共查询到20条相似文献,搜索用时 15 毫秒
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Dawid Krokowski Jaeseok Han Mridusmita Saikia Mithu Majumder Celvie L. Yuan Bo-Jhih Guan Elena Bevilacqua Ovidio Bussolati Stefan Br?er Peter Arvan Marek Tchórzewski Martin D. Snider Michelle Puchowicz Colleen M. Croniger Scot R. Kimball Tao Pan Antonis E. Koromilas Randal J. Kaufman Maria Hatzoglou 《The Journal of biological chemistry》2013,288(24):17202-17213
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Activating transcription factor 4 is translationally regulated by hypoxic stress 总被引:10,自引:0,他引:10 下载免费PDF全文
Blais JD Filipenko V Bi M Harding HP Ron D Koumenis C Wouters BG Bell JC 《Molecular and cellular biology》2004,24(17):7469-7482
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Marine Melixetian Daniela Bossi Marija Mihailovich Simona Punzi Iros Barozzi Federica Marocchi Alessandro Cuomo Tiziana Bonaldi Giuseppe Testa JeanChristophe Marine Eleonora Leucci Saverio Minucci Pier Giuseppe Pelicci Luisa Lanfrancone 《EMBO reports》2021,22(3)
Transition from proliferative‐to‐invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down‐regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR‐depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re‐expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor‐initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient‐rich conditions by repressing translation of selected ISR RNAs. 相似文献
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Nobuhiko Hiramatsu Carissa Messah Jaeseok Han Matthew M. LaVail Randal J. Kaufman Jonathan H. Lin 《Molecular biology of the cell》2014,25(9):1411-1420
Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress–induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop−/− cells are partially resistant to ER stress–induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK''s down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress–induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a “two-hit” model of ER stress–induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK. 相似文献
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Su Q Wang S Gao HQ Kazemi S Harding HP Ron D Koromilas AE 《The Journal of biological chemistry》2008,283(1):469-475
The endoplasmic reticulum (ER)-resident protein kinase PERK attenuates protein synthesis in response to ER stress through the phosphorylation of translation initiation factor eIF2alpha at serine 51. ER stress induces PERK autophosphorylation at several serine/threonine residues, a process that is required for kinase activation and phosphorylation of eIF2alpha. Herein, we demonstrate that PERK also possesses tyrosine kinase activity. Specifically, we show that PERK is capable of autophosphorylating on tyrosine residues in vitro and in vivo. We further show that tyrosine 615, which is embedded in a highly conserved region of the kinase domain of PERK, is essential for autocatalytic activity. That is, mutation of Tyr-615 to phenylalanine compromises the autophosphorylation capacity of PERK and the phosphorylation of eIF2alpha in vitro and in vivo. The Y615F mutation also impairs the ability of PERK to induce translation of ATF4. Immunoblot analyses with a phosphospecific antibody confirm the phosphorylation of PERK at Tyr-615 both in vitro and in vivo. Thus, our data classify PERK as a dual specificity kinase whose regulation by tyrosine phosphorylation contributes to its optimal activation in response to ER stress. 相似文献