The UPR and cell fate at a glance

Merksamer, Philip I.; Papa, Feroz R.

doi:10.1242/jcs.035832

Cited by 107 publications

(105 citation statements)

References 37 publications

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“…A second major response is called the unfolded protein response (UPR), which refers to the transcriptional up-regulation of genes that are thought to enable the cell to cope with and fold misfolded proteins. 15 Various stress stimuli such as hypoxia, ischemia, and starvation interfere with ER function, causing ER stress, which is defined by the accumulation of unfolded proteins in the ER. As a selective and potent inhibitor of the 26S proteasome, the inhibition of the 26S proteasome by bortezomib leads to the accumulation of misfolded proteins, resulting in ER stress followed by a coordinated cellular UPR.…”

Section: Introductionmentioning

confidence: 99%

Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition

Dang

et al. 2012

Blood

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Section: Introductionmentioning

confidence: 99%

Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition

Dang

et al. 2012

Blood

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“…Under various physiological (increased secretory load) or pathological conditions (accumulation of mutated proteins) folding or protein assembly is compromised leading to up-regulation of unfolded protein response (72). The ER quality control mechanism, including up-regulation of chaperone proteins, ensures that only properly folded proteins can be transported out of the ER, otherwise they get degraded in the cytosol by a process called ER-associated protein degradation (73). If the stress sustains, the compensatory mechanisms get overwhelmed leading to apoptosis or cell death (48,74).…”

Section: Discussionmentioning

confidence: 99%

Regulatory Coordination between Two Major Intracellular Homeostatic Systems

Dokładny¹,

Zuhl

Mandell

et al. 2013

Journal of Biological Chemistry

138

108

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Background: Both autophagy and the heat stress response represent protein management alternatives for the stressed cell. Their inter-relationship is not known. Results: Heat shock factor-1 knockdown increases and HSP70 overexpression inhibits autophagy in cell culture model. Preactivation of heat shock inhibits exercise-induced autophagy in humans. Conclusion: Heat shock response plays a negative role in autophagy regulation. Significance: Heat shock response regulates autophagy.

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“…This leads to the release of PERK, a pancreatic ER kinase that, when freely recovered in the cells, is activated by homodimerization and catalytic auto-phosphorylation (Merksamer and Papa, 2010). Phopho-PERK then phosphorylates the initiation factor peIF2a that increases the transcription of ATF4 (Zhang and Kaufman, 2006).…”

Section: Discussionmentioning

confidence: 99%

ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1

Duplan

Giaime

Viotti

et al. 2013

Journal of Cell Science

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SummaryParkin and DJ-1 are two multi-functional proteins linked to autosomal recessive early-onset Parkinson's disease (PD) that have been shown to functionally interact by as-yet-unknown mechanisms. We have delineated the mechanisms by which parkin controls DJ-1. Parkin modulates DJ-1 transcription and protein levels via a signaling cascade involving p53 and the endoplasmic reticulum (ER)-stressinduced active X-box-binding protein-1S (XBP-1S). Parkin triggers the transcriptional repression of p53 while p53 downregulates DJ-1 protein and mRNA expressions. We show that parkin-mediated control of DJ-1 is fully p53-dependent. Furthermore, we establish that p53 lowers the protein and mRNA levels of XBP-1S. Accordingly, we show that parkin ultimately upregulates XBP-1 levels. Subsequently, XBP-1S physically interacts with the DJ-1 promoter, thereby enhancing its promoter trans-activation, mRNA levels and protein expression. This data was corroborated by the examination of DJ-1 in both parkin-and p53-null mice brains. This transcriptional cascade is abolished by pathogenic parkin mutations and is independent of its ubiquitin-ligase activity. Our data establish a parkindependent ER-stress-associated modulation of DJ-1 and identifies p53 and XBP-1 as two major actors acting downstream of parkin in this signaling cascade in cells and in vivo. This work provides a mechanistic explanation for the increase in the unfolded protein response observed in PD pathology, i.e. that it is due to a defect in parkin-associated control of DJ-1.

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The UPR and cell fate at a glance

Cited by 107 publications

References 37 publications

Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition

Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition

Regulatory Coordination between Two Major Intracellular Homeostatic Systems

ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP-1

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