An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function
Heterozygous, germline nonsense mutations in AXIN2 have been reported in two families with oligodontia and colorectal cancer (CRC) predisposition, including an AXIN2 1989G>A mutation. Somatic AXIN2 mutations predicted to generate truncated AXIN2 (trAXIN2) proteins have been reported in some CRCs....
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-05-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558615000585 |
| _version_ | 1818000848925491200 |
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| author | Serina M. Mazzoni Elizabeth M. Petty Elena M. Stoffel Eric R. Fearon |
| author_facet | Serina M. Mazzoni Elizabeth M. Petty Elena M. Stoffel Eric R. Fearon |
| author_sort | Serina M. Mazzoni |
| collection | DOAJ |
| description | Heterozygous, germline nonsense mutations in AXIN2 have been reported in two families with oligodontia and colorectal cancer (CRC) predisposition, including an AXIN2 1989G>A mutation. Somatic AXIN2 mutations predicted to generate truncated AXIN2 (trAXIN2) proteins have been reported in some CRCs. Our studies of cells from an AXIN2 1989G>A mutation carrier showed that the mutant transcripts are not significantly susceptible to nonsense-mediated decay and, thus, could encode a trAXIN2 protein. In transient transfection assays, trAXIN2 was more abundant than wild-type AXIN2 protein, and in contrast to AXIN2, glycogen synthase kinase 3β inhibition did not increase trAXIN2 levels. Like AXIN2, the trAXIN2 protein interacts with β-catenin destruction complex proteins. When ectopically overexpressed, trAXIN2 inhibits β-catenin/T-cell factor–dependent reporter gene activity and SW480 CRC cell colony formation. These findings suggest the trAXIN2 protein may retain some wild-type functions when highly expressed. However, when stably expressed in rat intestinal IEC-6 cells, the trAXIN2 protein did not match AXIN2’s activity in inhibiting Wnt-mediated induction of Wnt-regulated target genes, and SW480 cells with stable expression of trAXIN2 but not AXIN2 could be generated. Our data suggest the AXIN2 1989G>A mutation may not have solely a loss-of-function role in CRC. Rather, its contribution may depend on context, with potential loss-of-function when AXIN2 levels are low, such as in the absence of Wnt pathway activation. However, given its apparent increased stability in some settings, the trAXIN2 protein might have gain-of-function in cells with substantially elevated AXIN2 expression, such as Wnt pathway–defective CRC cells. |
| first_indexed | 2024-04-14T03:27:05Z |
| format | Article |
| id | doaj.art-4a67d9ecaf584862aa8fe88ac94b13fd |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-14T03:27:05Z |
| publishDate | 2015-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-4a67d9ecaf584862aa8fe88ac94b13fd2022-12-22T02:15:08ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022015-05-0117546347210.1016/j.neo.2015.04.006An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein FunctionSerina M. Mazzoni0Elizabeth M. Petty1Elena M. Stoffel2Eric R. Fearon3Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USADepartment of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USADepartment of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USADepartment of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USAHeterozygous, germline nonsense mutations in AXIN2 have been reported in two families with oligodontia and colorectal cancer (CRC) predisposition, including an AXIN2 1989G>A mutation. Somatic AXIN2 mutations predicted to generate truncated AXIN2 (trAXIN2) proteins have been reported in some CRCs. Our studies of cells from an AXIN2 1989G>A mutation carrier showed that the mutant transcripts are not significantly susceptible to nonsense-mediated decay and, thus, could encode a trAXIN2 protein. In transient transfection assays, trAXIN2 was more abundant than wild-type AXIN2 protein, and in contrast to AXIN2, glycogen synthase kinase 3β inhibition did not increase trAXIN2 levels. Like AXIN2, the trAXIN2 protein interacts with β-catenin destruction complex proteins. When ectopically overexpressed, trAXIN2 inhibits β-catenin/T-cell factor–dependent reporter gene activity and SW480 CRC cell colony formation. These findings suggest the trAXIN2 protein may retain some wild-type functions when highly expressed. However, when stably expressed in rat intestinal IEC-6 cells, the trAXIN2 protein did not match AXIN2’s activity in inhibiting Wnt-mediated induction of Wnt-regulated target genes, and SW480 cells with stable expression of trAXIN2 but not AXIN2 could be generated. Our data suggest the AXIN2 1989G>A mutation may not have solely a loss-of-function role in CRC. Rather, its contribution may depend on context, with potential loss-of-function when AXIN2 levels are low, such as in the absence of Wnt pathway activation. However, given its apparent increased stability in some settings, the trAXIN2 protein might have gain-of-function in cells with substantially elevated AXIN2 expression, such as Wnt pathway–defective CRC cells.http://www.sciencedirect.com/science/article/pii/S1476558615000585 |
| spellingShingle | Serina M. Mazzoni Elizabeth M. Petty Elena M. Stoffel Eric R. Fearon An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function Neoplasia: An International Journal for Oncology Research |
| title | An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function |
| title_full | An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function |
| title_fullStr | An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function |
| title_full_unstemmed | An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function |
| title_short | An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function |
| title_sort | axin2 mutant allele associated with predisposition to colorectal neoplasia has context dependent effects on axin2 protein function |
| url | http://www.sciencedirect.com/science/article/pii/S1476558615000585 |
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