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Niwa, Maho; Patil, Christopher K.; DeRisi, Joe; Walter, Peter

doi:10.1186/gb-2004-6-1-r3

Cited by 65 publications

(40 citation statements)

References 37 publications

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“…Presumably, the activation of Xbp1 target genes is required during normal development, since Xbp1 ''knock-out'' mice are embryonic lethal and have defects during liver formation and plasma cell differentiation [70,71]. IRE1 and Hac1 function in a linear pathway in yeast, since Hac1 is the only substrate of IRE1 endonuclease activity and gene expression profiling revealed identical patterns in cells mutant for either gene [72]. However, this is not the case in C. elegans, where IRE1 and Xbp1 mutants do not have completely identical phenotypes, which suggests the existence of an Xbp1-independent pathway downstream of IRE1 [56].…”

Section: Er Stress and The Unfolded Protein Response (Upr)mentioning

confidence: 99%

Cellular responses to endoplasmic reticulum stress and apoptosis

2009

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The endoplasmic reticulum (ER) is the cell organelle where secretory and membrane proteins are synthesized and folded. Correctly folded proteins exit the ER and are transported to the Golgi and other destinations within the cell, but proteins that fail to fold properly-misfolded proteins-are retained in the ER and their accumulation may constitute a form of stress to the cell-ER stress. Several signaling pathways, collectively known as unfolded protein response (UPR), have evolved to detect the accumulation of misfolded proteins in the ER and activate a cellular response that attempts to maintain homeostasis and a normal flux of proteins in the ER. In certain severe situations of ER stress, however, the protective mechanisms activated by the UPR are not sufficient to restore normal ER function and cells die by apoptosis. Most research on the UPR used yeast or mammalian model systems and only recently Drosophila has emerged as a system to study the molecular and cellular mechanisms of the UPR. Here, we review recent advances in Drosophila UPR research, in the broad context of mammalian and yeast literature.

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Section: Er Stress and The Unfolded Protein Response (Upr)mentioning

confidence: 99%

Cellular responses to endoplasmic reticulum stress and apoptosis

2009

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“…To date, only two substrate mRNAs for IRE1 have been identified: homologous to ATF/CREB1 (HAC1) mRNA in yeast [127,128] and XBP-1 mRNA in mammals. Three independent genome-wide screens did not identify additional mRNA substrates for Ire1p in yeast [129]. The splicing mechanism for these mRNAs was extensively reviewed recently [1,2].…”

Section: Ire1mentioning

confidence: 99%

Divergent Roles of IRE1α and PERK in the Unfolded Protein Response

Schröder

Kaufman²

2006

CMM

117

104

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The endoplasmic reticulum (ER) provides unique machinery for the folding and posttranslational modification of many secretory and transmembrane proteins in eukaryotic cells. The unfolded protein response (UPR) is a signal transduction network from the ER to the nucleus activated when the folding demand imposed by nascent, unfolded polypeptide chains exceeds the capacity of the ER protein folding machinery. In all eukaryotes the UPR maintains the physiological balance between folding demand and capacity of the ER by regulating adaptive responses to this stress situation. These include an increase in the folding capacity of the ER through induction of ER resident molecular chaperones and protein foldases, and a decrease in the folding demand on the ER by upregulation of ER associated degradation (ERAD), attenuation of general translation in metazoans, and stimulation of ER synthesis to dilute the unfolded protein load. In higher eukaryotes the UPR gained control over inflammatory and immune responses by controlling the activity of the transcription factor NF-kappaB to combat viral infections associated with an increased synthesis of viral glycoproteins. Similarly, in multicellular organisms apoptotic programs are controlled by the UPR to eliminate cells whose folding problems in the ER cannot be resolved by coordinated regulation of adaptive, inflammatory, and immune responses. In this review we will summarize our current understanding of signal transduction mechanisms involved in the mammalian UPR, and discuss examples to highlight the regulation of adaptive, inflammatory, immune, and apoptotic responses by the UPR.

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“…The cytosolic endoribonuclease domain of Ire1p is then activated and excises the intron in the unspliced HAC1 mRNA, Hac1 u (u for uninduced), generating spliced HAC1 mRNA, Hac1 i (i for induced) (15)(16)(17). The splicing event is so specific that Hac1 u mRNA has been shown to be the only substrate for Ire1p in yeast (18). A tRNA ligase Rlg1p is then required to rejoin the cleaved ends (19).…”

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confidence: 99%

Ricin Inhibits Activation of the Unfolded Protein Response by Preventing Splicing of the HAC1 mRNA

Parikh

Tortora²,

et al. 2008

Journal of Biological Chemistry

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Ricin A chain (RTA) inhibits protein synthesis by removing a specific adenine from the highly conserved ␣-sarcin/ricin loop in the large rRNA. Expression of RTA with its own signal sequence in yeast resulted in its translocation into the endoplasmic reticulum (ER) and subsequent glycosylation. Because RTA must unfold within the ER, it may be vulnerable to host defenses, such as the unfolded protein response (UPR). UPR was induced in cells expressing an active site mutant but not the wild type RTA, indicating that the active site of RTA played a role in perturbing the ER stress response. The inactive RTA without the signal sequence did not induce UPR, indicating that translocation into the ER was critical for induction of UPR. The wild type RTA inhibited activation of UPR not only due to ER stress induced by the protein itself but also by global effectors such as tunicamycin and dithiothreitol. Mature RTA without the signal sequence also inhibited UPR, providing evidence that inhibition of UPR occurred on the cytosolic face of the ER. RTA could not inhibit UPR when the spliced form of HAC1 mRNA was provided in trans, indicating that it had a direct effect on UPR upstream of HAC1-dependent transcriptional activation. Only the precursor form of HAC1 mRNA was detected in cells expressing RTA after exposure to ER stress, demonstrating that ricin inhibits activation of UPR by preventing HAC1 mRNA splicing. The RTA mutants that depurinated ribosomes but did not kill cells were not able to inhibit activation of UPR by tunicamycin, providing evidence that the inability to activate UPR in response to ER stress contributes to the cytotoxicity of ricin.

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Cited by 65 publications

References 37 publications

Cellular responses to endoplasmic reticulum stress and apoptosis

Cellular responses to endoplasmic reticulum stress and apoptosis

Divergent Roles of IRE1α and PERK in the Unfolded Protein Response

Ricin Inhibits Activation of the Unfolded Protein Response by Preventing Splicing of the HAC1 mRNA

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Untitled

Cited by 65 publications

References 37 publications

Cellular responses to endoplasmic reticulum stress and apoptosis

Cellular responses to endoplasmic reticulum stress and apoptosis

Divergent Roles of IRE1&#945; and PERK in the Unfolded Protein Response

Ricin Inhibits Activation of the Unfolded Protein Response by Preventing Splicing of the HAC1 mRNA

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Divergent Roles of IRE1α and PERK in the Unfolded Protein Response