Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression

Sato, Naoya; Urano, Fumihiko; J, Yoon Leem; Sh, Kim; M, Li; Donoviel, Dorit B.; Bernstein, Alan; Lee, AS; Ron, David; Ml, Veselits; Ss, Sisodia; Wang, Shuai

doi:10.1038/35046500

Cited by 135 publications

(91 citation statements)

References 39 publications

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“…Recent studies using serial analysis of gene expression (SAGE) and DNA microarray analysis revealed that genes involved in ER stress including the CHOP gene are induced by a Parkinsonisminducing neurotoxin 6-hydroxydopamine, which forms free radicals. 100,101 Since NO plays an important role in dopaminergic neurodegeneration induced by another dopaminergic neurodegeneration neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), it is worth determining if disruption of the CHOP gene prevents neuronal cells from MPTP-induced apoptosis. 102 Several lines of evidence suggested a link between dysfunction of the ERAD system and the pathogenesis of Parkinson's and polyglutamine disease.…”

Section: Neurodegenerative Diseasementioning

confidence: 99%

Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrestand DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/ GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.

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Section: Neurodegenerative Diseasementioning

confidence: 99%

Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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“…29 UPR activation in cancer is an adaptive survival mechanism that protects cells from ERS-induced cell death. In this study, we characterized CD147 as a UPR inducer that increases Bip transcription, thus promoting human HCC cell survival and increasing chemoresistance in the ERS state.…”

Section: Discussionmentioning

confidence: 99%

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Tang

Zhang

et al. 2012

Cell Death Differ

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The unfolded protein response (UPR) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. However, tumor-specific UPR transducers are largely unknown. In the present study, we identified CD147, a cancer biomarker, as an UPR inducer in hepatocellular carcinoma (HCC). The expression of the major UPR target, Bip, was found to be positively associated with CD147 in human hepatoma tissues. By phosphorylating FAK and Src, CD147-enhanced TFII-I tyrosine phosphorylation at Tyr248. CD147 also induced p-TFII-I nuclear localization and binding to the Bip promoter where endoplasmic reticulum (ER) stress response element 1 (ERSE1) ( À 82/ À 50) is the most efficient target of the three ERSEs, thus increasing transcription of Bip. Furthermore, by inducing UPR, CD147 inhibited HCC cell apoptosis and decreased cell Adriamycin chemosensitivity, thus decreasing the survival rate of hepatoma-bearing nude mice. Together, these results reveal pivotal roles for CD147 in modulating the UPR in HCC and raise the possibility that CD147 is a target that promotes HCC cell apoptosis and increases the sensitivity of tumors to anti-cancer drugs. Therefore, CD147 inhibition provides an opportunity to enhance the efficacy of existing agents and represents a novel target for HCC treatment. The uncontrolled growth and insufficient vascularization of a tumor mass lead to a stressed state in the tumor microenvironment, which includes low oxygen supply, nutrient deprivation and pH changes. Microenvironment stresses directly impinge on the luminal milieu of the endoplasmic reticulum (ER) and might be sufficiently severe to cause ER stress (ERS). 1 These ERS conditions activate a range of cellular stress response pathways, including the unfolded protein response (UPR). 2,3 UPR activation has profound consequences for tumor growth and resistance to radiotherapy and chemotherapy. [4][5][6] Therefore, the UPR might be responsible for the failure of some patients to respond to treatment and is associated with a poor prognosis. 7 Given the observation that UPR is correlated with certain types of aggressive tumors, drug resistance, recurrence and poor survival, 8-11 the inhibition of the UPR pathway may yield more efficient treatments for cancer.Although there is sufficient evidence to indicate that the UPR is generally activated in solid tumors, the UPR remains poorly characterized in cancers. The three major UPR transducers are inositol-requiring enzyme 1 (IRE1), pancreatic kinase-like ER kinase (PERK) and the UPR-specific transcription factor, activating transcription factor 6 (ATF6).These factors all sense the presence of unfolded proteins in the ER lumen and transduce signals to the nucleus that activate the transcription of UPR target genes, such as Bip (also called glucose-regulated protein 78). 12-14 The overexpression of Bip as a result of the three major transducers has been reported in malignant breast disease, colon cancer and gastric and esophageal adenocarcinomas. [15][16][17][18] It has also been...

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“…Misfolded proteins that accumulate in the ER lumen stimulate expression of molecular chaperones, such as BiP, and transcription factors, such as CHOP (39 -41). Some studies claim that this ER stress response is significantly diminished by ADlinked presenilin mutations (23,42), while others demonstrate that up-regulation of the ER stress-induced signaling pathway and chaperones are independent of presenilin expression (25) and are not altered by knock-in presenilin-1 mutations (43). In addition to these discrepancies, the potential impact of alterations in the stress response caused by presenilin mutations has not been assessed at the synaptic level.…”

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confidence: 99%

“…Presenilin interacts directly with a number of proteins (17) and affects a range of physiological functions, including intracellular Ca 2ϩ homeostasis (18 -20), capacitative Ca 2ϩ entry (20 -22), the endoplasmic reticulum (ER) stress response (23)(24)(25), and apoptosis (26 -28). Some of these effects have been suggested to contribute to hyperproduction of Aß42 or otherwise promote neuronal toxicity that might be relevant to AD pathogenesis (22,29).…”

mentioning

confidence: 99%

Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons

et al. 2006

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It has been shown that presenilin is involved in maintaining Ca 2؉ homeostasis in neurons, including regulating endoplasmic reticulum (ER) Ca 2؉ storage. From studies of primary cultures and cell lines, however, its role in stress-induced responses is still controversial. In the present study we analyzed the effects of presenilin mutations on membrane currents and synaptic functions in response to stress using an in vivo preparation. We examined voltage-gated K ؉ and Ca 2؉ currents at the Drosophila larval neuromuscular junction (NMJ) with voltage-clamp recordings. Our data showed that both currents were generally unaffected by loss-of-function or Alzheimer's disease (AD) -associated presenilin mutations under normal or stress conditions induced by heat shock (HS) or ER stress. In larvae expressing the mutant presenilins, prolonged Ca 2؉ tail current, reflecting slower deactivation kinetics of Ca 2؉ channels, was observed 1 day after stress treatments were terminated. It was further demonstrated that the L-type Ca 2؉ channel was specifically affected under these conditions. Moreover, synaptic plasticity at the NMJ was reduced in larvae expressing the mutant presenilins. At the behavioral level, memory in adult flies was impaired in the presenilin mutants 1 day after HS. The results show that presenilin function is important during the poststress period and its impairment contributes to memory dysfunction observed during adaptation to normal conditions after stress. Our findings suggest a new stress-related mechanism by which presenilin may be implicated in the neuropathology of

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Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression

Cited by 135 publications

References 39 publications

Roles of CHOP/GADD153 in endoplasmic reticulum stress

Roles of CHOP/GADD153 in endoplasmic reticulum stress

CD147 induces UPR to inhibit apoptosis and chemosensitivity by increasing the transcription of Bip in hepatocellular carcinoma

Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons

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