The nonsense-mediated RNA decay pathway is disrupted in inflammatory myofibroblastic tumors

Lü, Jingwei; Plank, Terra-Dawn M.; Su, Fang; Shi, Xiujuan; Liu, Chen; Ji, Yuan; Li, ShuaiJun; Huynh, Andrew; Shi, Chao; Zhu, Bo; Yang, Guang‐Fu; Wu, Yanming; Wilkinson, Miles; Lu, Yi

doi:10.1172/jci86508

Cited by 49 publications

(48 citation statements)

References 18 publications

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“…Consistent with this, IMTs with UPF1 mutations were found to have elevated levels of chemokines and infiltrating B cells. Together, these data support a model in which UPF1 mutations downregulate NMD, leading to NIK mRNA upregulation and the consequent immune infiltration characteristic of benign IMTs [41]. …”

Section: Stress and Nmd In Tumorssupporting

confidence: 73%

“…In support of this notion, Wang et al found that overexpression of the NMD factor, UPF1, reduced both the number and size of PC3 prostate tumor cell colonies in soft agar [75]. Clinical evidence for this notion comes from recent studies showing that debilitating mutations in the UPF1 gene are extremely common in pancreatic adenosquamous (ASC) tumors [109] and inflammatory myofibroblastic tumors (IMT) [41]. In both ASC and IMT, the UPF1 mutations are somatic and they are clustered in specific regions of the gene that cause alternative UPF1 splicing, leading to low or undetectable levels of UPF1 protein.…”

Section: Stress and Nmd In Tumorsmentioning

confidence: 99%

“…Of note, however, NMD inhibition can also trigger events that favor tumor formation (such as changes in signaling pathways, including the TGFβ/BMP, Wnt, and Notch pathways [28]), and indeed evidence suggests the NMD pathway can act as a tumor suppressor pathway [41, 75, 109]. Thus, whether loss of NMD stimulates or inhibits tumor formation likely depends on a delicate balance of several pro- and anti-tumor mechanisms, with the GADD45B/Gadd45-dependent pro-apoptotic mechanism being just one of many events triggered by loss of NMD.…”

Section: Nmd and Apoptosismentioning

confidence: 99%

“…One example is cancer. NMD activator therapy would be predicted to be efficacious for the treatment of tumors, as increasing evidence suggests that NMD is a tumor suppressor pathway [41, 91, 109] and tumors are known to have suppressed NMD as a result of hypoxia and ER stress [60, 75]. NMD activator therapy could also potentially protect normal cells from chemotherapy-induced death.…”

Section: Perspectivesmentioning

confidence: 99%

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Stress and the nonsense-mediated RNA decay pathway

Goetz

Wilkinson

2017

Cell. Mol. Life Sci.

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Cells respond to internal and external cellular stressors by activating stress response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly-conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway—Nonsense-Mediated RNA Decay (NMD)—serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that “NMD therapy” may provide clinical benefit by downmodulating stress responses.

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Section: Stress and Nmd In Tumorssupporting

confidence: 73%

Section: Stress and Nmd In Tumorsmentioning

confidence: 99%

Section: Nmd and Apoptosismentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

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Stress and the nonsense-mediated RNA decay pathway

Goetz

Wilkinson

2017

Cell. Mol. Life Sci.

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“…Impaired UPF1 function and/or NMD has been identified in genetic diseases, cancer, and viral infection. For example, the disease gene DUX4 , which causes facioscapulohumeral muscular dystrophy, triggers UPF1 proteolysis (Feng et al, 2015); UPF1 is commonly subject to somatic mutations in pancreatic adenosquamous carcinoma (Liu et al, 2014) and inflammatory myofibroblastic tumors (Lu et al, 2016); the hepatitis C virus core protein interacts with a component of the exon-junction complex and disrupts NMD (Ramage et al, 2015). In each case, perturbations in UPF1 or associated NMD factors may inhibit normal protein decay as well as RNA decay, potentially implicating impaired protein quality control in these diseases.…”

Section: Discussionmentioning

confidence: 99%

The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity

2017

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SUMMARY UPF1 is an RNA helicase that orchestrates nonsense-mediated decay and other RNA surveillance pathways. While UPF1 is best known for its basal cytoprotective role in degrading aberrant RNAs, UPF1 also degrades specific normally occurring mRNAs to regulate diverse cellular processes. Here, we describe a role for UPF1 in regulated protein decay, wherein UPF1 acts as an E3 ubiquitin ligase to repress human skeletal muscle differentiation. Suppressing UPF1 accelerates myogenesis, while ectopically increasing UPF1 levels slows myogenesis. UPF1 promotes the decay of MYOD protein, a transcription factor that is a master regulator of myogenesis, while leaving MYOD mRNA stability unaffected. UPF1 acts as an E3 ligase via its RING domain to promote MYOD protein ubiquitination and degradation. Our data characterize a regulatory role for UPF1 in myogenesis and demonstrate that UPF1 provides a mechanistic link between the RNA and protein decay machineries in human cells.

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Tau‐induced deficits in nonsense‐mediated mRNA decay contribute to neurodegeneration

Zuniga

Levy

Ramirez

et al. 2022

Alzheimer's & Dementia

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Introduction While brains of patients with Alzheimer's disease and related tauopathies have evidence of altered RNA processing, we lack a mechanistic understanding of how altered RNA processing arises in these disorders and if such changes are causally linked to neurodegeneration. Methods Using Drosophila melanogaster models of tauopathy, we find that overall activity of nonsense‐mediated mRNA decay (NMD), a key RNA quality‐control mechanism, is reduced. Genetic manipulation of NMD machinery significantly modifies tau‐induced neurotoxicity, suggesting that deficits in NMD are causally linked to neurodegeneration. Mechanistically, we find that deficits in NMD are a consequence of aberrant RNA export and RNA accumulation within nuclear envelope invaginations in tauopathy. We identify a pharmacological activator of NMD that suppresses neurodegeneration in tau transgenic Drosophila, indicating that tau‐induced deficits in RNA quality control are druggable. Discussion Our studies suggest that NMD activators should be explored for their potential therapeutic value to patients with tauopathies.

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The nonsense-mediated RNA decay pathway is disrupted in inflammatory myofibroblastic tumors

Cited by 49 publications

References 18 publications

Stress and the nonsense-mediated RNA decay pathway

Stress and the nonsense-mediated RNA decay pathway

The RNA Surveillance Factor UPF1 Represses Myogenesis via Its E3 Ubiquitin Ligase Activity

Tau‐induced deficits in nonsense‐mediated mRNA decay contribute to neurodegeneration

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