Sequestosome 1/p62 facilitates HER2-induced mammary tumorigenesis through multiple signaling pathways
| العنوان: | Sequestosome 1/p62 facilitates HER2-induced mammary tumorigenesis through multiple signaling pathways |
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| المؤلفون: | X Cai-McRae, H Zhong, Vassiliki Karantza |
| المصدر: | Oncogene. 34:2968-2977 |
| بيانات النشر: | Springer Science and Business Media LLC, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Cancer Research, Cell Survival, NF-E2-Related Factor 2, Receptor, ErbB-2, Transgene, Cell Culture Techniques, Mice, Nude, Breast Neoplasms, Mice, Transgenic, Mice, Sequestosome 1, Cell Line, Tumor, Sequestosome-1 Protein, Genetics, Animals, Humans, PTEN, Tensin, education, Molecular Biology, Protein kinase B, Adaptor Proteins, Signal Transducing, education.field_of_study, Kelch-Like ECH-Associated Protein 1, biology, Intracellular Signaling Peptides and Proteins, PTEN Phosphohydrolase, Wnt signaling pathway, Signal transducing adaptor protein, Cell Transformation, Neoplastic, MCF-7 Cells, biology.protein, Cancer research, Female, Signal transduction, Neoplasm Transplantation, Signal Transduction |
| الوصف: | Previous studies have shown that increased levels of the adaptor protein Sequestosome 1/p62 are observed in human breast cancers and significantly correlate with HER2 overexpression. However, the role of p62 in the pathophysiology of HER2-induced mammary tumorigenesis has not yet been investigated. In this study, we report that p62 facilitates HER2-mediated cell survival in both two-dimensional and three-dimensional cell culture and that HER2-induced cellular transformation requires p62, as well as NRF2, which is known to become stabilized by its release from Kelch-like ECH-associated protein 1 (KEAP1) via p62-KEAP1 interaction. In agreement with these results, genetic ablation of p62 delays HER2-induced mammary tumorigenesis in tumor cell allografts in nude mice, and in MMTV-Neu transgenic mice. We also report that ablation of p62 impairs AKT and β-catenin activation in association with PTEN (phosphatase and tensin homolog deleted on chromosome ten) accumulation, both in vitro and in vivo. Further in vivo studies suggest that loss of p62 also impairs NF-κB and NRF2 activation. Collectively, our results provide compelling evidence that p62 contributes to HER2-induced mammary tumorigenesis through multiple signaling pathways, including the PTEN/phosphoinositide-3-kinase/AKT axis, WNT/β-catenin signaling, the NF-κB pathway and the NRF2-KEAP1 axis, and offer novel insights into the potential role of p62 in the regulation of the tumor suppressor PTEN. |
| تدمد: | 1476-5594 0950-9232 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4f78838383840d47bf17c7155fb2edc7Test https://doi.org/10.1038/onc.2014.244Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4f78838383840d47bf17c7155fb2edc7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765594 09509232 |
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