dc.creator | Mansier O., Prouzet-Mauléon V., Jégou G., Barroso K., Pelizzari Raymundo D., Chauveau A., Pierre-Yves D., Lagarde V., Turcq B., Jean-Max P., Jean-François V., James C., Praloran V., Voutetakis K., Chatziioannou A., François-Xavier M., Chevet E., Lippert E. | en |
dc.date.accessioned | 2023-01-31T08:56:54Z | |
dc.date.available | 2023-01-31T08:56:54Z | |
dc.date.issued | 2019 | |
dc.identifier | 10.3390/cancers11121921 | |
dc.identifier.issn | 20726694 | |
dc.identifier.uri | http://hdl.handle.net/11615/76288 | |
dc.description.abstract | Background: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase – Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes. © 2019, MDPI AG. All rights reserved. | en |
dc.language.iso | en | en |
dc.source | Cancers | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85076165629&doi=10.3390%2fcancers11121921&partnerID=40&md5=2d1555859e47fa7960016fdb087ebdee | |
dc.subject | calreticulin | en |
dc.subject | cell protein | en |
dc.subject | lectin | en |
dc.subject | mutant protein | en |
dc.subject | proteasome | en |
dc.subject | protein TXNDC11 | en |
dc.subject | small interfering RNA | en |
dc.subject | unclassified drug | en |
dc.subject | X box binding protein 1 | en |
dc.subject | Article | en |
dc.subject | controlled study | en |
dc.subject | endoplasmic reticulum | en |
dc.subject | endoplasmic reticulum associated degradation | en |
dc.subject | endoplasmic reticulum stress | en |
dc.subject | genetic transfection | en |
dc.subject | HEK293T cell line | en |
dc.subject | hematopoietic cell line | en |
dc.subject | homeostasis | en |
dc.subject | human | en |
dc.subject | human cell | en |
dc.subject | immunoprecipitation | en |
dc.subject | JAK-STAT signaling | en |
dc.subject | molecular dynamics | en |
dc.subject | myeloproliferative neoplasm | en |
dc.subject | protein degradation | en |
dc.subject | protein expression level | en |
dc.subject | protein motif | en |
dc.subject | RNA interference | en |
dc.subject | unfolded protein response | en |
dc.subject | wild type | en |
dc.subject | MDPI AG | en |
dc.title | The expression of myeloproliferative neoplasm-associated calreticulin variants depends on the functionality of er-associated degradation | en |
dc.type | journalArticle | en |