Epithelial X-Box Binding Protein 1 Coordinates Tumor Protein p53-Driven DNA Damage Responses and Suppression of Intestinal Carcinogenesis

Welz, Lina; Kakavand, Nassim; Xiang, Haitao; Laue, Georg; Ito, Go; Silva, Miguel G.; Plattner, Christina; Mishra, Neha; Tengen, Felicitas; Ogris, Christoph; Jesinghaus, Moritz; Wottawa, Felix; Arnold, Philipp; Kaikkonen, Leena; Stengel, Stefanie; Tran, Florian; Das, Saumya; Kaser, Arthur; Trajanoski, Zlatko; Blumberg, Richard S.; Roecken, Christoph; Saur, Dieter; Tschurtschenthaler, Markus; Schreiber, Stefan; Rosenstiel, Philip; Aden, Konrad

doi:10.1053/j.gastro.2021.09.057

Cited by 20 publications

(11 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although ER stress induced a strong ROS signature based on the amino acid exchange rates, central carbon metabolism remained largely unchanged in iXbp1 cells. Following a metabolic flux analysis with [U-13 C]glucose and [U- 13 C]glutamine no striking differences have been observed, suggesting that cells primarily repond to ROS stress by alterted amino acid exchange rates. (FigS2 B-E).…”

Section: Er Stress Induces Ros-dependent Metabolic Adaptation To Main...mentioning

confidence: 99%

“…Furthermore, an identical set of triplicate wells were plate-out to calculate the packed cell volume (PCV) by determining cell count and cell volume at the start and end of each tracing experiment (42). After 24h, growth medium was replaced by 13 C tracer medium and cells were cultured for an additional 24 h at 37°C. In parallel, starting PCV was determined by counting three wells per condition.…”

Section: Stable Isotope Tracing and Metabolite Extractionmentioning

confidence: 99%

“…The unfolded protein response (UPR) consists of three major pathways (specifically, the IRE1/XBP1-, PERK/ATF4- and ATF6-pathway) and aims to reinforce ER homeostasis, thus counteracting inflammation. Specific single-nucleotide-polymorphisms (SNPs) in the X-box binding protein 1 ( XBP1 ) gene result in hypomorphic variant predisposing for ER-stress and have been identified to mediate increased IBD susceptibility and mechanistically augment epithelial-derived mucosal inflammation (13, 14).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Metabolic plasticity of serine metabolism is crucial for cGAS/STING-signalling and innate immune response to viral infections in the gut

Wottawa

Becker

Bakr

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Mucosal cytomegalovirus (CMV) infection represents a leading cause for complicated disease behaviour and proctocolectomy in patients with inflammatory bowel disease (IBD). Using a genetic loss-of-function mouse model of the hypomorphic IBD risk gene X-box-binding protein 1 (XBP1), isotope-assisted metabolomics and pharmacologic approaches, we unravel the molecular control of gut epithelial STING signalling by unresolved endoplasmic reticulum (ER) stress. We demonstrate that unresolved epithelial ER stress, evoked by Xbp1 deficiency, leads to exhausted STING signalling and an impaired ability to control CMV infection, which is driven by the generation of reactive oxygen species (ROS). ROS generation is controlled by cellular glycine influx and de-novo serin synthesis enabling glutathione production, which can be pharmacologically exploited to restrore STING signaling. Pharmacological scavenging of ROS with N-acetly cysteine restores epithelial STING signalling and limits CMV infection in IECs. Our findings unravel the serine-glycine dependent metabolic control by ER stress that licences STING signaling and susceptibility to infection in gut epithelium.

show abstract

Section: Er Stress Induces Ros-dependent Metabolic Adaptation To Main...mentioning

confidence: 99%

Section: Stable Isotope Tracing and Metabolite Extractionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Metabolic plasticity of serine metabolism is crucial for cGAS/STING-signalling and innate immune response to viral infections in the gut

Wottawa

Becker

Bakr

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The study reveals an important role for TRPV1 in regulating the immune microenvironment during colorectal tumorigenesis and might be a potential target for CRC immunotherapy. Welz et al (2022) point out that the intestinal epithelium undergoes constant self-renewal from intestinal stem cells. Together with genotoxic stressors and failing DNA repair, this self-renewal causes susceptibility toward malignant transformation.…”

Section: Introduction and Goal Of Investigationmentioning

confidence: 99%

Sensor Technology for Opening New Pathways in Diagnosis and Therapeutics of Breast, Lung, Colorectal and Prostate Cancer

Roshani

Coccia

Mosleh

2022

Preprint

View full text Add to dashboard Cite

This study analyzes the interaction between sensor research and technology and different types of cancer (breast, lung, colorectal and prostate) that generates a high mortality in society with the goals of detecting new directions for improving diagnosis and therapeutics. This study develops an approach of computational scientometrics based on data of the Web of Science from 1991 to 2021 period. The results of this analysis show the vital role of biosensor and electrochemical biosensor applied in breast cancer, lung cancer, and prostate cancer research, except colorectal cancer for latter one. Instead, research of optical sensors is developing mainly in the directions of breast, prostate, and colorectal cancer for improving diagnostics. Finally, oxygen sensor research is developing for breast and lung cancer for applications in breath analysis in new treatment processes. Preliminary results presented here clearly illustrate the evolutionary paths of main sensor technologies that have a great potential in future diagnosis of cancer, but we also need additional examinations of other aspects and factors for supporting appropriate strategies of management of technology to foster the technology transfer of sensor technologies in cancer research for improving diagnosis and, whenever possible, reduce world-wide mortality of cancer ins society.

show abstract

“…More recently, targeting XBP1 has been reported to inhibit the inflammatory response, thus offering a potential option to treat CRSwNP [ 9 ]. In addition, XBP1 has been proposed to act as a hub gene to regulate epithelial DNA damage responses [ 10 ]. However, the regulatory role of XBP1 in CRSsNP remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

XBP1 Regulates the Transcription of HIF-1a in BALB/c Mice with Chronic Rhinosinusitis without Polyps

Meng

2022

Analytical Cellular Pathology

View full text Add to dashboard Cite

X-box binding protein 1 (XBP1) is a transcription factor that recognizes the CRE-like element in enhancers of human T-cell leukemia virus and MHC class II gene and induces their transcription. This study was performed to characterize the function of XBP1, which was identified to be a differentially expressed gene via GEO database, in chronic rhinosinusitis (CRS) without nasal polyps (CRSsNP). XBP1 expression was significantly elevated in both CRSsNP patients and mice who were accompanied with mucosal thickening, goblet cell hyperplasia and chemosis, glandular hyperplasia, and dense infiltration of inflammatory cells. Silencing of XBP1 suppressed the development of CRSsNP in mice. Mechanistically, knockdown of XBP1 downregulated the expression of hypoxia-inducible factor 1-alpha (HIF-1a), and overexpression of XBP1 led to the opposite result. Silencing of HIF-1a inhibited β-catenin expression and impaired the Wnt/β-catenin pathway. Further overexpression of HIF-1a in XBP1-silenced CRSsNP mice exacerbated pathological changes in mouse nasal mucosal tissues, promoted inflammation, and activated the Wnt/β-catenin pathway. Taken together, overexpression of XBP1 may be associated with increased expression of HIF-1a and possibly contribute to the Wnt/β-catenin pathway activation and the development of CRSsNP.

show abstract

Epithelial X-Box Binding Protein 1 Coordinates Tumor Protein p53-Driven DNA Damage Responses and Suppression of Intestinal Carcinogenesis

Cited by 20 publications

References 47 publications

Metabolic plasticity of serine metabolism is crucial for cGAS/STING-signalling and innate immune response to viral infections in the gut

Metabolic plasticity of serine metabolism is crucial for cGAS/STING-signalling and innate immune response to viral infections in the gut

Sensor Technology for Opening New Pathways in Diagnosis and Therapeutics of Breast, Lung, Colorectal and Prostate Cancer

XBP1 Regulates the Transcription of HIF-1a in BALB/c Mice with Chronic Rhinosinusitis without Polyps

Contact Info

Product

Resources

About