9,533 research outputs found
β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H
CREB-H is an endoplasmic reticulum-resident bZIP transcription factor which critically regulates lipid homeostasis and gluconeogenesis in the liver. CREB-H is proteolytically activated by regulated intramembrane proteolysis to generate a C-terminally truncated form known as CREB-H-ΔTC, which translocates to the nucleus to activate target gene expression. CREB-H-ΔTC is a fast turnover protein but the mechanism governing its destruction was not well understood. In this study, we report on β-TrCP-dependent ubiquitination and proteasomal degradation of CREB-H-ΔTC. The degradation of CREB-H-ΔTC was mediated by lysine 48-linked polyubiquitination and could be inhibited by proteasome inhibitor. CREB-H-ΔTC physically interacted with β-TrCP, a substrate recognition subunit of the SCFβ-TrCP E3 ubiquitin ligase. Forced expression of β-TrCP increased the polyubiquitination and decreased the stability of CREB-H-ΔTC, whereas knockdown of β-TrCP had the opposite effect. An evolutionarily conserved sequence, SDSGIS, was identified in CREB-H-ΔTC, which functioned as the β-TrCP-binding motif. CREB-H-ΔTC lacking this motif was stabilized and resistant to β-TrCP-induced polyubiquitination. This motif was a phosphodegron and its phosphorylation was required for β-TrCP recognition. Furthermore, two inhibitory phosphorylation sites close to the phosphodegron were identified. Taken together, our work revealed a new intracellular signaling pathway that controls ubiquitination and degradation of the active form of CREB-H transcription factor.published_or_final_versio
Differential Effects of Tyrosine Kinase Inhibitors on Volume-sensitive Chloride Current in Human Atrial Myocytes: Evidence for Dual Regulation by Src and EGFR Kinases
To determine whether protein tyrosine kinase (PTK) modulates volume-sensitive chloride current (I Cl.vol) in human atrial myocytes and to identify the PTKs involved, we studied the effects of broad-spectrum and selective PTK inhibitors and the protein tyrosine phosphatase (PTP) inhibitor orthovanadate (VO 4 -3). I Cl.vol evoked by hyposmotic bath solution (0.6-times isosmotic, 0.6T) was enhanced by genistein, a broad-spectrum PTK inhibitor, in a concentration-dependent manner (EC 50 = 22.4 μM); 100 μM genistein stimulated I Cl.vol by 122.4 ± 10.6%. The genistein-stimulated current was inhibited by DIDS (4,4′-diisothiocyanostilbene-2,2′-disulfonic acid, 150 μM) and tamoxifen (20 μM), blockers of I Cl.vol. Moreover, the current augmented by genistein was volume dependent; it was abolished by hyperosmotic shrinkage in 1.4T, and genistein did not activate Cl - current in 1T. In contrast to the stimulatory effects of genistein, 100 μM tyrphostin A23 (AG 18) and A25 (AG 82) inhibited I Cl.vol by 38.2 ± 4.9% and 40.9 ± 3.4%, respectively. The inactive analogs, daidzein and tyrphostin A63 (AG 43), did not alter I Cl.vol. In addition, the PTP inhibitor VO 4 -3 (1 mM) reduced I Cl.vol by 53.5 ± 4.5% (IC 50 = 249.6 μM). Pretreatment with VO 4 -3 antagonized genistein-induced augmentation and A23- or A25-induced suppression of I Cl.vol. Furthermore, the selective Src-family PTK inhibitor PP2 (5 μM) stimulated I Cl.vol, mimicking genistein, whereas the selective EGFR (ErbB-1) kinase inhibitor tyrphostin B56 (AG 556, 25 μM) reduced I Cl.vol, mimicking A23 and A25. The effects of both PP2 and B56 also were substantially antagonized by pretreatment with VO 4 -3. The results suggest that I Cl.vol is regulated in part by the balance between PTK and PTP activity. Regulation is complex, however. Src and EGFR kinases, distinct soluble and receptor-mediated PTK families, have opposing effects on I Cl.vol, and multiple target proteins are likely to be involved.published_or_final_versio
The extreme vulnerability of interdependent spatially embedded networks
Recent studies show that in interdependent networks a very small failure in
one network may lead to catastrophic consequences. Above a critical fraction of
interdependent nodes, even a single node failure can invoke cascading failures
that may abruptly fragment the system, while below this "critical dependency"
(CD) a failure of few nodes leads only to small damage to the system. So far,
the research has been focused on interdependent random networks without space
limitations. However, many real systems, such as power grids and the Internet,
are not random but are spatially embedded. Here we analytically and numerically
analyze the stability of systems consisting of interdependent spatially
embedded networks modeled as lattice networks. Surprisingly, we find that in
lattice systems, in contrast to non-embedded systems, there is no CD and
\textit{any} small fraction of interdependent nodes leads to an abrupt
collapse. We show that this extreme vulnerability of very weakly coupled
lattices is a consequence of the critical exponent describing the percolation
transition of a single lattice. Our results are important for understanding the
vulnerabilities and for designing robust interdependent spatial embedded
networks.Comment: 13 pages, 5 figure
Harmonic Mixing Using a HTS Step-Edge Josephson Junction at 0.6 THz Frequency
© 2002-2011 IEEE. A high-temperature superconducting (HTS) terahertz (THz) heterodyne mixer based on a thin-film antenna-coupled YBa 2Cu3O7-x step-edge Josephson junction is presented. The frequency down-conversion from 0.6 THz to an intermediate frequency (IF) of 2 GHz was achieved using high-order harmonic mixing of a local oscillator (LO), thus removing the need to use a second THz source as the LO pumping source. The DC and RF characteristics of the harmonic mixer as well as the relationship of the IF output power versus the harmonic number were experimentally studied and compared with simulated results. Most of our measurements were made at 40 K, but we also observed stable harmonic mixing at 77 K which we believe has not been reported previously in HTS junction mixers
Towards designing robust coupled networks
Natural and technological interdependent systems have been shown to be highly
vulnerable due to cascading failures and an abrupt collapse of global
connectivity under initial failure. Mitigating the risk by partial
disconnection endangers their functionality. Here we propose a systematic
strategy of selecting a minimum number of autonomous nodes that guarantee a
smooth transition in robustness. Our method which is based on betweenness is
tested on various examples including the famous 2003 electrical blackout of
Italy. We show that, with this strategy, the necessary number of autonomous
nodes can be reduced by a factor of five compared to a random choice. We also
find that the transition to abrupt collapse follows tricritical scaling
characterized by a set of exponents which is independent on the protection
strategy
LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription
published_or_final_versio
Neuromuscular electrical stimulation to improve exercise capacity in patients with severe COPD: a randomised double-blind, placebo-controlled trial.
Avoiding catastrophic failure in correlated networks of networks
Networks in nature do not act in isolation but instead exchange information,
and depend on each other to function properly. An incipient theory of Networks
of Networks have shown that connected random networks may very easily result in
abrupt failures. This theoretical finding bares an intrinsic paradox: If
natural systems organize in interconnected networks, how can they be so stable?
Here we provide a solution to this conundrum, showing that the stability of a
system of networks relies on the relation between the internal structure of a
network and its pattern of connections to other networks. Specifically, we
demonstrate that if network inter-connections are provided by hubs of the
network and if there is a moderate degree of convergence of inter-network
connection the systems of network are stable and robust to failure. We test
this theoretical prediction in two independent experiments of functional brain
networks (in task- and resting states) which show that brain networks are
connected with a topology that maximizes stability according to the theory.Comment: 40 pages, 7 figure
Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis
\ua9 2021, The Author(s). Profiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability, which coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into, how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation
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