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SQSTM1/p62 regulates the expression of junctional proteins through epithelial-mesenchymal transition factors.

ABSTRACT: The epithelial to mesenchymal transition (EMT) is an essential process during development and during tumor progression. Here, we observed the accumulation of the selective autophagy receptor and signaling adaptor sequestosome-1 (SQSTM1/p62) during growth factor-induced EMT in immortalized and tumor-derived epithelial cell lines. Modulation of the p62 level regulated the expression of junctional proteins. This effect was dependent on the ubiquitin-associated domain of p62, which stabilized the TGF?/Smad signaling co-activator Smad4 and the EMT transcription factor Twist. This study highlights a novel function of p62 in a major epithelial phenotypic alteration.

SUBMITTER: Bertrand M

PROVIDER: S-EPMC4353226 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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SQSTM1/p62 regulates the expression of junctional proteins through epithelial-mesenchymal transition factors.

Bertrand Matthieu M Petit Valérie V Jain Ashish A Amsellem Raymonde R Johansen Terje T Larue Lionel L Codogno Patrice P Beau Isabelle I

Cell cycle (Georgetown, Tex.) 20150101 3

The epithelial to mesenchymal transition (EMT) is an essential process during development and during tumor progression. Here, we observed the accumulation of the selective autophagy receptor and signaling adaptor sequestosome-1 (SQSTM1/p62) during growth factor-induced EMT in immortalized and tumor-derived epithelial cell lines. Modulation of the p62 level regulated the expression of junctional proteins. This effect was dependent on the ubiquitin-associated domain of p62, which stabilized the TG ...[more]

PMID: 25496309

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Project description:BACKGROUND:Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is progressive and not fully reversible. Cigarette smoking is one of the most commonly and important risk factors for COPD, which contributes to airway remodeling, the outstanding pathological changes in COPD. One potential mechanism which might be important for airway remodeling is the process called epithelial-mesenchymal transition (EMT). However, the underlying molecular mechanisms of EMT in CS-induced COPD are still poorly understood. METHODS:Two Gene Expression Omnibus (GEO) datasets (GSE108134 and GSE5058) were combined to identify the key genes involved in COPD. Then, single-gene analysis of Lyn was performed. Lyn expression was confirmed in patients with COPD. 16HBE cells were treated with cigarette smoking extracts (CSE). Wild type (WT) C57BL/6?J mice and Lyn+/+ transgenic mice were exposed to CSE to establish CS-exposed model. Pathological changes were observed by hematoxylin-eosin staining. The expression levels of EMT markers were examined by using western blot and immunofluorescence. The expression and phosphorylation levels of Lyn and Smad2/3 were detected as well. RESULTS:The gain of mesenchymal markers vimentin and ?-SMA with a concomitant loss of E-cadherin was observed in both in vivo and in vitro studies. Meanwhile, cigarette smoking extracts (CSE) induced EMT in 16HBE cells in a time- and dose- dependent manner. Furthermore, by analyzing GEO datasets and using molecular methods, we explored a kinase, Lyn, its expression correlated with the expression of E-cadherin, vimentin and ?-SMA in CS-exposed model. Moreover, we found that EMT induced by CSE was regulated by activated Lyn through phosphorylation of Smad2/3. CONCLUSIONS:In summary, we found that Lyn regulates epithelial-mesenchymal transition in CS-exposed model through Smad2/3 signaling. As a kinase, Lyn is "druggable", and might provide a therapeutic opportunity for targeting EMT. Therefore, our research might provide a new method to treat COPD by targeting Lyn kinase specifically.

Dataset Information

SQSTM1/p62 regulates the expression of junctional proteins through epithelial-mesenchymal transition factors.

Publications

SQSTM1/p62 regulates the expression of junctional proteins through epithelial-mesenchymal transition factors.

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