Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis

Nieborak, Anna; Lukauskas, Saulius; Capellades, Jordi; Heyn, Patricia; Santos, Gabriela Silva; Motzler, Karsten; Zeigerer, Anja; Bester, Romina; Protzer, Ulrike; Schelter, Florian; Wagner, Mirko; Carell, Thomas; Hruscha, Alexander; Schmid, Bettina; Yanes, Óscar; Schneider, Robert

doi:10.1016/j.molmet.2023.101748

Cited by 5 publications

(3 citation statements)

References 104 publications

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“…The internal exons of housekeeping genes ( Hounkpe et al 2021 ), genes expressed highly in HEK293 cells ( Nieborak et al 2023 ), and the exons of all other coding genes displayed similar read counts in the exon trapping data ( Supplemental Fig. S4A ).…”

Section: Resultsmentioning

confidence: 89%

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The human genome contains over a million autonomous exons

Stepankiw,

Yang,

Hughes

2023

Genome Res.

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Mammalian mRNA and lncRNA exons are often small compared to introns. The exon definition model predicts that exons splice autonomously, dependent on proximal exon sequence features, explaining their delineation within large introns. This model has not been examined on a genome-wide scale, however, leaving open the question of how often mRNA and lncRNA exons are autonomous. It is also unknown how frequently such exons can arise by chance. Here, we directly assayed large fragments (500–1000 bp) of the human genome by exon trapping, which detects exons spliced into a heterologous transgene, here designed with a large intron context. We define the trapped exons as “autonomous.” We obtained ∼1.25 million trapped exons, including most known mRNA and well-annotated lncRNA internal exons, demonstrating that human exons are predominantly autonomous. mRNA exons are trapped with the highest efficiency. Nearly a million of the trapped exons are unannotated, most located in intergenic regions and antisense to mRNA, with depletion from the forward strand of introns. These exons are not conserved, suggesting they are nonfunctional and arose from random mutations. They are nonetheless highly enriched with known splicing promoting sequence features that delineate known exons. Novel autonomous exons are more numerous than annotated lncRNA exons, and computational models also indicate they will occur with similar frequency in any randomly generated sequence. These results show that most human coding exons splice autonomously, and provide an explanation for the existence of many unconserved lncRNAs, as well as a new annotation and inclusion levels of spliceable loci in the human genome.

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Section: Resultsmentioning

confidence: 89%

“…HEK293 gene expression data was obtained from supplemental data for Nieborak et al (2023) ( ) which contains data for HEK293 wild type control samples. HEK293 transcript RPKM values are from the column “HEK293-WT-S20190326-S20190326”.…”

Section: Methodsmentioning

confidence: 99%

The human genome contains over a million autonomous exons

Stepankiw,

Yang,

Hughes

2023

Genome Res.

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“…Similarly, our in vivo experiments confirmed that TXNIP overexpression suppresses tumor cell proliferation and restricts tumor growth. However, TXNIP inhibition of thioredoxin potentially decreases the capacity of cells to eliminate ROS, potentially inducing intracellular oxidative damage [ 23 , 24 ]. Hang et al .…”

Section: Discussionmentioning

confidence: 99%

Suppression of pancreatic cancer proliferation through TXNIP-mediated inhibition of the MAPK signaling pathway

Fei,

Jin,

Shi

et al. 2024

ABBS

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Thioredoxin-interacting protein (TXNIP) is a crucial thioredoxin-binding protein that is recognized as a tumor suppressor in diverse malignancies, such as breast cancer, lung cancer, hepatocellular carcinoma, and thyroid cancer. However, the specific role and molecular mechanisms of TXNIP in the pathogenesis and progression of pancreatic cancer cells have not been determined. In this study, we investigate the relationship between TXNIP expression and overall survival prognosis in pancreatic cancer patients. Mechanistic studies are conducted to reveal the role of TXNIP in pancreatic cancer cell proliferation, migration, and regulation during malignancy. Our findings indicate that patients with high TXNIP expression have a more favorable prognosis. In vitro experiments with pancreatic cell lines show that overexpression of TXNIP suppresses the proliferation and migration of pancreatic cancer cells. Furthermore, we find that TXNIP inhibits the activation of the MAPK signaling pathway, thereby decreasing the malignant potential of pancreatic cancer. In conclusion, our study reveals TXNIP as a promising new predictive marker and therapeutic target for pancreatic cancer.

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