14-3-3σ Gene Loss Leads to Activation of the Epithelial to Mesenchymal Transition Due to the Stabilization of c-Jun Protein
| Autor: | Neelam Chaudhary, Mansa Gurjar, Sorab N. Dalal, Jazeel F. Limzerwala, Subbareddy Maddika, Roseline D'Souza, Kumarkrishna Raychaudhuri |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition Tumor suppressor gene Proto-Oncogene Proteins c-jun Active Transport Cell Nucleus Biology Biochemistry Cell Line 03 medical and health sciences Humans Epithelial–mesenchymal transition Nuclear export signal Molecular Biology Transcription factor Regulation of gene expression Cell Nucleus Protein Stability Tumor Suppressor Proteins c-jun Ubiquitination Cell Biology Cell biology Ubiquitin ligase 030104 developmental biology 14-3-3 Proteins Gene Expression Regulation Tumor progression Gene Knockdown Techniques biology.protein Cancer research Snail Family Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 291(31) |
| ISSN: | 1083-351X |
| Popis: | Loss of 14-3-3σ has been observed in multiple tumor types; however, the mechanisms by which 14-3-3σ loss leads to tumor progression are not understood. The experiments in this report demonstrate that loss of 14-3-3σ leads to a decrease in the expression of epithelial markers and an increase in the expression of mesenchymal markers, which is indicative of an induction of the epithelial to mesenchymal transition (EMT). The EMT was accompanied by an increase in migration and invasion in the 14-3-3σ(-/-) cells. 14-3-3σ(-/-) cells show increased stabilization of c-Jun, resulting in an increase in the expression of the EMT transcription factor slug. 14-3-3σ induces the ubiquitination and degradation of c-Jun in an FBW7-dependent manner. c-Jun ubiquitination is dependent on the presence of an intact nuclear export pathway as c-Jun is stabilized and localized to the nucleus in the presence of a nuclear export inhibitor. Furthermore, the absence of 14-3-3σ leads to the nuclear accumulation and stabilization of c-Jun, suggesting that 14-3-3σ regulates the subcellular localization of c-Jun. Our results have identified a novel mechanism by which 14-3-3σ maintains the epithelial phenotype by inhibiting EMT and suggest that this property of 14-3-3σ might contribute to its function as a tumor suppressor gene. |
| Databáze: | OpenAIRE |
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