共查询到20条相似文献,搜索用时 31 毫秒
1.
《Cell cycle (Georgetown, Tex.)》2013,12(19):3555-3558
CEP192 is a centrosome protein that plays a critical role in centrosome biogenesis and function in mammals, Drosophila and C. elegans.1-6 Moreover, CEP192-depleted cells arrest in mitosis with disorganized microtubules, suggesting that CEP192’s function in spindle assembly goes beyond its role in centrosome activity and pointing to a potentially more direct role in the regulation of the mitotic microtubule landscape.7 To better understand CEP192 function in mitosis, we used mass spectrometry to identify CEP192-interacting proteins. We previously reported that CEP192 interacts with NEDD1, a protein that associates with the γ-tubulin ring complex (γ-TuRC) and regulates its phosphorylation status during mitosis.8 Additionally, within the array of proteins that interact with CEP192, we identified the microtubule binding K63-deubiquitinase CYLD. Further analyses show that co-depletion of CYLD alleviates the bipolar spindle assembly defects observed in CEP192-depleted cells. This functional relationship exposes an intriguing role for CYLD in spindle formation and raises the tantalizing possibility that CEP192 promotes robust mitotic spindle assembly by regulating K63-polyubiquitin-mediated signaling through CYLD. 相似文献
2.
《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
3.
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
4.
《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
5.
《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
6.
《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
7.
《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
8.
9.
《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
10.
《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
11.
《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
12.
Sabine Elowe 《Cell cycle (Georgetown, Tex.)》2017,16(8):746-748
Tyrosine phosphorylation is rare, representing only about 0.5% of phosphorylations in the cell under basal conditions. While mitogenic tyrosine kinase signaling has been extensively explored, the role of phosphotyrosine signaling across the cell cycle and in particular during mitosis is poorly understood.
Two recent, independent studies tackled this question from different angles to reveal exciting new insights into the role of this modification during cell division. Caron et al.1 exploited mitotic phosphoproteomics data sets to determine the extent of mitotic tyrosine phosphorylation, and St-Denis et al.2 identified protein tyrosine phosphatases from all subfamilies as regulators of mitotic progression or spindle formation. These studied collectively revealed that tyrosine phosphorylation may play a more prominent and active role in mitotic progression than previously appreciated. 相似文献
13.
Hana Popelka 《Autophagy》2017,13(3):449-451
Atg13 is an essential subunit of the Atg1 autophagy initiation complex in yeast and its mammalian counterpart, ATG13, is indispensable for autophagy induction by the ULK1 complex. The N terminus of the protein folds into a HORMA domain, an architecture that has been revealed by crystallography.1-4 In human cells, the ATG13 HORMA domain interacts directly with ATG14, a subunit of the class III phosphatidylinositol 3-kinase complex.5 In budding yeast, the HORMA domain of Atg13 recruits Atg14, but a direct interaction remains to be proven.1 The amino acid sequence that follows the HORMA domain does not adopt any 3-dimensional structure on its own; therefore, it is termed an intrinsically disordered region (IDR). Here we discuss the results of 2 recent studies in light of previous reports on Atg13 from yeast. Together, they yield an insight into the molecular mechanism for the function of this intriguing protein, and reveal why Atg13, as well as the mammalian homolog ATG13, cannot have a structurally rigid architecture. 相似文献
14.
Sequestration of aggregates into specialized deposition sites occurs in many species across all kingdoms of life ranging from bacteria to mammals and is commonly believed to have a cytoprotective function. Yeast cells possess at least 3 different spatially separated deposition sites, one of which is termed “Insoluble Protein Deposit (IPOD)” and harbors amyloid aggregates. We have recently discovered that recruitment of amyloid aggregates to the IPOD uses an actin cable based recruitment machinery that also involves vesicular transport.1 Here we discuss how different proteins known to be involved in vesicular transport processes to the vacuole might act to guide amyloid aggregates to the IPOD. These factors include the Myosin V motor protein Myo2 involved in transporting vacuolar vesicles along actin cables, the transmembrane protein Atg9 involved in the recruitment of large precursor hydrolase complexes to the vacuole, the phosphatidylinositol/ phosphatidylcholine (PI/PC) transfer protein Sec 14 and the SNARE chaperone Sec 18. Furthermore, we present new data suggesting that the yeast dynamin homolog Vps1 is also crucial for faithful delivery of the amyloid model protein PrD-GFP to the IPOD. This is in agreement with a previously identified role for Vps1 in recruitment of heat-denatured aggregates to a perivacuolar deposition site.2 相似文献
15.
The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid separation, and cell division. Mathematical models describing the biochemical interaction networks of cell cycle regulators attribute these properties to underlying bistable switches, which inherently generate robust, switch-like, and irreversible transitions between states. We have recently presented new mathematical models for two control systems that regulate crucial transitions in the cell cycle: mitotic entry and exit,1 and the mitotic checkpoint.2 Each of the two control systems is characterized by two interlinked bistable switches. In the case of mitotic checkpoint control, these switches are mutually activating, whereas in the case of the mitotic entry/exit network, the switches are mutually inhibiting. In this Perspective we describe the qualitative features of these regulatory motifs and show that having two interlinked bistable mechanisms further enhances robustness and irreversibility. We speculate that these network motifs also underlie other cell cycle transitions and cellular transitions between distinct biochemical states. 相似文献
16.
17.
《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
18.
《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
19.
《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
20.
The influence of the geometry of the porcine cornea on the biomechanical response of inflation tests
Anna Pandolfi Federica Boschetti 《Computer methods in biomechanics and biomedical engineering》2013,16(1):64-77
To withstand the high probability of success, the growing diffusion of laser surgery for the correction of visual defects, corneal surgeons are regarding with interest numerical tools able to provide reliable predictions of the intervention outcomes. The main obstacle to the definition of a predictive numerical instrument is the objective difficulty in evaluating the in vivo mechanical properties of the human cornea. In this study, we assess the ability of a parametrised numerical model of the cornea (Pandolfi and Manganiello 2006) to describe individual pressurisation tests on whole porcine corneas once the mechanical parameters of the model have been calibrated over average data. We also aim at estimating the sensitivity of the mechanical response with the variation of basic geometrical parameters, such as the central corneal thickness, the curvature and the in-plane diameter. We conclude that the actual geometry of a cornea has a minor role in the overall mechanical response, and therefore the material properties must be considered carefully and individually in any numerical application. This study makes use of the data obtained from a wide experimental program, where a set of 21 porcine corneas has been fully characterised in terms of mechanical and geometrical properties (Boschetti et al. 2012). 相似文献