Increased expression of pgph-1, T23F2.4, and cyp-14A5 in C. elegans dpy-7 mutants and by high salt

Scolaro, Gabrielle E.; Bridges, Kelsey; Curry, Shayla; Jacobson, Stephanie; LoPresti, Marissa; Pappas, Katina; Ramı́rez, Nicolás; Savigne, Lindsay; Sherman, S.; Upshaw, Katherine; Walsh, Erin; Choe, Keith P.

doi:10.17912/micropub.biology.000136

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…3a). The gene expression of pgph-1 has been previously shown to increase with high osmolarities and in C. elegans dpy-7 mutant animals 39 .…”

Section: Resultsmentioning

confidence: 95%

“…However, the enzyme responsible for the hydrolysis of Gro3P to produce glycerol has not been identified. High osmolarities have been recently shown to induce pgph-1 gene expression 39 . Here, we demonstrate that pgph genes are strongly induced following hyperosmotic and glucotoxic stresses and are required for glycerol production and survival under these stresses.…”

Section: Discussionmentioning

confidence: 99%

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Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans

et al. 2022

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Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.

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“…3a). The gene expression of pgph-1 has been previously shown to increase with high osmolarities and in C. elegans dpy-7 mutant animals 39 .…”

Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans

et al. 2022

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“…For RT-qPCR, wild type N2 or mutant worms without transgene reporters were exposed to compounds in 96-well plates as described above for imaging. Because stress response gene expression can change quickly and may be sensitive to processing, we collected worms by picking into lysis buffer and freezing as we and others have described previously with some modifications; − this approach is rapid, selective for the developmental stage and condition, and has few processing steps limiting artifacts that can be introduced during bulk collection and washing of entire plates of worms. At the end of exposures, worms and incubation buffer containing compounds or vehicle controls were transferred to the surface of agar plates by pipet; for each replicate, 5 or 10 young adult worms were picked to tubes containing lysis buffer and proteinase K and frozen by placement in a prechilled rack in an ultracold freezer.…”

Section: Methodsmentioning

confidence: 99%

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response

Abraham,

Athapaththu,

Atanasova

et al. 2024

ACS Chem. Biol.

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C. elegans numr-1/2 (nuclear-localized metalresponsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts for numr-1p::GFP activation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activates numr-1/2 strongly in the alimentary canal but is distinct from metal exposure, because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism in C. elegans as genetic disruption and RNAi screening of homologues did not induce numr-1/2 in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to induce numr-1/2. ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect on numr-1/2, suggesting a dimer requirement. Chetomin inhibits C. elegans growth at low micromolar levels, and loss of numr-1/2 increases sensitivity; C. elegans and Chaetomiaceae fungi inhabit similar environments raising the possibility that numr-1/2 functions as a defense mechanism. There is no direct orthologue of numr-1/2 in humans, but RNaseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.

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“…qRT-PCR assays were run using the delta-delta Ct method with primer efficiencies determined from standard curves as described previously ( Scolaro et al 2019 ) with the following modifications; after lysis, genomic DNA was removed with dsDNAse (Thermo Fisher product EN007). Numbers of worms picked to each replicate were adjusted to account for worm sizes as follows: 20 L1, 15 L2, or 10 L3 larvae for all strains; 8 wild-type or 12 dpy L4 larvae; 7 wild-type and 10 dpy young adults.…”

Section: Methodsmentioning

confidence: 99%

Extracellular matrix regulation of stress response genes during larval development in Caenorhabditis elegans

Chandler

Choe

2022

G3 Genes|Genomes|Genetics

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Mutation or loss of six extracellular matrix collagen genes disrupts annular furrows in adult C. elegans cuticles, causes a wide ‘Dumpy’ body morphology, and activates osmotic, detoxification, and antimicrobial defense genes. High environmental osmolarity reduces internal turgor pressure, physically distorts the epidermis, and activates the same stress responses. Collagen gene mutations that that cause Dumpy without furrow disruption do not activate stress responses. These results are consistent with an extracellular damage sensor associated with furrows in the adult cuticle that regulates environmental stress responses in adjacent cells. Several cuticle characteristics change between molts, but all stages have annular furrows and express furrow collagen genes. We compared body shape, furrow organization imaged with DIC microscopy, and stress response gene expression in three furrow collagen gene mutants at all post-embryonic stages. We find that most body shape and furrow disorganization phenotypes start at the L3 stage and increase in severity with each molt afterwards. Stress response genes were induced the strongest in adults, correlating with the greatest Dumpy and furrow phenotypes. Although weaker than in adults, osmolyte transporter gene hmit-1.1 and antimicrobial gene nlp-29 were also induced in some early larvae that had weak or undetectable cuticle phenotypes. Our data are consistent with progressive cuticle phenotypes in which each new cuticle is at least partially directed by organization of the former cuticle. Gene expression and cuticle data support the role of furrow disruption as a signal in L4 larvae and adults, but also suggest a role for other cuticle organization or epidermal cell effects in early larvae.

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Increased expression of pgph-1, T23F2.4, and cyp-14A5 in C. elegans dpy-7 mutants and by high salt

Cited by 5 publications

References 17 publications

Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans

Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response

Extracellular matrix regulation of stress response genes during larval development in Caenorhabditis elegans

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