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Trends in Cell Biology,
1996]
Keeling and Logsdon propose that the y-like sequences from Caenorhabditis elegans and Saccharomyces cerevisiae are bona fide y-tubulins that have undergone rapid evolutionary divergence. Indeed, genetic and localization studies with the yeast epsilon-tubulin (encoded by the TUB4 gene) reveal striking similarities to the bona fide y-tubulins, whereas there is no apparent human analogue to the C. elegans delta-tubulin among the 60 available human y-tubulin expressed-sequence tags. (ESTs).
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J Physiol,
2014]
Dietary proteins are cleaved within the intestinal lumen to oligopeptides which are further processed to small peptides (di- and tripeptides) and free amino acids. Although the transport of amino acids is mediated by several specific amino acid transporters, the proton-coupled uptake of the more than 8000 different di- and tripeptides is performed by the high-capacity/low-affinity peptide transporter isoform PEPT1 (SLC15A1). Its wide substrate tolerance also allows the transport of a repertoire of structurally closely related compounds and drugs, which explains their high oral bioavailability and brings PEPT1 into focus for medical and pharmaceutical approaches. Although the first evidence for the interplay of nutrient supply and PEPT1 expression and function was described over 20 years ago, many aspects of the molecular processes controlling its transcription and translation and modifying its transporter properties are still awaiting discovery. The present review summarizes the recent knowledge on the factors modulating PEPT1 expression and function in Caenorhabditis elegans, Danio rerio, Mus musculus and Homo sapiens, with focus on dietary ingredients, transcription factors and functional modulators, such as the sodium-proton exchanger NHE3 and selected scaffold proteins.
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Cell Motility and the Cytoskeleton,
1995]
The tubilin family has been considered to have two members, the a- and B-tubulins, which interact to form the heterodimers which in turn assemble to form the eukaryotic microtubules. A third member, y-tubulin, was identified in 1989 and has since been shown to be specifically localized in Microtubule Organizing Centers and has been implicated in the nucleation of microtubules in vivo. Comparisons of individual a-, B-, and y-tubulin sequences within the three subfamilies yield homologies of 65-100% identity. By contrast, comparisons between the three subfamilies typically yield homologies of only about 30-40% identity. The Caenorhabditis and yeast genome projects have recently identified two putative y-tubulin sequences. Analysis of these sequences, however, shows that they are significantly different from those of bona fide y-tubulins...
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Klin Padiatr,
2009]
Twenty years ago the fist bona fide death receptor, APO-1/FAS/CD95 was discovered along with the pathways that regulate programmed cell death or apoptosis. From the very beginning, this research was considered to have substantial impact on diseases and to provide a rational strategy for therapeutic intervention. In particular cell death research proved to be the key for the development of novel strategies for cancer therapy. In the past two decades, deregulated apoptosis in tumors has been delineated and possible targets for therapeutic intervention have been identified. However, it still took a long way until this work could be translated into clinical trials only in the past few years. Current strategies involve modification of apoptosis signalling based on our knowledge of sensitivity and resistance for apoptosis induction rather than the use of individual agents for cytotoxicity. In this review, an overview of the developments in the field from basic discoveries to the recent clinical trials is given.
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Dev Dyn,
2010]
We review the application of Caenorhabditis elegans as a model system to understand key aspects of stem cell biology. The only bona fide stem cells in C. elegans are those of the germline, which serves as a valuable paradigm for understanding how stem-cell niches influence maintenance and differentiation of stem cells and how somatic differentiation is repressed during germline development. Somatic cells that share stem cell-like characteristics also provide insights into principles in stem-cell biology. The epidermal seam cell lineages lend clues to conserved mechanisms of self-renewal and expansion divisions. Principles of developmental plasticity and reprogramming relevant to stem-cell biology arise from studies of natural transdifferentiation and from analysis of early embryonic progenitors, which undergo a dramatic transition from a pluripotent, reprogrammable condition to a state of committed differentiation. The relevance of these developmental processes to our understanding of stem-cell biology in other organisms is discussed.
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Trends Microbiol,
2008]
Bubonic plague, one of history''s deadliest infections, is transmitted by fleas infected with Yersinia pestis. The bacteria can starve fleas by blocking their digestive tracts, which stimulates the insects to bite repeatedly and thereby infect new hosts. Direct examination of infected fleas, aided by in vitro studies and experiments with the nematode Caenorhabditis elegans, have established that Y. pestis forms a biofilm in the insect. The extracellular matrix of the biofilm seems to contain a homopolymer of N-acetyl-d-glucosamine, which is a constituent of many bacterial biofilms. A regulatory mechanism involved in Y. pestis biofilm formation, cyclic-di-GMP signaling, is also widespread in bacteria; yet only Y. pestis forms biofilms in fleas. Here, the historical background of bubonic plague is briefly described and recent studies investigating the mechanisms by which these unique and deadly biofilms are formed are discussed.
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Mech Ageing Dev,
2004]
Melendez et al. [Science 301 (2003) 1387] have recently shown that the increased longevity of Caenorhabditis elegans mutants with defective Daf-2 protein, i.e. an insulin receptor analog, involves increased autophagy. Autophagy increases the free amino acid pool and is in certain cells essential for survival at times of limited amino acid availability. In addition, autophagy plays an important role in the turnover of proteins and organelles including mitochondria. The autophagic activity is sensitive to changes in physiological conditions, i.e. it is strongly inhibited by an increase in amino acid concentrations or in insulin receptor signaling. In line with this fact, clinical studies indicate that autophagy mainly occurs at times of low plasma amino acid and insulin concentrations in the post-absorptive (fasted) state, and that the post-absorptive amino acid-sensitive protein catabolism may be taken as a bona fide indicator of autophagic activity. The increased longevity of insulin receptor mutants or of organisms subjected to calorie restriction may, therefore, be attributed to an increase in autophagic activity. Importantly, the autophagic activity decreases with age. Recent studies suggest that this decrease may result from an age-related increase in post-absorptive amino acid levels and/or from an increase in baseline insulin receptor signaling. If so, it is potentially reversible.
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Endocr Rev,
2001]
Targeted gene mutations have established distinct, yet overlapping, developmental roles for receptors of the insulin/IGF family. IGF-I receptor mediates IGF-I and IGF-II action on prenatal growth and IGF-I action on postnatal growth. Insulin receptor mediates prenatal growth in response to IGF-II and postnatal metabolism in response to insulin. In rodents, unlike humans, insulin does not participate in embryonic growth until late gestation. The ability of the insulin receptor to act as a bona fide IGF-II-dependent growth promoter is underscored by its rescue of double knockout Igf1r/Igf2r mice. Thus, IGF-II is a true bifunctional ligand that is able to stimulate both insulin and IGF-I receptor signaling, although with different potencies. In contrast, the IGF-II/cation-independent mannose-6-phosphate receptor regulates IGF-II clearance. The growth retardation of mice lacking IGF-I and/or insulin receptors is due to reduced cell number, resulting from decreased proliferation. Evidence from genetically engineered mice does not support the view that insulin and IGF receptors promote cellular differentiation in vivo or that they are required for early embryonic development. The phenotypes of insulin receptor gene mutations in humans and in mice indicate important differences between the developmental roles of insulin and its receptor in the two species.
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Philos Trans R Soc Lond B Biol Sci,
2013]
The PAR clan of polarity regulating genes was initially discovered in a genetic screen searching for genes involved in asymmetric cell divisions in the Caenorhabditis elegans embryo. Today, investigations in worms, flies and mammals have established PAR proteins as conserved and fundamental regulators of animal cell polarization in a broad range of biological phenomena requiring cellular asymmetries. The human homologue of invertebrate PAR-4, a serine-threonine kinase LKB1/STK11, has caught attention as a gene behind Peutz-Jeghers polyposis syndrome and as a bona fide tumour suppressor gene commonly mutated in sporadic cancer. LKB1 functions as a master regulator of AMP-activated protein kinase (AMPK) and 12 other kinases referred to as the AMPK-related kinases, including four human homologues of PAR-1. The role of LKB1 as part of the energy sensing LKB1-AMPK module has been intensively studied, whereas the polarity function of LKB1, in the context of homoeostasis or cancer, has gained less attention. Here, we focus on the PAR-4 identity of LKB1, discussing the weight of evidence indicating a role for LKB1 in regulation of cell polarity and epithelial integrity across species and highlight recent investigations providing new insight into the old question: does the PAR-4 identity of LKB1 matter in cancer?
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Biomolecules,
2020]
A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients' families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism <i>Caenorhabditis elegans</i> offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients.