共查询到20条相似文献,搜索用时 31 毫秒
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G. M. C. Janssen P. Schwertman T. A. T. Wanga R. S. Jahangir Tafrechi P. J. A. van den Broek A. K. Raap 《Cellular and molecular life sciences : CMLS》2009,66(4):721-730
Cytoplasmic translation is under sophisticated control but how cells adapt its rate to constitutive loss of mitochondrial
oxidative phosphorylation is unknown. Here we show that translation is repressed in cells with the pathogenic A3243G mtDNA
mutation or in mtDNA-less ρ0 cells by at least two distinct pathways, one transiently targeting elongation factor eEF-2 and the other initiation factor
eIF-2α constitutively. Under conditions of exponential cell growth and mammalian target of rapamycin (mTOR) activation, eEF-2
becomes transiently phosphorylated by an AMP-activated protein kinase (AMPK)-dependent pathway, especially high in mutant
cells. Independent of AMPK and mTOR, eIF-2α is constitutively phosphorylated in mutant cells, likely a signature of endoplasmic
reticulum (ER)-stress response induced by the loss of oxidative phosphorylation. While the AMPK/eEF-2K/eEF-2 pathway appears
to function in adaptation to physiological fluctuations in ATP levels in the mutant cells, the ER stress signified by constitutive
protein synthesis inhibition through eIF-2α-mediated repression of translation initiation may have pathobiochemical consequences.
Received 29 October 2008; received after revision 11 December 2008; accepted 16 December 2008 相似文献
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Signal regulation by family conspiracy 总被引:6,自引:0,他引:6
The signal regulating proteins (SIRPs) are a family of ubiquitously expressed transmembrane glycoproteins composed of two
subgroups: SIRPα and SIRPβ, containing more than ten members. SIRPα has been shown to inhibit signalling through a variety of receptors including receptor tyrosine kinases and cytokine receptors.
This function involves protein tyrosine kinases and is dependent on immunoreceptor tyrosine-based inhibition motifs which
recruit key protein tyrosine phosphatases to the membrane. Negative regulation by SIRPα may also involve its ligand, CD47, in a bi-directional signalling mechanism. The SIRPβ subtype has no cytoplasmic domain but instead associates with at least one other transmembrane protein (DAP-12, or KARAP).
DAP-12 possesses immunoreceptor tyrosine-based activation motifs within its cytoplasmic domain that are thought to link SIRPβ to activating machinery. SIRPα and SIRPβ thus have complementary roles in signal regulation and may conspire to tune the response to a stimulus.
Received 6 July 2000; revised 2 August 2000; accepted 5 August 2000 相似文献
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Blasic JR Lane Brown R Robinson PR 《Cellular and molecular life sciences : CMLS》2012,69(9):1551-1562
Melanopsin-based phototransduction is involved in non-image forming light responses including circadian entrainment, pupil
constriction, suppression of pineal melatonin synthesis, and direct photic regulation of sleep in vertebrates. Given that
the functions of melanopsin involve the measurement and summation of total environmental luminance, there would appear to
be no need for the rapid deactivation typical of other G-protein coupled receptors. In this study, however, we demonstrate
that heterologously expressed mouse melanopsin is phosphorylated in a light-dependent manner, and that this phosphorylation
is involved in regulating the rate of G-protein activation and the lifetime of melanopsin’s active state. Furthermore, we
provide evidence for light-dependent phosphorylation of melanopsin in the mouse retina using an in situ proximity ligation
assay. Finally, we demonstrate that melanopsin preferentially interacts with the GRK2/3 family of G-protein coupled receptor
kinases through co-immunoprecipitation assays. Based on the complement of G-protein receptor kinases present in the melanopsin-expressing
retinal ganglion cells, GRK2 emerges as the best candidate for melanopsin’s cognate GRK. 相似文献
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The rapid migration of intestinal epithelial cells (IEC) is important for the healing of mucosal wounds. We have previously
shown that polyamine depletion inhibits migration of IEC-6 cells. Akt activation and its downstream target GSK-3β have been
implicated in the regulation of migration. Here we investigated the significance of elevated phosphatidylinositol 3-kinase
(PI3K)/Akt signaling on migration of polyamine-depleted cells. Polyamine-depleted cells had high Akt (Ser473) and GSK-3β (Ser9)
phosphorylation. Pretreatment with 20 μM LY294002 (PI3K inhibitor) for 30 min inhibited phosphorylation of Akt, increased
migration by activating Rac1 in polyamine-depleted IEC-6 cells, and restored the actin structure similar to that in cells
grown in control medium. Treatment of cells with a GSK-3β inhibitor (AR-A014418) altered the actin cytoskeleton and inhibited
migration, mimicking the effects of polyamine depletion. Thus, our results indicate that sustained activation of Akt in response
to polyamine depletion inhibits migration through GSK-3β and Rac1.
Received 25 August 2006; received after revision 3 October 2006; accepted 16 October 2006 相似文献
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Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance 总被引:3,自引:0,他引:3
Balaraman Y Limaye AR Levey AI Srinivasan S 《Cellular and molecular life sciences : CMLS》2006,63(11):1226-1235
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading
cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the
serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in
the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review,
we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor
protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt,
Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD.
Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006 相似文献
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Kraft B Johswich A Kauczor G Scharenberg M Gerardy-Schahn R Bakker H 《Cellular and molecular life sciences : CMLS》2011,68(24):4091-4100
The glycolipid specific Drosophila melanogaster β1,4-N-acetylgalactosaminyltransferase B (β4GalNAcTB) depends on a zinc finger DHHC protein family member named GalNAcTB pilot (GABPI)
for activity and translocation to the Golgi. The six-membrane spanning protein actually lacks the cysteine in the cytoplasmic
DHHC motif, displaying DHHS instead. Here we show that the whole conserved region around the DHHS sequence, which is essential
for palmitoylation in DHHC proteins, is not required for GABPI to interact with β4GalNAcTB. In contrast, the two luminal loops
between transmembrane domain 3–4 and 5–6 contain conserved amino acids, which are crucial for activity. Besides the dependence
on GABPI, β4GalNAcTB requires its exceptional short stem region for activity. A few hydrophobic amino acids positioned close
to the transmembrane domain are essential for the interaction with GABPI. Along with its catalytic domain, β4GalNAcTB, thus,
requires an area in its own stem region and two small luminal loops of GABPI as "add-on" domains. Moreover, some inactive
GABPI mutants could be rescued by fusion with β4GalNAcTB, indicating their importance in direct GABPI-β4GalNAcTB interaction. 相似文献
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Dong Gao Ruipeng Wang Bingfeng Li Yongkang Yang Zhonghe Zhai Dan-Ying Chen 《Cellular and molecular life sciences : CMLS》2009,66(15):2573-2584
Toll-like receptors (TLRs) act as sensors of microbial components and elicit innate immune responses. All TLR signaling pathways
activate the nuclear factor-kappaB (NF-κB), which controls the expression of inflammatory cytokine genes. Transforming growth
factor-β-activated kinase 1 (TAK1) is a serine/threonine protein kinase that is critically involved in the activation of NF-κB
by tumor necrosis factor (TNFα), interleukin-1β (IL-1β) and TLR ligands. In this study, we identified a novel protein, WD40
domain repeat protein 34 (WDR34) as a TAK1-interacting protein in yeast two-hybrid screens. WDR34 interacted with TAK1, TAK1-binding
protein 2 (TAB2), TAK1-binding protein 3 (TAB3) and tumor necrosis factor receptor-associated factor 6 (TRAF6) in overexpression
and under physiological conditions. Overexpression of WDR34 inhibited IL-1β-, polyI:C- and lipopolysaccharide (LPS)-induced
but not TNFα-induced NF-κB activation, whereas knockdown of WDR34 by a RNA-interference construct potentiated NF-κB activation
by these ligands. Our findings suggest that WDR34 is a TAK1-associated inhibitor of the IL-1R/TLR3/TLR4-induced NF-κB activation
pathway.
D. Gao and R. Wang contributed equally to this work. 相似文献
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Alemu EA Sjøttem E Outzen H Larsen KB Holm T Bjørkøy G Johansen T 《Cellular and molecular life sciences : CMLS》2011,68(11):1953-1968
The protein kinase C (PKC) family of serine/threonine kinases consists of ten different isoforms grouped into three subfamilies,
denoted classical, novel and atypical PKCs (aPKCs). The aPKCs, PKCι/λ and PKCζ serve important roles during development and
in processes subverted in cancer such as cell and tissue polarity, cell proliferation, differentiation and apoptosis. In an
effort to identify novel interaction partners for aPKCs, we performed a yeast two-hybrid screen with the regulatory domain
of PKCι/λ as bait and identified the Krüppel-like factors family protein TIEG1 as a putative interaction partner for PKCι/λ.
We confirmed the interaction of both aPKCs with TIEG1 in vitro and in cells, and found that both aPKCs phosphorylate the DNA-binding
domain of TIEG1 on two critical residues. Interestingly, the aPKC-mediated phosphorylation of TIEG1 affected its DNA-binding
activity, subnuclear localization and transactivation potential. 相似文献
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Alzheimer’s disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid
beta peptide (Aβ) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared
spectroscopy to provide structural information on the entire aggregation pathway of Aβ(1–40), starting from monomeric Aβ to
the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition
from antiparallel to parallel β-sheet. These structural changes are described in terms of H-bonding rupture/formation, β-strands
reorientation and β-sheet elongation. As antiparallel β-sheet structure is also observed for other amyloidogenic proteins
forming oligomers, reorganization of the β-sheet implicating a reorientation of β-strands could be a generic mechanism determining
the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could
be essential in a search for therapies inhibiting aggregation or disrupting aggregates. 相似文献
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Endogenous electrical fields (EFs) at corneal and skin wounds send a powerful signal that directs cell migration during wound
healing. This signal therefore may serve as a fundamental regulator directing cell polarization and migration. Very little
is known of the intracellular and molecular mechanisms that mediate EF-induced cell polarization and migration. Here, we report
that Chinese hamster ovary (CHO) cells show robust directional polarization and migration in a physiological EF (0.3–1 V/cm)
in both dissociated cell culture and monolayer culture. An EF of 0.6 V/cm completely abolished cell migration into wounds
in monolayer culture. An EF of higher strength (≥1 V/cm) is an overriding guidance cue for cell migration. Application of
EF induced quick phosphorylation of glycogen synthase kinase 3β (GSK-3β) which reached a peak as early as 3 min in an EF.
Inhibition of protein kinase C (PKC) significantly reduced EF-induced directedness of cell migration initially (in 1–2 h).
Inhibition of GSK-3β completely abolished EF-induced GA polarization and significantly inhibited the directional cell migration,
but at a later time (2–3 h in an EF). Those results suggest that GSK-3β is essential for physiological EF-induced Golgi apparatus
(GA) polarization and optimal electrotactic cell migration. 相似文献
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Dekki N Refai E Holmberg R Köhler M Jörnvall H Berggren PO Juntti-Berggren L 《Cellular and molecular life sciences : CMLS》2012,69(10):1733-1743
Transthyretin (TTR) is a functional protein in the pancreatic β-cell. It promotes insulin release and protects against β-cell
death. We now demonstrate by ligand blotting, adsorption to specific magnetic beads, and surface plasmon resonance that TTR
binds to glucose-regulated proteins (Grps)78, 94, and 170, which are members of the endoplasmic reticulum chaperone family,
but Grps78 and 94 have also been found at the plasma membrane. The effect of TTR on changes in cytoplasmic free Ca2+ concentration ([Ca2+]i) was abolished if the cells were treated with either dynasore, a specific inhibitor of dynamin GTPase that blocks clathrin-mediated
endocytosis, or an antibody against Grp78, that prevents TTR from binding to Grp78. The conclusion is that TTR binds to Grp78
at the plasma membrane, is internalized into the β-cell via a clathrin-dependent pathway, and that this internalization is
necessary for the effects of TTR on β-cell function. 相似文献
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Apolipoprotein E (apoE) ɛ4 allele is a genetic risk factor for late-onset familial and sporadic Alzheimer’s disease (AD).
In the central nervous system, apoE is secreted mainly by astrocytes as a constituent of high-density lipoproteins. A recent
study using apoE knockout mice provided strong evidence that apoE promotes cerebral deposition of amyloid β protein (Aβ).
However, no clear explanation of the pathogenesis of apoE-induced AD has been provided. Here we discuss two possible mechanisms
by which apoE might enhance Aβ deposition. One is the intracellular pathway in which apoE is internalized by neurons and induces
lysosomal accumulation of Aβ and amyloidogenic APP (amyloid precursor protein) fragments, leading to neuronal death. The other
is the extracellular pathway in which apoE-containing lipoproteins are trapped by Aβ1–42 deposits mobilizing soluble Aβ peptides
and consequently enlarge amyloid plaques. These two mechanisms may operate at different stages of AD pathogenesis and suggest
a chaperone-like function for the apoE molecule.
Received 4 February 1999; received after revision 9 April 1999; accepted 23 April 1999 相似文献
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AMP-activated protein kinase in skeletal muscle: From structure and localization to its role as a master regulator of cellular metabolism 总被引:1,自引:0,他引:1
Witczak CA Sharoff CG Goodyear LJ 《Cellular and molecular life sciences : CMLS》2008,65(23):3737-3755
The AMP-activated protein kinase (AMPK) is a metabolite sensing serine/threonine kinase that has been termed the master regulator
of cellular energy metabolism due to its numerous roles in the regulation of glucose, lipid, and protein metabolism. In this
review, we first summarize the current literature on a number of important aspects of AMPK in skeletal muscle. These include
the following: (1) the structural components of the three AMPK subunits (i.e. AMPKα, β, and γ), and their differential localization
in response to stimulation in muscle; (2) the biochemical regulation of AMPK by AMP, protein phosphatases, and its three known
upstream kinases, LKB1, Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), and transforming growth factor-β-activated kinase 1 (TAK1); (3) the pharmacological
agents that are currently available for the activation and inhibition of AMPK; (4) the physiological stimuli that activate
AMPK in muscle; and (5) the metabolic processes that AMPK regulates in skeletal muscle.
Received 04 May 2008; received after revision 14 June 2008; accepted 14 July 2008 相似文献
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R. J. S. Viana A. F. Nunes R. E. Castro R. M. Ramalho J. Meyerson S. Fossati J. Ghiso A. Rostagno C. M. P. Rodrigues 《Cellular and molecular life sciences : CMLS》2009,66(6):1094-1104
The vasculotropic E22Q mutant of the amyloid-β (Aβ) peptide is associated with hereditary cerebral hemorrhage with amyloidosis
Dutch type. The cellular mechanism(s) of toxicity and nature of the AβE22Q toxic assemblies are not completely understood.
Comparative assessment of structural parameters and cell death mechanisms elicited in primary human cerebral endothelial cells
by AβE22Q and wild-type Aβ revealed that only AβE22Q triggered the Bax mitochondrial pathway of apoptosis. AβE22Q neither
matched the fast oligomerization kinetics of Aβ42 nor reached its predominant β-sheet structure, achieving a modest degree
of oligomerization with a secondary structure that remained a mixture of β and random conformations. The endogenous molecule
tauroursodeoxycholic acid (TUDCA) was a strong modulator of AβE22Q-triggered apoptosis but did not significantly change the
secondary structures and fibrillogenic propensities of Aβ peptides. These data dissociate the pro-apoptotic properties of
Aβ peptides from their distinct mechanisms of aggregation/fibrillization in vitro, providing new perspectives for modulation of amyloid toxicity.
Received 20 November 2008; received after revision 12 December 2008; accepted 12 January 2009 相似文献
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James R. Ketudat Cairns Asim Esen 《Cellular and molecular life sciences : CMLS》2010,67(20):3389-3405
β-Glucosidases (3.2.1.21) are found in all domains of living organisms, where they play essential roles in the removal of
nonreducing terminal glucosyl residues from saccharides and glycosides. β-Glucosidases function in glycolipid and exogenous
glycoside metabolism in animals, defense, cell wall lignification, cell wall β-glucan turnover, phytohormone activation, and
release of aromatic compounds in plants, and biomass conversion in microorganisms. These functions lead to many agricultural
and industrial applications. β-Glucosidases have been classified into glycoside hydrolase (GH) families GH1, GH3, GH5, GH9,
and GH30, based on their amino acid sequences, while other β-glucosidases remain to be classified. The GH1, GH5, and GH30
β-glucosidases fall in GH Clan A, which consists of proteins with (β/α)8-barrel structures. In contrast, the active site of GH3 enzymes comprises two domains, while GH9 enzymes have (α/α)6 barrel structures. The mechanism by which GH1 enzymes recognize and hydrolyze substrates with different specificities remains
an area of intense study. 相似文献