| Written | 2007-01 | Thomas A Hughes |
| Pathology and Tumour Biology Section, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK |
| Identity |
| Alias_symbol (synonym) | MGC126582 |
| DKFZp781B0869 | |
| Other alias | axil (mostly in rat) |
| conductin | |
| DKFZp781B0869 (single database entry only) | |
| MGC126582 (single database entry only) | |
| HGNC (Hugo) | AXIN2 |
| LocusID (NCBI) | 8313 |
| Atlas_Id | 456 |
| Location | 17q24.1 [Link to chromosome band 17q24] |
| Location_base_pair | Starts at 65528565 and ends at 65561622 bp from pter ( according to hg19-Feb_2009) [Mapping AXIN2.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| AXIN2 (17q24.1) / CFDP1 (16q23.1) | BCAS3 (17q23.2) / AXIN2 (17q24.1) | CYP19A1 (15q21.2) / AXIN2 (17q24.1) | |
| INTS2 (17q23.2) / AXIN2 (17q24.1) | KAT7 (17q21.33) / AXIN2 (17q24.1) |
| DNA/RNA |
 | |
| The 5' end of the human AXIN2 gene. An alignment of human genomic DNA (top line) with the 5' end of different Axin2 mRNA variants. Exons are shown as boxes (non-coding: filled; coding: open) and the translational start codon is marked (ATG). | |
| Description | The AXIN2 gene spans about 35 kbp including 10 coding exons and 3 non-coding 5' exons (E0a, 0b and 0c; see above). Nearby genes: about 70 kbp upstream is CCDC46 (coiled-coil domain containing 46), about 300 kbp downstream is RGS9 (regulator of G-protein signalling 9). In addition, there is a putative gene that overlaps the AXIN2 non-coding 5' exons and coding exon 1 (E1) and is transcribed from the same strand (Gnomon model hmm119498); there is no published data on whether this is actually expressed. |
| Transcription | Transcription occurs from three separate promoters leading to initiation at each of the three non-coding 5' exons. mRNAs are spliced so that that each non-coding exon is expressed separately, rather than in combinations. It is unclear whether transcription can initiate at the first coding exon (E1). Promoters can be activated by TCF transcription factors binding at multiple sites and by E2F1 binding at up to 4 sites, although E2F1 can also induce transcription in the absence of consensus sites. It has been reported that exon 6 can be omitted in an alternatively-spliced form. |
| Pseudogene | None identified |
| Protein |
 | |
| Description | Human Axin2 is an 843 amino acids protein (777 amino acids from delta exon 6 mRNAs) containing an RGS domain (regulator of G protein signalling; amino acids 81-200), a GSK-3 beta binding domain (amino acids 327-413), a beta-catenin binding domain (amino acids 413-476), and a DIX domain (domain in dishevelled and axin; amino acids 761-843). |
| Expression | Expression appears to be ubiquitous in adult tissues (although at differing levels), but is limited to specific regions during embryonic development. Expression is regulated at multiple levels including transcription, mRNA stability, translation and protein stability. |
| Localisation | Axin2 protein has been localised to the cytoplasm, the nucleus and the mitotic spindle. |
| Function | Molecular functions : 1) Axin2 acts as a negative regulator of canonical Wnt/TCF signalling by enhancing formation of the beta-catenin destruction complex. Since expression of Axin2 is itself activated by canonical Wnt/TCF signalling, this results in a negative feedback-loop that restricts TCF activity. 2) Axin2 may influence TCF activity by re-localising beta-catenin to the cytoplasm. 3) Activity of the GSK-3 beta target snail1 can be regulated by Axin2's ability to influence the nucleo-cytoplasmic localisation of GSK-3 beta. 4) Axin2 binds polo-like kinase 1 (PLK1) during mitosis and influences the accuracy of chromosome segregation. Cellular/physiological functions : 1) Axin2 expression oscillates during early embryogenesis in response to Wnt3a - this is required to achieve correct the temporal TCF activity to allow somatogenesis. 2) A requirement for Axin2 for correct calvarial morphogenesis and craniosynostosis has been revealed in Axin2 -/- mice. 3) Axin2 appears to act as a tumour suppressor, and somatic mutations have been seen in many different tumour types (see below). |
| Homology | Axin2 is 44% identical to axin in mice and knock-in experiments suggest that the proteins can be functionally equivalent. |
| Mutations |
| Note | A large number of different mutations in the AXIN2 gene have been identified. In many cases (but not all) these lead to premature translational termination and protein truncation. Truncated Axin2 protein is more stable than the wild type, while there has been speculation that the mRNA may be less stable. |
| Germinal | Heterozygous germ line mutations in exon 7 that lead to premature termination are associated with familial tooth agenesis and a predisposition to colorectal cancer. Further germ line polymorphisms associated with familial tooth agenesis have been identified in exons 2 and 7. A polymorphism within exon 1 has been identified that is associated with risk of lung cancer. Many other polymorphisms that have yet to be associated with any function have been detected. |
| Somatic | The genomic region containing the AXIN2 gene shows loss of heterozygosity and re-arrangements in a variety of cancers. In addition somatic point mutations and deletions have been identified in colorectal cancer, hepatocellular carcinomas, ovarian endometrioid adenocarcinomas and hepatoblastomas. Many of these mutations/deletions result in translation of truncated proteins that are likely to be functionally inactive, although one report has suggested that these truncated proteins have a dominant negative activity. |
| Implicated in |
| Note | |
| Entity | Colorectal cancer (CRC) |
| Oncogenesis | Axin2 is often over-expressed in CRC as a result of the deregulation of canonical Wnt/beta-catenin signalling that is an early event in CRC development (usually caused by mutations/deletions in APC or beta-catenin). Somatic inactivating mutations within Axin2 have been reported in CRC and theoretically these could contribute to further deregulation of Wnt/beta-catenin - suggesting that Axin2 is a tumour suppressor. However mutations have only been seen in microsatellite unstable tumours and often within regions of mono-nucleotide repeats (exon 7), hence whether Axin2 mutations are cause or effect in these tumours remains undetermined. In support of Axin2's role as a tumour suppressor are observations that Axin2 is silenced by promoter methylation in many microsatellite unstable tumours. As discussed above, heterozygotes for some germ line mutations in AXIN2 are predisposed to CRC although this seems to be involved with only a very small proportion of familial colorectal cancer. |
| Entity | Other cancers (hepatocellular carcinomas, hepatoblastomas, ovarian endometrioid adenocarcinomas) |
| Oncogenesis | Somatic mutations in Axin2 have been detected in a range of cancer types. It is usually assumed that these lead to partial inactivation of Axin2 function thereby deregulation of canonical Wnt/beta-catenin signalling. In most cases this has not formally been demonstrated, and the contribution of Axin2 mutations to any putative change in Wnt/beta-catenin activity and to the development of these cancers remains mostly unclear. |
| Entity | Familial Tooth Agenesis (see above) |
| Bibliography |
| Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. |
| Anderson CB, Neufeld KL, White RL |
| Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (13) : 8683-8688. |
| PMID 12072559 |
| Wnt3a plays a major role in the segmentation clock controlling somitogenesis. |
| Aulehla A, Wehrle C, Brand-Saberi B, Kemler R, Gossler A, Kanzler B, Herrmann BG |
| Developmental cell. 2003 ; 4 (3) : 395-406. |
| PMID 12636920 |
| Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. |
| Behrens J, Jerchow BA, Würtele M, Grimm J, Asbrand C, Wirtz R, Kühl M, Wedlich D, Birchmeier W |
| Science (New York, N.Y.). 1998 ; 280 (5363) : 596-599. |
| PMID 9554852 |
| Mouse axin and axin2/conductin proteins are functionally equivalent in vivo. |
| Chia IV, Costantini F |
| Molecular and cellular biology. 2005 ; 25 (11) : 4371-4376. |
| PMID 15899843 |
| Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene. |
| Dong X, Seelan RS, Qian C, Mai M, Liu W |
| Cytogenetics and cell genetics. 2001 ; 93 (1-2) : 26-28. |
| PMID 11474173 |
| Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer. |
| Hadjihannas MV, Brückner M, Jerchow B, Birchmeier W, Dietmaier W, Behrens J |
| Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (28) : 10747-10752. |
| PMID 16815967 |
| Regulation of axin2 expression at the levels of transcription, translation and protein stability in lung and colon cancer. |
| Hughes TA, Brady HJ |
| Cancer letters. 2006 ; 233 (2) : 338-347. |
| PMID 15885887 |
| Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. |
| Ishizaki Y, Ikeda S, Fujimori M, Shimizu Y, Kurihara T, Itamoto T, Kikuchi A, Okajima M, Asahara T |
| International journal of oncology. 2004 ; 24 (5) : 1077-1083. |
| PMID 15067328 |
| Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. |
| Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F |
| Molecular and cellular biology. 2002 ; 22 (4) : 1172-1183. |
| PMID 11809808 |
| Single nucleotide polymorphism of the AXIN2 gene is preferentially associated with human lung cancer risk in a Japanese population. |
| Kanzaki H, Ouchida M, Hanafusa H, Yano M, Suzuki H, Aoe M, Imai K, Shimizu N, Nakachi K, Shimizu K |
| International journal of molecular medicine. 2006 ; 18 (2) : 279-284. |
| PMID 16820935 |
| Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. |
| Koch A, Weber N, Waha A, Hartmann W, Denkhaus D, Behrens J, Birchmeier W, von Schweinitz D, Pietsch T |
| The Journal of pathology. 2004 ; 204 (5) : 546-554. |
| PMID 15538750 |
| Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability. |
| Koinuma K, Yamashita Y, Liu W, Hatanaka H, Kurashina K, Wada T, Takada S, Kaneda R, Choi YL, Fujiwara SI, Miyakura Y, Nagai H, Mano H |
| Oncogene. 2006 ; 25 (1) : 139-146. |
| PMID 16247484 |
| Nucleo-cytoplasmic distribution of beta-catenin is regulated by retention. |
| Krieghoff E, Behrens J, Mayr B |
| Journal of cell science. 2006 ; 119 (Pt 7) : 1453-1463. |
| PMID 16554443 |
| Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. |
| Lammi L, Arte S, Somer M, Jarvinen H, Lahermo P, Thesleff I, Pirinen S, Nieminen P |
| American journal of human genetics. 2004 ; 74 (5) : 1043-1050. |
| PMID 15042511 |
| Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. |
| Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR, Fearon ER |
| The Journal of biological chemistry. 2002 ; 277 (24) : 21657-21665. |
| PMID 11940574 |
| Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. |
| Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Boardman LA, Qian C, Christensen E, Schmidt SS, Roche PC, Smith DI, Thibodeau SN |
| Nature genetics. 2000 ; 26 (2) : 146-147. |
| PMID 11017067 |
| Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. |
| Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, Behrens J |
| Molecular and cellular biology. 2002 ; 22 (4) : 1184-1193. |
| PMID 11809809 |
| Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis. |
| Mostowska A, Biedziak B, Jagodzinski PP |
| Journal of human genetics. 2006 ; 51 (3) : 262-266. |
| PMID 16432638 |
| Germline mutations of AXIN2 are not associated with nonsyndromic colorectal cancer. |
| Peterlongo P, Howe LR, Radice P, Sala P, Hong YJ, Hong SI, Mitra N, Offit K, Ellis NA |
| Human mutation. 2005 ; 25 (5) : 498-500. |
| PMID 15841489 |
| Consortium study on 1280 breast carcinomas: allelic loss on chromosome 17 targets subregions associated with family history and clinical parameters. |
| Phelan CM, Borg A, Cuny M, Crichton DN, Baldersson T, Andersen TI, Caligo MA, Lidereau R, Lindblom A, Seitz S, Kelsell D, Hamann U, Rio P, Thorlacius S, Papp J, Olah E, Ponder B, Bignon YJ, Scherneck S, Barkardottir R, Borresen-Dale AL, Eyfjörd J, Theillet C, Thompson AM, Larsson C |
| Cancer research. 1998 ; 58 (5) : 1004-1012. |
| PMID 9500463 |
| Four regions of allelic imbalance on 17q12-qter associated with high-grade breast tumors. |
| Plummer SJ, Paris MJ, Myles J, Tubbs R, Crowe J, Casey G |
| Genes, chromosomes & cancer. 1997 ; 20 (4) : 354-362. |
| PMID 9408751 |
| The links between axin and carcinogenesis. |
| Salahshor S, Woodgett JR |
| Journal of clinical pathology. 2005 ; 58 (3) : 225-236. |
| PMID 15735151 |
| Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines. |
| Suraweera N, Robinson J, Volikos E, Guenther T, Talbot I, Tomlinson I, Silver A |
| International journal of cancer. Journal international du cancer. 2006 ; 119 (8) : 1837-1842. |
| PMID 16708370 |
| Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. |
| Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W |
| Oncogene. 2002 ; 21 (31) : 4863-4871. |
| PMID 12101426 |
| Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability. |
| Thorstensen L, Lind GE, L&oring;vig T, Diep CB, Meling GI, Rognum TO, Lothe RA |
| Neoplasia (New York, N.Y.). 2005 ; 7 (2) : 99-108. |
| PMID 15802015 |
| Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. |
| Wu R, Zhai Y, Fearon ER, Cho KR |
| Cancer research. 2001 ; 61 (22) : 8247-8255. |
| PMID 11719457 |
| Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos. |
| Yamamoto H, Kishida S, Uochi T, Ikeda S, Koyama S, Asashima M, Kikuchi A |
| Molecular and cellular biology. 1998 ; 18 (5) : 2867-2875. |
| PMID 9566905 |
| A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. |
| Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J, Fearon ER, Weiss SJ |
| Nature cell biology. 2006 ; 8 (12) : 1398-1406. |
| PMID 17072303 |
| The role of Axin2 in calvarial morphogenesis and craniosynostosis. |
| Yu HM, Jerchow B, Sheu TJ, Liu B, Costantini F, Puzas JE, Birchmeier W, Hsu W |
| Development (Cambridge, England). 2005 ; 132 (8) : 1995-2005. |
| PMID 15790973 |
| Citation |
| This paper should be referenced as such : |
| Hughes, TA |
| AXIN2 (axin 2) |
| Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):113-116. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/AXIN2ID456ch17q24.html |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 4 ] |
|
Colon: Colorectal adenocarcinoma
t(17;17)(q21;q24) KAT7/AXIN2 t(17;17)(q23;q24) BCAS3/AXIN2 t(17;17)(q23;q24) INTS2/AXIN2 |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Nov 13 21:03:03 CET 2019 |
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