was screened for mutations in a range of human tumor cell lines and primary breast tumor samples [16].
• Wnt11/{beta}-catenin signaling in both oocytes and early embryos acts through LRP6-mediated regulation of axin [17].

Associations of AXIN1 with chemical compounds

• Using bisulfite sequencing, we examined methylation at the promoter region of the AXIN1 gene in these twins and in twin and age-matched singleton controls [18].
• Mutation of LRP6 Ser(1420) and Ser(1430) to alanine strengthens its interaction with axin, suggesting a mechanism by which CKIepsilon may negatively regulate Wnt signaling [19].

Physical interactions of AXIN1

• Axin physically interacted with Smad3 through its C-terminal region located between the beta-catenin binding site and Dishevelled-homologous domain [20].
• We show that transposition of an axin-binding site can confer beta-catenin regulatory activity to a fragment of APC normally lacking this activity [21].
• The canonical pathway is induced by the Axin/adenomatous polyposis coli (APC)/glycogen synthase kinase-3beta (GSK-3beta) complex which is dependent on GSK-3beta phosphorylation [22].
• Furthermore, Ccd1 physically interacted with MEKK4 in their physiological concentrations and prevented MEKK4 from binding to Axin [23].
• It is concluded, that uncomplexed cytoplasmic pools of beta-catenin associate more readily with the Axin complex in the absence of E-cadherin [24].

Co-localisations of AXIN1

• In the absence of ligand stimulation, Axin was colocalized with Smad3 in the cytoplasm in vivo [20].

Regulatory relationships of AXIN1

• Axin down-regulated beta-catenin in SW480 cells, but not Axin(delta)(beta)(-catenin) [25].
• Adenomatous polyposis coli is down-regulated by the ubiquitin-proteasome pathway in a process facilitated by Axin [26].
• These results suggest that p53 induces a faster mobilization of Axin into the degradation complex thereby enhancing beta-catenin turnover as part of a protective mechanism against the development of cancer [27].
• In the full-grown oocyte, before maturation, we find that axin levels are also regulated by Wnt11 and LRP6 [17].
• This suggests that even when Axin is "switched" to activate the JNK pathway, it is still capable of sequestering free beta-catenin, which is a critical aspect for cellular homeostasis [28].

Other interactions of AXIN1

• These results suggest that the axin-dependent phosphorylation of APC is mediated in part by CKIepsilon and is involved in the regulation of APC function [21].
• Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway [20].
• The phosphorylation did not require glycogen synthase kinase 3beta but instead required casein kinase 1epsilon, which bound directly to axin [21].
• Axin and Dishevelled are two downstream components of the Wnt signaling pathway [29].
• A protease-resistant domain of Axin that contains the APC-binding site is a member of the regulators of G-protein signaling (RGS) superfamily [30].

Analytical, diagnostic and therapeutic context of AXIN1

• Since there are multiple complementary, inverted sequences present in the AXIN1 gene, these large deletions may represent RT-PCR errors due to stem-loop secondary structures [31].
• AXIN1 protein immunohistochemistry revealed cytoplasmic expression in all tumours irrespective of the presence of AXIN1 locus LOH [5].
• Purification of GSK-3 by affinity chromatography on immobilized axin [11].
• By means of a cDNA microarray, we compared expression profiles of LoVo cells infected with either adenoviruses expressing wild-type AXIN1 (Ad-Axin) or those expressing a control gene (Ad-LacZ) [32].
• We employed PCR amplification with 23 sets of primers against introns that encompassed the whole coding region of AXIN1 followed by single-strand conformation polymorphism (SSCP) analysis [33].

References