The impact of the endoplasmic reticulum protein-folding environment on cancer development

Wang, Miao; Kaufman, Randal J.

doi:10.1038/nrc3800

Cited by 930 publications

(902 citation statements)

References 195 publications

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“…Similarly, ATF6α protects glioblastoma cells from UV-induced cell death by transactivating BiP, suggesting proto-oncogenic effects of ATF6α. Finally, as BiP expression frequently correlates with tumor status, chemoresistance, and prognosis (Lee and Hendershot 2006;Wang and Kaufman 2014) and as ATF6α is the primary driver of BiP expression, targeting BiP expression via the ATFT6α pathway should be considered a therapeutic approach for cancer (Gutierrez and Simmen 2014;Obacz et al 2017).…”

Section: Atf6αmentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

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Section: Atf6αmentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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“…These transcription factors maintain ER homeostasis. In general, infected hepatocytes cope with ER stress in four steps 5. First, infected cells induce transcription of UPR to reduce the protein load in the ER.…”

Section: Introductionmentioning

confidence: 99%

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

Aydın

Chatterjee

Chandra

et al. 2017

Hepatology Communications

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The mechanism why hepatitis C virus (HCV) clearance by direct‐acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)‐stress response. In this study, we examined whether HCV clearance by interferon‐alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes. The unfolded protein response induces chaperone‐mediated autophagy (CMA) in infected primary human hepatocytes and Huh‐7.5 cells that results in degradation of p53 and induced expression of mouse double minute 2 (Mdm2). Inhibition of p53/Mdm2 interactions by small molecule (nutlin‐3) or silencing Mdm2 did not rescue the p53 degradation, indicating that HCV infection induces degradation of p53 independent of the Mdm2 pathway. Interestingly, we found that HCV infection degrades p53 in a lysosome‐dependent mechanism because lysosome‐associated membrane protein 2A silencing restored p53 degradation. Our results show that HCV clearance induced by interferon‐alpha‐based antiviral therapies normalizes the ER‐stress response and restores p53, whereas HCV clearance by DAAs does neither. We show that decreased expression of p53 in HCV‐infected cirrhotic liver is associated with expression of chaperones associated with ER stress and the CMA response. Conclusion: HCV‐induced ER stress and CMA promote p53 degradation in advanced liver cirrhosis. HCV clearance by DAAs does not restore p53, which provides a potential explanation for why a viral cure by DAAs does not eliminate the HCC risk among patients with advanced liver disease. We propose that resolving the ER‐stress response is an alternative approach to reducing HCC risk among patients with cirrhosis after viral cure. (Hepatology Communications 2017;1:256‐269)

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“…The accumulated misfolded proteins will trigger ER stress as well as its corresponding cellular response called unfolded protein response (UPR), which is a protective action to sustain cell survival. Nevertheless, if the stress is too severe to be handled, apoptosis signaling will be subsequently activated and results in cell death instead (Hetz, 2012; Wang & Kaufman, 2014). Across mammalian species, three key ER stress sensors contribute to the initiation of UPR, including activating transcription factor 6 (ATF6), double‐stranded RNA‐activated protein kinase‐like ER kinase (PERK), and inositol‐requiring transmembrane kinase 1 (IRE1).…”

Section: The Important Role Of Protein Synthesis Pathways In Cancer Amentioning

confidence: 99%

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

et al. 2018

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Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

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The impact of the endoplasmic reticulum protein-folding environment on cancer development

Cited by 930 publications

References 195 publications

Physiological/pathological ramifications of transcription factors in the unfolded protein response

Physiological/pathological ramifications of transcription factors in the unfolded protein response

Interferon‐alpha‐induced hepatitis C virus clearance restores p53 tumor suppressor more than direct‐acting antivirals

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

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