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Publication : SIRT2 interacts with β-catenin to inhibit Wnt signaling output in response to radiation-induced stress.

First Author  Nguyen P Year  2014
Journal  Mol Cancer Res Volume  12
Issue  9 Pages  1244-53
PubMed ID  24866770 Mgi Jnum  J:213501
Mgi Id  MGI:5585208 Doi  10.1158/1541-7786.MCR-14-0223-T
Citation  Nguyen P, et al. (2014) SIRT2 interacts with beta-catenin to inhibit Wnt signaling output in response to radiation-induced stress. Mol Cancer Res 12(9):1244-53
abstractText  UNLABELLED: Wnt signaling is critical to maintaining cellular homeostasis via regulation of cell division, mitigation of cell stress, and degradation. Aberrations in Wnt signaling contribute to carcinogenesis and metastasis, whereas sirtuins have purported roles in carcinogenesis, aging, and neurodegeneration. Therefore, the hypothesis that sirtuin 2 (SIRT2) directly interacts with beta-catenin and whether this interaction alters the expression of Wnt target genes to produce an altered cellular phenotype was tested. Coimmunoprecipitation studies, using mouse embryonic fibroblasts (MEF) from Sirt2 wild-type and genomic knockout mice, demonstrate that beta-catenin directly binds SIRT2. Moreover, this interaction increases in response to oxidative stress induced by ionizing radiation. In addition, this association inhibits the expression of important Wnt target genes such as survivin (BIRC5), cyclin D1 (CCND1), and c-myc (MYC). In Sirt2 null MEFs, an upregulation of matrix metalloproteinase 9 (MMP9) and decreased E-cadherin (CDH1) expression is observed that produces increased cellular migration and invasion. Together, these data demonstrate that SIRT2, a tumor suppressor lost in multiple cancers, inhibits the Wnt signaling pathway in nonmalignant cells by binding to beta-catenin and that SIRT2 plays a critical role in the response to oxidative stress from radiation. IMPLICATIONS: Disruption of the SIRT2-beta-catenin interaction represents an endogenous therapeutic target to prevent transformation and preserve the integrity of aging cells against exogenous stressors such as reactive oxygen species.
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