The role of NUPR1 in response to stress and cancer development

Liu, Shan; Costa, Max

doi:10.1016/j.taap.2022.116244

Cited by 22 publications

(17 citation statements)

References 86 publications

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“…The cellular localization of NUPR1 appears to be associated with pathological conditions. Prominent cytoplasmic staining has been observed in large papillary tumors, tumors exhibiting lymph node metastasis, and NSCLC [ 38 ]. Our IHC analysis corroborated these findings.…”

Section: Discussionmentioning

confidence: 99%

Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma

Liu,

Lin,

Qian

et al. 2024

BMC Med Genomics

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Background Lung cancer is a highly prevalent malignancy worldwide and is associated with high mortality rates. While the involvement of endoplasmic reticulum (ER) stress in the development of lung adenocarcinoma (LUAD) has been established, the underlying mechanism remains unclear. Methods In this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify differentially expressed endoplasmic reticulum stress-related genes (ERSRGs) between LUAD and normal tissues. We performed various bioinformatics analyses to investigate the biological functions of these ERSRGs. Using LASSO analysis and multivariate stepwise regression, we constructed a novel prognostic model based on the ERSRGs. We further validated the performance of the model using two independent datasets from the Gene Expression Omnibus (GEO). Additionally, we conducted functional enrichment analysis, immune checkpoint analysis, and immune infiltration analysis and drug sensitivity analysis of LUAD patients to explore the potential biological function of the model. Furthermore, we conducted a battery of experiments to verify the expression of ERSRGs in a real-world cohort. Results We identified 106 ERSRGs associated with LUAD, which allowed us to classify LUAD patients into two subtypes based on gene expression differences. Using six prognostic genes (NUPR1, RHBDD2, VCP, BAK1, EIF2AK3, MBTPS2), we constructed a prognostic model that exhibited excellent predictive performance in the training dataset and was successfully validated in two independent external datasets. The risk score derived from this model emerged as an independent prognostic factor for LUAD. Confirmation of the linkage between this risk model and immune infiltration was affirmed through the utilization of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The q-PCR results verified significant differences in the expression of prognostic genes between cancer and paracancer tissues. Notably, the protein expression of NUPR1, as determined by immunohistochemistry (IHC), exhibited an opposite pattern compared to the mRNA expression patterns. Conclusion This study establishes a novel prognostic model for LUAD based on six ER stress-related genes, facilitating the prediction of LUAD prognosis. Additionally, NUPR1 was identified as a potential regulator of stress in LUAD.

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Section: Discussionmentioning

confidence: 99%

Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma

Liu,

Lin,

Qian

et al. 2024

BMC Med Genomics

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“…The upregulation of Fgf21 in the vulnerable spinal motor neurons may also be indicative of the increased energy demand on these cells during disease. There is a clear correlation between increased serum levels of FGF21 and metabolic diseases conditions such as diabetes, The upregulation of Nupr1 (nuclear protein 1) in CN12 and spinal motor neurons is indicative of the stress these cells are experiencing, as this transcriptional regulator is involved in ER stress, oxidative stress response, DNA repair, autophagy, apoptosis and chromatin remodeling (reviewed in Liu et al 2022). In spinal motor neurons it was regulated already at the presymptomatic stage while in CN12 neurons only at the symptomatic stage, demonstrating that these cell types follow a similar path at distinct paces, where spinal motor neurons have taken the lead to destruction.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations

Mei,

Nichterwitz,

Leboeuf

et al. 2024

Preprint

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons (MNs), which innervate skeletal muscles. However, certain MN groups including ocular MNs that regulate eye movement are relatively resilient to ALS. To reveal mechanisms of differential MN vulnerability, we investigate the transcriptional dynamics of two vulnerable and two resilient MN populations in SOD1G93A ALS mice. Differential gene expression analysis shows that each neuron type displays a largely unique spatial and temporal response to ALS. Resilient MNs regulate few genes in response to disease, but show clear divergence in baseline gene expression compared to vulnerable MNs, which in combination may hold the key to their resilience. EASE, fGSEA and ANUBIX enrichment analysis demonstrate that vulnerable MN groups share pathway activation, including regulation of neuronal death, inflammatory response, ERK and MAPK cascades, cell adhesion and synaptic signaling. These pathways are largely driven by 11 upregulated genes, including Atf3, Cd44, Gadd45a, Ngfr, Ccl2, Ccl7, Gal, Timp1, Nupr1, Serpinb1a and Chl1, and indicate that cell death occurs through similar mechanisms across vulnerable MNs albeit with distinct timing. Machine learning using DEGs upregulated in our SOD1G93A spinal MNs predict disease in human stem cell-derived MNs harboring the SOD1E100G mutation, and show that dysregulation of VGF, PENK, INA and NTS are strong disease-predictors across SOD1 mutations and species. Meta-analysis across mouse SOD1 transcriptome datasets identified a shared transcriptional vulnerability code of 32 genes including e.g Sprr1a, Atf3, Fgf21, C1qb, Nupr1, Gap43, Adcyap1, Vgf, Ina and Mt1. In conclusion our study reveals vulnerability-specific gene regulation that may act to preserve neurons and can be used to predict disease.

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“…NUPR1 (Nuclear protein 1) is a transcriptional factor acting in response to multiple internal (DNA damage, ER stress, oxidative stress, inflammation, and metabolic stress) and external stress signals 55 , 56 . It is involved in a wide range of biological functions, including regulation of DNA damage and repair, cell cycle, autophagy, and cell death 57 – 68 . The structure and affinity of NUPR1 for its interactors are regulated by its phosphorylation by kinases, such as PKA 61 , which suggests an indirect activation by microgravity.…”

Section: Discussionmentioning

confidence: 99%

Microgravity triggers ferroptosis and accelerates senescence in the MG-63 cell model of osteoblastic cells

Garbacki,

Willems,

Neutelings

et al. 2023

npj Microgravity

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In space, cells sustain strong modifications of their mechanical environment. Mechanosensitive molecules at the cell membrane regulate mechanotransduction pathways that induce adaptive responses through the regulation of gene expression, post-translational modifications, protein interactions or intracellular trafficking, among others. In the current study, human osteoblastic cells were cultured on the ISS in microgravity and at 1 g in a centrifuge, as onboard controls. RNAseq analyses showed that microgravity inhibits cell proliferation and DNA repair, stimulates inflammatory pathways and induces ferroptosis and senescence, two pathways related to ageing. Morphological hallmarks of senescence, such as reduced nuclear size and changes in chromatin architecture, proliferation marker distribution, tubulin acetylation and lysosomal transport were identified by immunofluorescence microscopy, reinforcing the hypothesis of induction of cell senescence in microgravity during space flight. These processes could be attributed, at least in part, to the regulation of YAP1 and its downstream effectors NUPR1 and CKAP2L.

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The role of NUPR1 in response to stress and cancer development

Cited by 22 publications

References 86 publications

Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma

Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma

Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations

Microgravity triggers ferroptosis and accelerates senescence in the MG-63 cell model of osteoblastic cells

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