TEAD-independent cell growth of Hippo-inactive mesothelioma cells: Unveiling resistance to TEAD inhibitor K-975 through MYC signaling activation.

Inactivation of the Hippo tumor suppressive pathway is frequently observed in mesothelioma, which leads to the activation of YAP and TAZ (YAP/TAZ) transcriptional coactivators. YAP/TAZ form complexes with TEAD family members, DNA-binding proteins, to activate transcription, which promotes cancer cell growth and proliferation. Recently developed TEAD inhibitors exhibit antitumor activity by inhibiting the formation of the transcription complex through binding to TEAD; however, the antitumor activity of TEAD inhibitors against mesothelioma remains to be fully elucidated.

Action Mechanisms of Exosomes Derived from GD3/GD2-Positive Glioma Cells in the Regulation of Phenotypes and Intracellular Signaling: Roles of Integrins.

Extracellular vesicles (EVs) play important roles in intercellular communication in various biological events. In particular, EVs released from cancer cells have attracted special attention. Although it has been reported that cancer-associated glycosphingolipids play important roles in the enhancement of malignant properties of cancer cells, the presence, behavior, and roles of glycosphingolipids in EVs have not been elucidated.

γ-Secretase Cleaves Bifunctional Fatty Acid-Conjugated Small Molecules with Amide Bonds in Mammalian Cells.

Connecting two small molecules, such as ligands, fluorophores, or lipids, together via a linker with amide bonds is a widely used strategy to generate synthetic bifunctional molecules for various biological and biomedical applications. Such bifunctional molecules have been used in live-cell experiments under the assumption that they should be stable in cells. However, we recently found that a membrane-targeting bifunctional molecule, composed of a lipopeptide and the small-molecule ligand trimethoprim, referred to as mgcTMP, underwent amide-bond cleavage in mammalian cells.

Synthesis and preclinical testing of a selective beta-subtype agonist of thyroid hormone receptor ZTA-261.

Background: Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide.

Isocitrate dehydrogenase 1 upregulation in urinary extracellular vesicles from proximal tubules of type 2 diabetic rats.

Diabetic nephropathy (DN) is a major cause of chronic kidney disease. Microalbuminuria is currently the most common non-invasive biomarker for the early diagnosis of DN. However, renal structural damage may have advanced when albuminuria is detected.

Ser/Leu-swapped cell-free translation system constructed with natural/in vitro transcribed-hybrid tRNA set.

The Ser/Leu-swapped genetic code can act as a genetic firewall, mitigating biohazard risks arising from horizontal gene transfer in genetically modified organisms. Our prior work demonstrated the orthogonality of this swapped code to the standard genetic code using a cell-free translation system comprised of 21 in vitro transcribed tRNAs. In this study, to advance this system for protein engineering, we introduce a natural/in vitro transcribed-hybrid tRNA set.

Lipid droplets in leaves contain myosin-binding proteins and enzymes associated with furan-containing fatty acid biosynthesis.

Lipid droplets (LDs) are lipid storage organelles in plant leaves and seeds. Seed LD proteins are well known, and their functions in lipid metabolism have been characterized; however, many leaf LD proteins remain to be identified. We therefore isolated LDs from leaves of the leaf LD-overaccumulating mutant () of by centrifugation or co-immunoprecipitation.

Measurement of the intracellular active metabolites of thiopurine drugs to evaluate the enzymatic activity of nudix hydrolase 15 in human blood samples.

Thiopurine is metabolized to 6-thio-(deoxy) guanosine triphosphate (6-thio-(d) GTP), which is then incorporated into DNA or RNA and causes cytotoxicity. Nudix hydrolase 15 (NUDT15) reduces the cytotoxic effects of thiopurine by converting 6-thio-(d) GTP to 6-thio-(d) guanosine monophosphate (6-thio-(d) GMP). NUDT15 polymorphisms like the Arg139Cys variant are strongly linked to thiopurine-induced severe leukocytopenia and alopecia.

TGF-β signaling promotes desmoid tumor formation via CSRP2 upregulation.

Desmoid tumors (DTs), also called desmoid-type fibromatoses, are locally aggressive tumors of mesenchymal origin. In the present study, we developed a novel mouse model of DTs by inducing a local mutation in the Ctnnb1 gene, encoding β-catenin in PDGFRA-positive stromal cells, by subcutaneous injection of 4-hydroxy-tamoxifen. Tumors in this model resembled histologically clinical samples from DT patients and showed strong phosphorylation of nuclear SMAD2.

Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia.

Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver.

Palmitoylation-Dependent Small-Molecule Fluorescent Probes for Live-Cell Golgi Imaging.

Small-molecule fluorescent probes enabling visualization of the Golgi apparatus in living cells are essential tools for studying Golgi-associated biological processes and diseases. So far, several fluorescent Golgi stains have been developed by linking ceramide lipids to fluorophores. However, ceramide-based probes suffer from cumbersome staining procedures and low Golgi specificity.

Discovery of 2,6-Dihalopurines as Stomata Opening Inhibitors: Implication of an LRX-Mediated H-ATPase Phosphorylation Pathway.

Stomata are pores in the leaf epidermis of plants and their opening and closing regulate gas exchange and water transpiration. Stomatal movements play key roles in both plant growth and stress responses. In recent years, small molecules regulating stomatal movements have been used as a powerful tool in mechanistic studies, as well as key players for agricultural applications.

The cAMP/PKA/CREB and TGFβ/SMAD4 Pathways Regulate Stemness and Metastatic Potential in Colorectal Cancer Cells.

This study identifies signaling pathways essential for maintaining the stemness and metastatic potential of colorectal cancer cells and proposes CREB as a therapeutic target in metastatic colorectal cancer.

Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation.

Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on cell proliferation and progression.

Stromal iodothyronine deiodinase 2 (DIO2) promotes the growth of intestinal tumors in Apc mutant mice.

Iodothyronine deiodinase 2 (DIO2) converts the prohormone thyroxine (T4) to bioactive T3 in peripheral tissues and thereby regulates local thyroid hormone (TH) levels. Although epidemiologic studies suggest the contribution of TH to the progression of colorectal cancer (CRC), the role of DIO2 in CRC remains elusive. Here we show that Dio2 is highly expressed in intestinal polyps of Apc mice, a mouse model of familial adenomatous polyposis and early stage sporadic CRC.

TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation.

Malignant mesothelioma (MM) constitutes a very aggressive tumor that is caused by asbestos exposure after long latency. The NF2 tumor suppressor gene is mutated in 40-50% of MM; moreover, one of its downstream signaling cascades, the Hippo signaling pathway, is also frequently inactivated in MM cells. Although the YAP transcriptional coactivator, which is regulated by the Hippo pathway, can function as a pro-oncogenic protein, the role of TAZ, a paralog of YAP, in MM cells has not yet been clarified.

Crystal structure of human tyrosylprotein sulfotransferase-2 reveals the mechanism of protein tyrosine sulfation reaction.

Post-translational protein modification by tyrosine sulfation has an important role in extracellular protein-protein interactions. The protein tyrosine sulfation reaction is catalysed by the Golgi enzyme called the tyrosylprotein sulfotransferase. To date, no crystal structure is available for tyrosylprotein sulfotransferase.

Molecular characterization and biological function of neuroendocrine regulatory peptide-3 in the rat.

Neuroendocrine regulatory peptide (NERP)-3, derived from the neurosecretory protein VGF (non-aconymic), is a new biologically active peptide identified through peptidomic analysis of the peptides secreted by an endocrine cell line. Using a specific antibody recognizing the C-terminal region of NERP-3, immunoreactive (ir)-NERP-3 was identified in acid extracts of rat brain and gut as a 30-residue NERP-3 with N-terminal pyroglutamylation. Assessed by radioimmunoassay, ir-NERP-3 was more abundant in the brain, including the posterior pituitary (PP), than in the gut.

Distribution of neuroendocrine regulatory peptide-1 and -2, and proteolytic processing of their precursor VGF protein in the rat.

Neuroendocrine regulatory peptide (NERP)-1 and NERP-2 are biologically active peptides recently discovered by peptidomic analysis. NERPs are processed out from the 594-residue VGF protein which contains many prohormone convertase cleavage motifs. VGF-deficient mice exhibit a hypermetabolic and infertile phenotype, for which VGF protein-derived peptides including NERPs are presumably responsible.