14-3-3σ Gene Loss Leads to Activation of the Epithelial to Mesenchymal Transition Due to the Stabilization of c-Jun Protein.
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.
From the KS215, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
Kumarkrishna
K
Raychaudhuri
Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India, and Graduate Studies, Manipal University, Manipal, Karnataka 576104, India.
Neelam
N
Chaudhary
From the KS215, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
Mansa
M
Gurjar
From the KS215, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
Roseline
R
D'Souza
From the KS215, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
Jazeel
J
Limzerwala
Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India, and.
Subbareddy
S
Maddika
From the KS215, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India, sdalal@actrec.gov.in.
Sorab N
SN
Dalal
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D055550:Protein Stability; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D048948:14-3-3 Proteins; D016755:Proto-Oncogene Proteins c-jun; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D025521:Tumor Suppressor Proteins; C572235:YWHAZ protein, human
14–3-3 protein; E3 ubiquitin ligase; EMT transcription factors; c-Jun transcription factor; epithelial-mesenchymal transition (EMT); nuclear export; tumor progression and metastasis; tumor suppressor gene; ubiquitin-mediated proteolysis