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Bhaumik, Dipa, Lithgow, Gordon, Mark, Karla, Gibson, Bradford, Schilling, Birgit, Price, Milena, Holick, Michael
[
International Worm Meeting,
2013]
Vitamin D3, a fat-soluble secosteroid functions in the body to regulate bone mineral homeostasis, and other aspects of metabolism through genomic and nongenomic mechanisms. The principle action of vitamin D3 is thought to be mediated through binding to the nuclear vitamin D3 hormone receptor (VDR). Moreover, in the presence of vitamin D3, VDRs are known to form heterodimer complexes which in turn bind to vitamin D responsive elements (VDREs), and enhance the transcription of target genes. Although multiple studies report that low serum levels of vitamin D3 are associated with an increased risk of several central nervous system (CNS) diseases including multiple sclerosis, Alzheimer's and Parkinson's disease, there is little information as to the mechanisms for why this occurs. In this study, we show that vitamin D3 treatment suppresses the aggregation of proteins in several adult Caenorhabditis elegans (c. elegans) models, such as, the amyloid fragment, Ab3-42. Furthermore, we show that vitamin D3 prevents a large number of proteins which normally become insoluble during aging in the worm. Using Mass Spectrometry, we have extended these data to identify the specific proteins affected by vitamin D3 during aging. Another interesting finding from this study is that vitamin D3 also extends lifespan, a trait commonly seen for compounds that promote protein homeostasis. Currently, we have identified several nuclear hormone receptor candidates in the worm, and will be following up on these to determine the signaling pathways involved in vitamin D3's effect on lifespan and protein aggregation. The use of vitamin D3 supplements in the elderly population is controversial. A number of large human clinical trials are underway or about to begin. The discovery that vitamin D3 can suppress age-related pathology (protein aggregation) and slow aging is therefore likely to be highly significant.
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[
Elife,
2020]
Worms with increased levels of the epigenetic mark H3K9me2 have a longer lifespan that can be passed down to future generations.
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[
Curr Top Dev Biol,
2017]
PAR-1/MARK kinases are conserved serine/threonine kinases that are essential regulators of cell polarity. PAR-1/MARK kinases localize and function in opposition to the anterior PAR proteins to control the asymmetric distribution of factors in a wide variety polarized cells. In this review, we discuss the mechanisms that control the localization and activity of PAR-1/MARK kinases, including their antagonistic interactions with the anterior PAR proteins. We focus on the role PAR-1 plays in the asymmetric division of the Caenorhabditis elegans zygote, in the establishment of the anterior/posterior axis in the Drosophila oocyte and in the control of microtubule dynamics in mammalian neurons. In addition to conserved aspects of PAR-1 biology, we highlight the unique ways in which PAR-1 acts in these distinct cell types to orchestrate their polarization. Finally, we review the connections between disruptions in PAR-1/MARK function and Alzheimer's disease and cancer.
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[
Worm Breeder's Gazette,
1994]
DNA fingerprinting in C. elegans - an approach Mark Beneckea, Jorg T. Epplenb and Einhard Schierenberga a Zoologisches Institut der Univeritat, 50923 Koln, Germany b Ruhr-Universitat, Ab1. fur Molekulare Humangenetik, 44780 Bochum, Germany
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[
Sci Rep,
2016]
Adapters bind motor proteins to cargoes and therefore play essential roles in Kinesin-1 mediated intracellular transport. The regulatory mechanisms governing adapter functions and the spectrum of cargoes recognized by individual adapters remain poorly defined. Here, we show that cargoes transported by the Kinesin-1 adapter FEZ1 are enriched for presynaptic components and identify that specific phosphorylation of FEZ1 at its serine 58 regulatory site is mediated by microtubule affinity-regulating kinases (MARK/PAR-1). Loss of MARK/PAR-1 impairs axonal transport, with adapter and cargo abnormally co-aggregating in neuronal cell bodies and axons. Presynaptic specializations are markedly reduced and distorted in FEZ1 and MARK/PAR-1 mutants. Strikingly, abnormal co-aggregates of unphosphorylated FEZ1, Kinesin-1 and its putative cargoes are present in brains of transgenic mice modelling aspects of Alzheimer's disease, a neurodegenerative disorder exhibiting impaired axonal transport and altered MARK activity. Our findings suggest that perturbed FEZ1-mediated synaptic delivery of proteins arising from abnormal signalling potentially contributes to the process of neurodegeneration.
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[
Mol Cell,
2013]
In this issue of Molecular Cell, Castellano-Pozo etal. (2013) describe a connection between R loop structures and histone 3 S10 phosphorylation (H3S10P), a mark of chromatin compaction. Their results constitute asignificant advance in our understanding of the role of R loops in genomic instability.
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[
Curr Biol,
2010]
The small GTPases Rab5 and Rab7 mark temporally distinct but sequentially connected stages in phagosome maturation, but the mechanism underlying the transition between these stages has been unclear. Recent studies in Caenorhabditis elegans have now uncovered a new protein complex that connects Rab5 to Rab7.
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[
Trends Genet,
2001]
Four recent papers mark a major shift in functional genomic analysis for multicellular organisms. RNA-mediated interference was applied to inactivate individual genes systematically on a genomic scale. These studies subjected a third of the genes in the genome of Caenorhabditis elegans to reverse genetic analysis.
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[
Worm Breeder's Gazette,
1990]
The CGC Bibliography has been translated into a couple of programs other than dBase by various worm people. David Barker and Andy Fire both have sent HyperCard versions to the CGC and Mark Blaxter has sent us a version in FileMaker 2.0. None of these is perfectly up-to-date, so you'll have to be somewhat familiar with the programs to add new references. The data files are available free from the CGC; to get yours, just send a blank 3.5' diskette to Mark Edgley at the CGC with a request letter. In addition, Lew Jacobson has translated the bibliography into a DOS program called Memory Mate and he is willing to distribute the data file to anyone who sends him a blank 5.25' 360 Kb diskette. Memory Mate can be operated as a TSR and called up with a hotkey from the middle of a word processor or other program. Addresses for Mark and Lew can be found in the Subscriber Directory Update in this issue.
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[
Development,
2019]
The MARK/PAR-1 family of kinases are conserved regulators of cell polarity that share a conserved C-terminal kinase-associated domain (KA1). Localization of MARK/PAR-1 kinases to specific regions of the cell cortex is a hallmark of polarized cells. In <i>C. elegans</i> zygotes, PAR-1 localizes to the posterior cortex under the influence of another polarity kinase, aPKC/PKC-3. Here we report that asymmetric localization of PAR-1 protein is not essential, and that PAR-1 kinase activity is also regulated spatially. We find that, as in human MARK1, the PAR-1 KA1 domain is an auto-inhibitory domain that suppresses kinase activity. Auto-inhibition by the KA1 domain functions in parallel with phosphorylation by PKC-3 to suppress PAR-1 activity in the anterior cytoplasm. The KA1 domain also plays an additional role essential for germ plasm maintenance and fertility. Our findings suggest that modular regulation of kinase activity by redundant inhibitory inputs contributes to robust symmetry breaking by MARK/PAR-1 kinases in diverse cell types.