Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis
- PMID: 15994955
- DOI: 10.1158/0008-5472.CAN-05-1021
Kinase-inactive glycogen synthase kinase 3beta promotes Wnt signaling and mammary tumorigenesis
Abstract
Recent studies have implicated ectopic activation of the Wnt pathway in many human cancers, including breast cancer. beta-catenin is a critical coactivator in this signaling pathway and is regulated in a complex fashion by phosphorylation, degradation, and nuclear translocation. Glycogen synthase kinase 3beta (GSK3beta) phosphorylation of the NH2-terminal domain of beta-catenin targets it for ubiquitination and proteosomal degradation. We hypothesized that expression of kinase-inactive GSK3beta (KI-GSK3beta) in mammary glands would function in a dominant-negative fashion by antagonizing the endogenous activity of GSK3beta and promoting breast cancer development. Consistent with this, we find that KI-GSK3beta stabilizes beta-catenin expression, catalyzes its localization to the nucleus, and up-regulates the downstream target gene, cyclin D1, in vitro. In vivo, transgenic mice overexpressing the KI-GSK3beta under the control of the mouse mammary tumor virus-long terminal repeat develop mammary tumors with overexpression of beta-catenin and cyclin D1. Thus, antagonism of GSK3beta activity is oncogenic in the mammary epithelium; mutation or pharmacologic down-regulation of GSK3beta could promote mammary tumors.
Similar articles
-
A Wnt-ow of opportunity: targeting the Wnt/beta-catenin pathway in breast cancer.Curr Drug Targets. 2010 Sep;11(9):1074-88. doi: 10.2174/138945010792006780. Curr Drug Targets. 2010. PMID: 20545611 Review.
-
CK2 as a positive regulator of Wnt signalling and tumourigenesis.Mol Cell Biochem. 2005 Jun;274(1-2):63-7. doi: 10.1007/s11010-005-3078-0. Mol Cell Biochem. 2005. PMID: 16342409 Review.
-
Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits wnt-1-induced mammary tumorigenesis.Cancer Res. 2005 Aug 1;65(15):6864-73. doi: 10.1158/0008-5472.CAN-05-0181. Cancer Res. 2005. PMID: 16061670
-
Activation of p53-dependent apoptosis by acute ablation of glycogen synthase kinase-3beta in colorectal cancer cells.Clin Cancer Res. 2005 Jun 15;11(12):4580-8. doi: 10.1158/1078-0432.CCR-04-2624. Clin Cancer Res. 2005. PMID: 15958644
-
Activation of different Wnt/beta-catenin signaling components in mammary epithelium induces transdifferentiation and the formation of pilar tumors.Oncogene. 2002 Aug 15;21(36):5548-56. doi: 10.1038/sj.onc.1205686. Oncogene. 2002. PMID: 12165853
Cited by
-
Sodium New Houttuyfonate Induces Apoptosis of Breast Cancer Cells via ROS/PDK1/AKT/GSK3β Axis.Cancers (Basel). 2023 Mar 6;15(5):1614. doi: 10.3390/cancers15051614. Cancers (Basel). 2023. PMID: 36900408 Free PMC article.
-
Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario.Pharmaceutics. 2023 Feb 16;15(2):664. doi: 10.3390/pharmaceutics15020664. Pharmaceutics. 2023. PMID: 36839989 Free PMC article. Review.
-
Systems Drug Design for Muscle Invasive Bladder Cancer and Advanced Bladder Cancer by Genome-Wide Microarray Data and Deep Learning Method with Drug Design Specifications.Int J Mol Sci. 2022 Nov 10;23(22):13869. doi: 10.3390/ijms232213869. Int J Mol Sci. 2022. PMID: 36430344 Free PMC article.
-
Systemic TM4SF5 overexpression in ApcMin/+ mice promotes hepatic portal hypertension associated with fibrosis.BMB Rep. 2022 Dec;55(12):609-614. doi: 10.5483/BMBRep.2022.55.12.104. BMB Rep. 2022. PMID: 36104259 Free PMC article.
-
Decrypting a path based approach for identifying the interplay between PI3K and GSK3 signaling cascade from the perspective of cancer.Genes Dis. 2022 Feb 22;9(4):868-888. doi: 10.1016/j.gendis.2021.12.025. eCollection 2022 Jul. Genes Dis. 2022. PMID: 35685456 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous