In a healthy cell, transmembrane and secretory proteins are folded within the ER lumen. However, ER dysfunction causes luminal protein folding to stall, triggering chaperone expression and the transient inhibition of translation, among other effects. On page 477, Bruno Di Jeso and colleagues explore a new cellular response to ER stress. The authors show that PC Cl3 thyroid cells that are treated with the ER stressors thapsigargin (TH) or tunicamycin (TN) undergo dedifferentiation – that is, they selectively downregulate thyroid-specific gene expression. Moreover, in a second thyroid cell line, treatment with TH or TN leads to lower E-cadherin levels, the formation of actin stress fibres and decreased transepithelial electrical resistance – three hallmarks of epithelial-to-mesenchymal transition. The authors go on to show that downregulation of E-cadherin and dedifferentiation are both blocked by PP2, an inhibitor of the tyrosine kinase Src. They propose a Src-dependent protective mechanism, in which the downregulation of tissue-specific genes and loss of epithelial structure promotes cell survival in the face of ER stress. These results highlight the diversity of cellular stress responses and survival tactics.
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