The Pervasive Effects of ER Stress on a Typical Endocrine Cell: Dedifferentiation, Mesenchymal Shift and Antioxidant Response in the Thyrocyte

Ulianich, Luca; Mirra, Paola; Garbi, Corrado; Calı̀, Gaetano; Conza, Domenico; Treglia, Antonella Sonia; Miraglia, Alessandro; Punzi, Dario; Miele, Claudia; Raciti, Gregory Alexander; Béguinot, Francesco; Consiglio, Eduardo; Jeso, Bruno Di

doi:10.3389/fendo.2020.588685

Cited by 7 publications

(7 citation statements)

References 50 publications

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“…The consequence of this dedifferentiation would be at best an impairment of normal liver function and at worst an increased propensity toward hepatocellular transformation. The association of dedifferentiation with exacerbated ER stress has also been observed in other cell types, most notably secretory cells including pancreatic beta cells (56–58) and thyrocytes (59), suggesting that it could be a conserved feature of UPR signaling in professional secretory cells.…”

Section: Discussionmentioning

confidence: 83%

Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes

Shah

Huck

Duncan

et al. 2023

Preprint

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In all eukaryotic cell types, the unfolded protein response (UPR) upregulates factors that promote protein folding and misfolded protein clearance to help alleviate endoplasmic reticulum (ER) stress. Yet ER stress in the liver is uniquely accompanied by the suppression of metabolic genes, the coordination and purpose of which is largely unknown. Here, we used unsupervised machine learning to identify a cluster of correlated genes that were profoundly suppressed by persistent ER stress in the liver. These genes, which encode diverse functions including metabolism, coagulation, drug detoxification, and bile synthesis, are likely targets of the master regulator of hepatocyte differentiation HNF4α. The response of these genes to ER stress was phenocopied by liver-specific deletion of HNF4α. Strikingly, while deletion of HNF4α exacerbated liver injury in response to an ER stress challenge, it also diminished UPR activation and partially preserved ER ultrastructure, suggesting attenuated ER stress. Conversely, pharmacological maintenance of hepatocyte identity in vitro enhanced sensitivity to stress. Several pathways potentially link HNF4α to ER stress sensitivity, including control of expression of the tunicamycin transporter MFSD2A; modulation of IRE1/XBP1 signaling; and regulation of Pyruvate Dehydrogenase. Together, these findings suggest that HNF4α activity is linked to hepatic ER homeostasis through multiple mechanisms.

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Section: Discussionmentioning

confidence: 83%

Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes

Shah

Huck

Duncan

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…4 B ) but again was not more elevated in TG rdw/rdw mice (4.1 ± 2.2 fold) than in TG cog/cog mice (13.2 ± 8.7 fold). Moreover, because chronic continuous ER stress has been associated with subtle signs of dedifferentiation in thyrocytes ( 11 , 33 ) as well as Ire1-mediated mRNA decay (in various cell types ( 34 , 35 , 36 )), we examined thyroidal TG mRNA levels and observed an average decrease of 56 ± 8% of WT levels in TG rdw/rdw mice and 62 ± 14% in TG cog/cog mice—both significantly different from WT but not different from each other ( Fig. 4 C ).…”

Section: Resultsmentioning

confidence: 99%

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

Zhang

Malik

Young

et al. 2022

Journal of Biological Chemistry

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“…ER stress, for example, induces EMT and, thus, increases the migration of lens epithelial cells ( 97 ). ER stress inhibits cell differentiation, downregulates the expression of cadherin-1 and cadherin-16, and upregulates the expression of vimentin and SNAI1, thereby indicating the loss of epithelial features and a shift toward a mesenchymal phenotype in thyroid cells ( 98 ). Alveolar epithelial cells undergo ER stress in a hypoxic microenvironment, which is accompanied by the increased expression of mesenchymal markers both in vivo and in vitro ( 99 ).…”

Section: Er Stress and Cancer Cell Plasticitymentioning

confidence: 99%

“…In noncancerous cells, ER stress has been shown to exert a direct effect on EMP. ER stress, for example, induces EMT and, thus, increases the migration of lens epithelial cells (97). ER stress inhibits cell differentiation, downregulates the expression of cadherin-1 and cadherin-16, and upregulates the expression of vimentin and SNAI1, thereby indicating the loss of epithelial features and a shift toward a mesenchymal phenotype in thyroid cells (98).…”

Section: Er Stress and Empmentioning

confidence: 99%

Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells

Wang

2023

Front. Oncol.

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Cellular plasticity is a well-known dynamic feature of tumor cells that endows tumors with heterogeneity and therapeutic resistance and alters their invasion–metastasis progression, stemness, and drug sensitivity, thereby posing a major challenge to cancer therapy. It is becoming increasingly clear that endoplasmic reticulum (ER) stress is a hallmark of cancer. The dysregulated expression of ER stress sensors and the activation of downstream signaling pathways play a role in the regulation of tumor progression and cellular response to various challenges. Moreover, mounting evidence implicates ER stress in the regulation of cancer cell plasticity, including epithelial–mesenchymal plasticity, drug resistance phenotype, cancer stem cell phenotype, and vasculogenic mimicry phenotype plasticity. ER stress influences several malignant characteristics of tumor cells, including epithelial-to-mesenchymal transition (EMT), stem cell maintenance, angiogenic function, and tumor cell sensitivity to targeted therapy. The emerging links between ER stress and cancer cell plasticity that are implicated in tumor progression and chemoresistance are discussed in this review, which may aid in formulating strategies to target ER stress and cancer cell plasticity in anticancer treatments.

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The Pervasive Effects of ER Stress on a Typical Endocrine Cell: Dedifferentiation, Mesenchymal Shift and Antioxidant Response in the Thyrocyte

Cited by 7 publications

References 50 publications

Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes

Interference with the HNF4-dependent gene regulatory network diminishes ER stress in hepatocytes

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells

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