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1.
《Cell cycle (Georgetown, Tex.)》2013,12(12):2391-2401
Numerous stimuli, including oncogenic signaling, DNA damage or eroded telomeres trigger proliferative arrest, termed cellular senescence. Accumulating evidence suggests that cellular senescence is a potent barrier to tumorigenesis in vivo, however oncogene induced senescence can also promote cellular transformation.1,2 Several oncogenes, whose overexpression results in cellular senescence, converge on the TOR (target of rapamycin) pathway. We therefore examined whether attenuation of TOR results in delay or reversal of cellular senescence. By using primary human fibroblasts undergoing either replicative or oncogenic RAS-induced senescence, we demonstrated that senescence can be delayed, and some aspects of senescence can be reversed by inhibition of TOR, using either the TOR inhibitor rapamycin or by depletion of TORC1 (TOR Complex 1). Depletion of TORC2 fails to affect the course of replicative or RAS-induced senescence. Overexpression of REDD1 (Regulated in DNA Damage Response and Development), a negative regulator of TORC1, delays the onset of replicative senescence. These results indicate that TORC1 is an integral component of the signaling pathway that mediates cellular senescence. 相似文献
2.
《Cell Adhesion & Migration》2013,7(4):378-383
Cell migration is a highly integrated, multistep process that plays an important role in physiological and pathological processes. The migrating cell is highly polarized, with complex regulatory pathways that integrate its component processes spatially and temporally.1 The Drosophila tumor suppressor, Lethal (2) giant larvae (Lgl), regulates apical-basal polarity in epithelia and asymmetric cell division.2 But little is known about the role of Lgl in establishing cell polarity in migrating cells. Recently, we showed that the mammalian Lgl1 interacts directly with non-muscle myosin IIA (NMIIA), inhibiting its ability to assemble into filaments in vitro.3 Lgl1 also regulates the cellular localization of NMIIA, the maturation of focal adhesions, and cell migration.3 We further showed that phosphorylation of Lgl1 by aPKCζ prevents its interaction with NMIIA and is important for Lgl1 and acto-NMII cytoskeleton cellular organization.4 Lgl is a critical downstream target of the Par6-aPKC cell polarity complex; we showed that Lgl1 forms two distinct complexes in vivo, Lgl1-NMIIA and Lgl1-Par6-aPKCζ in different cellular compartments.4 We further showed that aPKCζ and NMIIA compete to bind directly to Lgl1 through the same domain. These data provide new insights into the role of Lgl1, NMIIA, and Par6-aPKCζ in establishing front-rear polarity in migrating cells. In this commentary, I discuss the role of Lgl1 in the regulation of the acto-NMII cytoskeleton and its regulation by the Par6-aPKCζ polarity complex, and how Lgl1 activity may contribute to the establishment of front-rear polarity in migrating cells. 相似文献
3.
《Organogenesis》2013,9(3):289-298
A recent paper demonstrated that decellularized extracellular matrix (DECM) deposited by synovium-derived stem cells (SDSCs), especially from fetal donors, could rejuvenate human adult SDSCs in both proliferation and chondrogenic potential, in which expanded cells and corresponding culture substrate (such as DECM) were found to share a mutual reaction in both elasticity and protein profiles (see ref. 1). It seems that young DECM may assist in the development of culture strategies that optimize proliferation and maintain “stemness” of mesenchymal stem cells (MSCs), helping to overcome one of the primary difficulties in MSC-based regenerative therapies. In this paper, the effects of age on the proliferative capacity and differentiation potential of MSCs are reviewed, along with the ability of DECM from young cells to rejuvenate old cells. In an effort to highlight some of the potential molecular mechanisms responsible for this phenomenon, we discuss age-related changes to extracellular matrix (ECM)'s physical properties and chemical composition. 相似文献
4.
Andre Schmandke Alice C Mosberger Antonio Schmandke Zeliha Celen Martin E Schwab 《Cell Adhesion & Migration》2013,7(6):451-453
After central nervous system (CNS) insults, such as spinal cord injury or traumatic brain injury, neurons encounter a complex microenvironment where mechanisms that promote regeneration compete with inhibitory processes. Sprouting and axonal re-growth are key components of functional recovery, but are often counteracted by inhibitory molecules. Several strategies are being pursued whereby these inhibitory molecules are either being neutralized with blocking antibodies, with enzymatic degradation or downstream signaling events are being interfered with. Two recent studies1,2 show that activating integrin signaling in dorsal root ganglion (DRG) neurons renders them able to overcome inhibitory signals, and could possibly lead to new strategies to improve neuronal regeneration. 相似文献
5.
《Channels (Austin, Tex.)》2013,7(3):157-165
L-type voltage gated calcium channels (VGCCs) interact with a variety of proteins that modulate both their function and localization. A-Kinase Anchoring Proteins (AKAPs) facilitate L-type calcium channel phosphorylation through β adrenergic stimulation. Our previous work indicated a role of neuronal AKAP79/150 in the membrane targeting of CaV1.2 L-type calcium channels, which involved a proline rich domain (PRD) in the intracellular II-III loop of the channel.1 Here, we show that mutation of proline 857 to alanine (P857A) into the PRD does not disrupt the AKAP79-induced increase in Cav1.2 membrane expression. Furthermore, deletion of two other PRDs into the carboxy terminal domain of CaV1.2 did not alter the targeting role of AKAP79. In contrast, the distal carboxy terminus region of the channel directly interacts with AKAP79. This protein-protein interaction competes with a direct association of the channel II-III linker on the carboxy terminal tail and modulates membrane targeting of CaV1.2. Thus, our results suggest that the effects of AKAP79 occur through relief of an autoinhibitory mechanism mediated by intramolecular interactions of Cav1.2 intracellular regions. 相似文献
6.
7.
《朊病毒》2013,7(5):433-436
Mutations in the gene encoding the amyloid precursor protein (APP) or the enzymes that process APP are correlated with familial Alzheimer disease. Alzheimer disease is also associated with insulin resistance (type 2 diabetes). In our recently published study,1 we obtained genetic evidence that the extracellular fragment of APL-1, the C. elegans ortholog of human APP, may act as a signaling molecule to modulate insulin and nuclear hormone pathways in C. elegans development. In addition, independent of insulin and nuclear hormone signaling, high levels of the extracellular fragment of APL-1 (sAPL-1) leads to a temperature-sensitive embryonic lethality, which is dependent on activity of a predicted receptor protein tyrosine phosphatase (MOA-1/R155.2). Furthermore, this embryonic lethality is enhanced by knockdown of a predicted prion-like protein (pqn-29). The precise molecular mechanisms underlying these processes remain to be determined. Here, we present hypothetical models as to how sAPL-1 signaling influences metabolic and developmental pathways. Together, with previous findings in mammals that the extracellular domain of mammalian APP (sAPP) binds to a death-receptor,2 our findings support the model that sAPP signaling affects critical biological processes. 相似文献
8.
《朊病毒》2013,7(5):417-419
Mammalian prions with significant levels of specific infectivity can be formed in vitro from mixtures of prion protein (PrP) and cofactor molecules, but not from PrP alone. We recently isolated and identified the essential membrane phospholipid phosphatidylethanolamine (PE) as an endogenous cofactor for prion propagation in vitro.1 In this article, we discuss the potential role of PE and other essential cofactor molecules as a molecular link between the processes of prion formation and prion-induced neurodegeneration. 相似文献
9.
Christopher J. Derrick 《Cell cycle (Georgetown, Tex.)》2017,16(1):23-32
Localized mRNA translation is a widespread mechanism for targeting protein synthesis, important for cell fate, motility and pathogenesis. In Drosophila, the spatiotemporal control of gurken/TGF-α mRNA translation is required for establishing the embryonic body axes. A number of recent studies have highlighted key aspects of the mechanism of gurken mRNA translational control at the dorsoanterior corner of the mid-stage oocyte. Orb/CPEB and Wispy/GLD-2 are required for polyadenylation of gurken mRNA, but unlocalized gurken mRNA in the oocyte is not fully polyadenylated.1 At the dorsoanterior corner, Orb and gurken mRNA have been shown to be enriched at the edge of Processing bodies, where translation occurs.2 Over-expression of Orb in the adjacent nurse cells, where gurken mRNA is transcribed, is sufficient to cause mis-expression of Gurken protein.3 In orb mutant egg chambers, reducing the activity of CK2, a Serine/Threonine protein kinase, enhances the ventralized phenotype, consistent with perturbation of gurken translation.4 Here we show that sites phosphorylated by CK2 overlap with active Orb and with Gurken protein expression. Together with our new findings we consolidate the literature into a working model for gurken mRNA translational control and review the role of kinases, cell cycle factors and polyadenylation machinery highlighting a multitude of conserved factors and mechanisms in the Drosophila egg chamber. 相似文献
10.
《Autophagy》2013,9(8):801-802
Considerable attention has been paid to the topic of autophagy induction. In part, this is because of the potential for modulating this process for therapeutic purposes. Of course we know that induced autophagy can also be problematic—for example, when trying to eliminate an established tumor that might be relying on autophagy for its own cytoprotective uses. Accordingly, inhibitory mechanisms have been considered; however, the corresponding studies have tended to focus on the pathways that block autophagy under noninducing conditions, such as when nutrients are available. In contrast, relatively little is known about the mechanisms for inhibiting autophagy under inducing conditions. Yet, this type of regulation must be occurring on a routine basis. We know that dysregulation of autophagy, e.g., due to improper activation of Beclin 1 leading to excessive autophagy activity, can cause cell death.1 Accordingly, we assume that during starvation or other inducing conditions there must be a mechanism to modulate autophagy. That is, once you turn it on, you do not want to let it continue unchecked. But how is autophagy downregulated when the inducing conditions still exist? 相似文献
11.
Zlatko Janeba Noha Maklad Morris J. Robins 《Nucleosides, nucleotides & nucleic acids》2013,32(10-12):1729-1743
Copper(I)-catalyzed 5-endo-dig cyclizations of 5-(alkyn-1-yl)uracil derivatives had given poor yields of substituted furo[2, 3]pyrimidin-2-ones unless the uracil ring was substituted at N1 with alkyl or glycosyl groups. This limited flexibility for the synthesis of analogues with varied substituents at N3 and/or C6 of the furo[2, 3]pyrimidin-2-one core has been overcome with 5-(3-hydroxyalkyn-1-yl)uracil compounds with no substituent at N1. Manipulation of the side-chain hydroxyl group gives access to additional furo[2,3-d]pyrimidin-2-one analogues. 相似文献
12.
《Fly》2013,7(4):155-159
ABSTRACTAnimals have modular cis-regulatory regions in their genomes, and expression of a single gene is often regulated by multiple enhancers residing in such a region. In the laboratory, and also in natural populations, loss of an enhancer can result in a loss of gene expression. Although only a few examples have been well characterized to date, some studies have suggested that an evolutionary gain of a new enhancer function can establish a new gene expression domain. Our recent study showed that Drosophila guttifera has more enhancers and additional expression domains of the wingless gene during the pupal stage, compared to D. melanogaster, and that these new features appear to have evolved in the ancestral lineage leading to D. guttifera.1 Gain of a new expression domain of a developmental regulatory gene (toolkit gene), such as wingless, can cause co-option of the expression of its downstream genes to the new domain, resulting in duplication of a preexisting structure at this new body position. Recently, with the advancement of evo-devo studies, we have learned that the developmental regulatory systems are strikingly similar across various animal taxa, in spite of the great diversity of the animals' morphology. Even behind “new” traits, co-options of essential developmental genes from known systems are very common. We previously provided concrete evidence of gains of enhancer activities of a developmental regulatory gene underlying gains of new traits.1 Broad occurrence of this scenario is testable and should be validated in the future. 相似文献
13.
The natural remobilization of an initially static mixed dense non-aqueous phase liquid (DNAPL) pool due to dissolution was demonstrated by (Roy et al. 2002, 2004) using a compositional mathematical model and laboratory experiments with open pools over a porous medium. The purposes of this study were to: a) demonstrate natural remobilization for a pool within porous media (as opposed to an open pool); and b) analyze the capillary effects associated with residual formation, a changing saturation profile, hysteresis, and aging, as these processes may reduce the potential for natural remobilization of pools in porous media. DNAPL pools comprised of tetrachloroethene and benzene were created within a zone of larger glass beads overlying smaller glass beads, in a water-saturated 2-D flow cell. In one case, remobilization occurred in the form of a DNAPL finger, after 56 days of flushing. In another case, no remobilization had occurred after 64 days of flushing, though the density increased by 430 kg m ?3 and remobilization was predicted by the compositional model. Comparison of observations with model predictions suggest that contact angle hysteresis, related to an observed change in wettability, was the most significant contributing factor causing overprediction of the potential for natural remobilization. 相似文献
14.
《Epigenetics》2013,8(6):798-802
The epigenetic marks displayed by a cancer cell originate from two separate processes: The most prominent epigenetic signatures are associated with the cell of origin, i.e., the lineage and cell type identity imposed during development. The second set comprises those aberrant cancer-specific epigenetic marks that appear during tumor initiation or subsequent malignant progression. These are generally thought to associate with tumor-promoting pathways. As biochemical pathways regulating epigenetic mechanisms are potentially “druggable” and reversible, there is considerable interest in defining their roles in tumor genesis and growth, as they may represent therapeutic targets for treatment of human neoplasias.1 However, despite the potential importance of epigenetic modifications in human cancer, it has been difficult to determine when, where and how epigenetic disruptions occur, and if they have important functional roles in sustaining the malignant state. 相似文献
15.
Background: Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death.1 The cause of sFI was recently mapped to a mutation in a protein, the prion, found in the human brain. It is the unfolding of the prion that leads to the generation of toxic oligomers that destroy brain tissue and function. Recent studies have confirmed that a methionine mutation at codon 129 of the human Prion is characteristic of sFI. Current treatment slows down the progression of the disease, but no cure has been found, yet. Methods: We used Molecular Docking and Molecular Dynamics simulation methods, to study the toxic Fatal-Insomnia-prion conformations at local unfolding. The idea was to determine these sites and to stabilise these regions against unfolding and miss-folding, using a small ligand, based on a phenothiazine "moiety". Conclusion: As a result we here discuss current fatal insomnia therapy and present seven novel possible compounds for in vitro and in vivo screening. 相似文献
16.
In Disney/Pixar's phenomenally popular animated film Finding Nemo (Stanton, 2003), one of the central themes of fish welfare was highlighted when the moorish idol, Gill, commented, “Fish aren't meant to be kept in a box, kid. It does things to you.” The notion that fish might have the capacity to suffer in captivity (Chandroo, Duncan, & Moccia, 2004a, 2004b) links to the larger question of sentiency, which remains a fundamental tenet when justifying concerns for nonhuman animal welfare (Dawkins, 2006; Huntingford et al., 2006). Although terrestrial nonhuman-animal welfare has been discussed and explored for many years, the development of aquatic animal welfare concepts and approaches remains relatively new and beyond public awareness (Braastad, Damsgård, & Juell, 2006; Broom, 2007; Farmed Animal Welfare Council, 1996; Fisheries Society of the British Isles, 2002; Håstein, Scarfe, & Lund, 2005; Iwama, 2007; Schreck, 1981). 相似文献
17.
《朊病毒》2013,7(3):234-239
Most prions in yeast form amyloid fibrils that must be severed by the protein disaggregase Hsp104 to be propagated and transmitted efficiently to newly formed buds. Only one yeast prion, [PSI+], is cured by Hsp104 overexpression. We investigated the interaction between Hsp104 and Sup35, the priongenic protein in yeast that forms the [PSI+] prion.1 We found that a 20-amino acid segment within the highly-charged, unstructured middle domain of Sup35 contributes to the physical interaction between the middle domain and Hsp104. When this segment was deleted from Sup35, the efficiency of [PSI+] severing was substantially reduced, resulting in larger Sup35 particles and weakening of the [PSI+] phenotype. Furthermore, [PSI+] in these cells was completely resistant to Hsp104 curing. The affinity of Hsp104 was considerably weaker than that of model Hsp104-binding proteins and peptides, implying that Sup35 prions are not ideal substrates for Hsp104-mediated remodeling. In light of this finding, we present a modified model of Hsp104-mediated [PSI+] propagation and curing that requires only partial remodeling of Sup35 assembled into amyloid fibrils. 相似文献
18.
《朊病毒》2013,7(6):405-411
ABSTRACTWithin the mammalian prion field, the existence of recombinant prion protein (PrP) conformers with self-replicating (ie. autocatalytic) activity in vitro but little to no infectious activity in vivo challenges a key prediction of the protein-only hypothesis of prion replication – that autocatalytic PrP conformers should be infectious. To understand this dissociation of autocatalysis from infectivity, we recently performed a structural and functional comparison between a highly infectious and non-infectious pair of autocatalytic recombinant PrP conformers derived from the same initial prion strain.1 We identified restricted, C-terminal structural differences between these 2 conformers and provided evidence that these relatively subtle differences prevent the non-infectious conformer from templating the conversion of native PrPC substrates containing a glycosylphosphatidylinositol (GPI) anchor.1 In this article we discuss a model, consistent with these findings, in which recombinant PrP, lacking post-translational modifications and associated folding constraints, is capable of adopting a wide variety of autocatalytic conformations. Only a subset of these recombinant conformers can be adopted by post-translationally modified native PrPC, and this subset represents the recombinant conformers with high specific infectivity. We examine this model's implications for the generation of highly infectious recombinant prions and the protein-only hypothesis of prion replication. 相似文献
19.
《Journal of biological dynamics》2013,7(2):117-130
We address several conjectures raised in Cantrell et al. [Evolution of dispersal and ideal free distribution, Math. Biosci. Eng. 7 (2010), pp. 17–36 [9]] concerning the dynamics of a diffusion–advection–competition model for two competing species. A conditional dispersal strategy, which results in the ideal free distribution of a single population at equilibrium, was found in Cantrell et al. [9]. It was shown in [9] that this special dispersal strategy is a local evolutionarily stable strategy (ESS) when the random diffusion rates of the two species are equal, and here we show that it is a global ESS for arbitrary random diffusion rates. The conditions in [9] for the coexistence of two species are substantially improved. Finally, we show that this special dispersal strategy is not globally convergent stable for certain resource functions, in contrast with the result from [9], which roughly says that this dispersal strategy is globally convergent stable for any monotone resource function. 相似文献
20.
We investigated the morphology, morphogenesis and small subunit rRNA gene-based phylogeny of three marine urostylids, Uncinata gigantea Bullington, 1940, Holosticha heterofoissneri Hu & Song, 2001, and Holosticha cf. heterofoissneri. The dorsal morphogenesis of Uncinata gigantea shows de novo formation of two groups of anlagen near the marginal rows. Holosticha cf. heterofoissneri demonstrates fragmentation of the first dorsal kinety anlage as in Holosticha heterofoissneri. Our population of H. heterofoissneri corresponds well with previously described populations in terms of its general morphology and ciliary pattern. Uncinata gigantea can be recognized by its large and highly contractile body, yellowish to brownish cell colour, two types of cortical granules, and 20–30 transversely oriented and densely arranged cirri in the left marginal row, which often overlie the buccal vertex. Based on the new data, especially infraciliature, the genus Uncinata is here redefined. Both the morphology and phylogenetic analyses suggest that the genus Uncinata should be classified within the family Urostylidae. In addition, both morphological and morphogenetic data suggest that Holosticha bradburyae Gong et al., 2001 should be transferred to Uncinata as U. bradburyae (Gong et al., 2001) comb. nov., due to its possession of a characteristically prominent beak-like, leftwards curved projection and the developmental mode of the dorsal kineties. This assignment is supported by the phylogenetic analyses, which placed Uncinata gigantea in a clade with U. bradburyae (Gong et al., 2001) comb. nov., and revealed only 1.13% (19 bp) difference in their SSU-rDNA gene sequence. 相似文献