共查询到20条相似文献,搜索用时 903 毫秒
1.
Sreerupa Challa Francis Ka-Ming Chan 《Cellular and molecular life sciences : CMLS》2010,67(19):3241-3253
Recent evidence indicates that cell death can be induced through multiple mechanisms. Strikingly, the same death signal can
often induce apoptotic as well as non-apoptotic cell death. For instance, inhibition of caspases often converts an apoptotic
stimulus to one that causes necrosis. Because a dedicated molecular circuitry distinct from that controlling apoptosis is
required for necrotic cell injury, terms such as “programmed necrosis” or “necroptosis” have been used to distinguish stimulus-dependent
necrosis from those induced by non-specific traumas (e.g., heat shock) or secondary necrosis induced as a consequence of apoptosis.
In several experimental models, programmed necrosis/necroptosis has been shown to be a crucial control point for pathogen-
or injury-induced inflammation. In this review, we will discuss the molecular mechanisms that regulate programmed necrosis/necroptosis
and its biological significance in pathogen infections, drug-induced cell injury, and trauma-induced tissue damage. 相似文献
2.
Ribot JC debarros A Silva-Santos B 《Cellular and molecular life sciences : CMLS》2011,68(14):2345-2355
T cell activation requires the integration of signals that arise from various types of receptors. Although TCR triggering
is a necessary condition, it is often not sufficient to induce full T-cell activation, as reflected in cell proliferation
and cytokine secretion. This has been firmly demonstrated for conventional αβ T cells, for which a large panel of costimulatory
receptors has been identified. By contrast, the area remains more obscure for unconventional, innate-like γδ T cells, as the
literature has been scarce and at times contradictory. Here we review the current state of the art on the costimulatory requirements
of γδ T cell activation. We highlight the roles of members of the immunoglobulin (like CD28 or JAML) or tumour necrosis factor
receptor (like CD27) superfamilies of coreceptors, but also of more atypical costimulatory molecules, such as NKG2D or CD46.
Finally, we identify various areas where our knowledge is still markedly insufficient, hoping to provoke future research on
γδ T cell costimulation. 相似文献
3.
Sally A. Nicholas Vladimir V. Bubnov Inna M. Yasinska Vadim V. Sumbayev 《Cellular and molecular life sciences : CMLS》2011,68(1):151-158
Inflammatory reactions to ssRNA viruses are induced by the endosomal Toll-like receptors (TLRs) 7 and 8. TLR7/8-mediated inflammatory
reaction results in activation of the Nalp3 inflammasome via an unknown mechanism. Here we report for the first time that
TLR7/8 mediate activation of xanthine oxidase (XOD) in an HIF-1α-dependent manner. XOD produces uric acid and reactive oxygen
species, which could activate Nalp3 and therefore induce activation of caspase 1, known to convert inactive pro-IL-1β into
active IL-1β. Specific inhibition of the XOD activity attenuates TLR7/8-mediated activation of caspase 1 and IL-1β release.
These results were obtained using human THP-1 myeloid macrophages. The findings were verified by conducting in vivo experiments
on mice. 相似文献
4.
In renal carcinoma cells (RCC4) hypoxia inducible factor-1 (HIF-1) is constitutively expressed due to a von Hippel Lindau
protein deficiency, but can be degraded by calpain, independently of the 26S proteasome, when exposed to hypoxia/nitric oxide
(NO). In this study we examined molecular mechanisms to explain calpain activation. The inability of hypoxia/NO to degrade
HIF-1α in respiratory-deficient RCC4-ρ0 cells pointed to the requirement for mitochondria-derived reactive oxygen species.
A prerequisite for O
2
−
in combination with NO to destabilize HIF-1α was corroborated in RCC4-p0 cells, when the redox cycler 2,3-dimethoxy-1,4-naphthoquinone
was used as a source of superoxide. Degradation of HIF-1α required intracellular calcium transients and calpain activation.
Using uric acid to interfere with signal transmission elicited by NO/O
2
−
blocked HIF-1α degradation and attenuated a calcium increase. We conclude that an oxidative signal as a result of NO/O
2
−
coformation triggers a calcium increase that activates calpain to degrade HIF-1α, independently of the proteasome.
Received 14 August 2007; received after revision 4 October 2007; accepted 22 October 2007 相似文献
5.
Jérémie Gautheron Gilles Courtois 《Cellular and molecular life sciences : CMLS》2010,67(18):3101-3113
Ubiquitination has emerged over the years as the most sophisticated way to modify proteins to affect their fate and function.
In particular, it has been reported to be instrumental in regulating several steps of the NF-κB signalling pathway which controls
inflammation, immunity, adhesion and cell survival. Integrating ubiquitination into NF-κB activation requires the regulatory
subunit of IKK, NEMO, which not only displays affinity for polyubiquitin chains, but is also posttranslationally modified
by a complex set of reactions involving ubiquitin. Here, we examine how studies of the NEMO/ubiquitin relationship have provided
novel insights into the IKK activation process and have uncovered molecular mechanisms that should represent in the future
attractive targets for specifically modulating NF-κB function. 相似文献
6.
The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis, and is implicated
in human disease. Wnts transduce signals via transmembrane receptors of the Frizzled (Fzd/Fz) family and the low density lipoprotein
receptor-related protein 5/6 (Lrp5/6). A key mechanism in their signal transduction is that Wnts induce Lrp6 signalosomes,
which become phosphorylated at multiple conserved sites, notably at PPSPXS motifs. Lrp6 phosphorylation is crucial to β-catenin
stabilization and pathway activation by promoting Axin and Gsk3 recruitment to phosphorylated sites. Here, we summarize how
proline-directed kinases (Gsk3, PKA, Pftk1, Grk5/6) and non-proline-directed kinases (CK1 family) act upon Lrp6, how the phosphorylation
is regulated by ligand binding and mitosis, and how Lrp6 phosphorylation leads to β-catenin stabilization. 相似文献
7.
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
8.
E. Cohen-Hillel R. Mintz T. Meshel B.-Z. Garty A. Ben-Baruch 《Cellular and molecular life sciences : CMLS》2009,66(5):884-899
The chemokine CXCL8 is a powerful inducer of directional cell motility, primarily during inflammation. In this study, we found
that CXCL8 stimulation led to paxillin phosphorylation in normal neutrophils, and that both CXCL8 receptors (CXCR1 and CXCR2)
mediated CXCL8-induced paxillin phosphorylation. In CXCR2-transfected cells, the process depended on Gαi and Gαs coupling to CXCR2. Dominant negative (DN) paxillin increased CXCL8-induced adhesion and migration, indicating that endogenous
paxillin keeps migration at submaximal levels. Furthermore, using activating antibodies to β1 integrins, analyses with focal
adhesion kinase (FAK) DN variant (FRNK) and co-immunoprecipitations of FAK and paxillin, we found that β1 integrin ligation
cooperates with CXCL8-induced stimulation, leading to FAK activation and thereafter to FAK-mediated paxillin phosphorylation.
Our findings indicate that paxillin keeps directional motility at a restrained magnitude, and suggest that perturbations in
its activation may lead to chemotactic imbalance and to pathological conditions associated with excessive or reduced leukocyte
migration.
R. Mintz, T. Meshel: These authors contributed equally to this work.
Received 31 July 2008; received after revision 14 December 2008; accepted 16 December 2008 相似文献
9.
The activation and signalling activity of the membrane μ-opioid receptor (MOP-R) involve interactions among the receptor,
G-proteins, effectors and many other membrane or cytosolic proteins. Decades of investigation have led to identification of
the main biochemical processes, but the mechanisms governing the successive protein–protein interactions have yet to be established.
We will need to unravel the dynamic membrane organisation of this complex and multifaceted molecular machinery if we are to
understand these mechanisms. Here, we review and discuss advances in our understanding of the signalling mechanism of MOP-R
resulting from biochemical or biophysical studies of the organisation of this receptor in the plasma membrane. 相似文献
10.
The structure and function of heterotrimeric G protein subunits is known in considerable detail. Upon stimulation of a heptahelical
receptor by the appropriate agonists, the cognate G proteins undergo a cycle of activation and deactivation; the α-subunits and the βγ-dimers interact sequentially with several reaction partners (receptor, guanine nucleotides and effectors as well as regulatory
proteins) by exposing appropriate binding sites. For most of these domains, low molecular weight ligands have been identified
that either activate or inhibit signal transduction. These ligands include short peptides derived from receptors, G protein
subunits and effectors, mastoparan and related insect venoms, modified guanine nucleotides, suramin analogues and amphiphilic
cations. Because compounds that act on G proteins may be endowed with new forms of selectivity, we propose that G protein
subunits may therefore be considered as potential drug targets.
Received 18 September 1998; received after revision 6 November 1998; accepted 11 November 1998 相似文献
11.
Double-strand breaks (DSBs) are the most detrimental form of DNA damage. Failure to repair these cytotoxic lesions can result
in genome rearrangements conducive to the development of many diseases, including cancer. The DNA damage response (DDR) ensures
the rapid detection and repair of DSBs in order to maintain genome integrity. Central to the DDR are the DNA damage checkpoints.
When activated by DNA damage, these sophisticated surveillance mechanisms induce transient cell cycle arrests, allowing sufficient
time for DNA repair. Since the term “checkpoint” was coined over 20 years ago, our understanding of the molecular mechanisms
governing the DNA damage checkpoint has advanced significantly. These pathways are highly conserved from yeast to humans.
Thus, significant findings in yeast may be extrapolated to vertebrates, greatly facilitating the molecular dissection of these
complex regulatory networks. This review focuses on the cellular response to DSBs in Saccharomyces cerevisiae, providing a comprehensive overview of how these signalling pathways function to orchestrate the cellular response to DNA
damage and preserve genome stability in eukaryotic cells. 相似文献
12.
Massicotte G 《Cellular and molecular life sciences : CMLS》2000,57(11):1542-1550
Long-term potentiation (LTP) and long-term depression (LTD) are two electrophysiological models that have been studied extensively in recent years as they may represent basic mechanisms in many neuronal networks to store certain types of information. In several brain regions, it has been shown that these two forms of synaptic plasticity require sufficient dendritic depolarization, with the amplitude of the calcium signal being crucial for the generation of either LTP or LTD. The rise in calcium concentration mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been proposed to stimulate various calcium-dependent enzymatic processes that could convert the induction signal into long-lasting changes in synaptic structure; protein kinases and phosphatases have so far been considered predominantly with regard to LTP and LTD formation. According to several lines of experimental evidence, changes in synaptic function observed with LTP and LTD are thought to be the result of modifications of postsynaptic currents mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. Moreover, it has become apparent recently that activation of the calcium-dependent enzyme phospholipase A2 (PLA2) could be part of the molecular mechanisms involved in alterations of AMPA receptor properties during long-term changes in synaptic operation. In the present review, we will first describe the results that indicate a critical role of the phospholipases in regulating synaptic function. Next, sections will be devoted to the effects of PLA2 and phospholipids on the binding properties of glutamate receptors, and a revised biochemical model will be presented as an attempt to integrate the PLA2 enzyme into the mechanisms ( in particular kinases and phosphatases) that participate in adaptive neural plasticity. Finally, we will review data relevant to the issue of selective changes in AMPA binding after environmental enrichment and LTP. 相似文献
13.
Marsango S Bonaccorsi di Patti MC Barra D Miele R 《Cellular and molecular life sciences : CMLS》2011,68(17):2919-2929
Prokineticins are proteins that regulate diverse biological processes including gastrointestinal motility, angiogenesis, circadian
rhythm, and innate immune response. Prokineticins bind two closed related G-protein coupled receptors (GPCRs), PKR1 and PKR2.
In general, these receptors act as molecular switches to relay activation to heterotrimeric G-proteins and a growing body
of evidence points to the fact that GPCRs exist as homo- or heterodimers. We show here by Western-blot analysis that PKR2
has a dimeric structure in neutrophils. By heterologous expression of PKR2 in Saccharomyces cerevisiae, we examined the mechanisms of intermolecular interaction of PKR2 dimerization. The potential involvement of three types
of mechanisms was investigated: coiled-coil, disulfide bridges, and hydrophobic interactions between transmembrane domains.
Characterization of differently deleted or site-directed PKR2 mutants suggests that dimerization proceeds through interactions
between transmembrane domains. We demonstrate that co-expressing binding-deficient and signaling-deficient forms of PKR2 can
re-establish receptor functionality, possibly through a domain-swapping mechanism. 相似文献
14.
Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR 总被引:1,自引:0,他引:1
Kleinau G Jaeschke H Mueller S Worth CL Paschke R Krause G 《Cellular and molecular life sciences : CMLS》2008,65(22):3664-3676
Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications
are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated
receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant
mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling.
Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating
mutations (CAMs). Our results suggest that the conformation of a basally ‘silenced’ GPCR might impair its intrinsic capacity
for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR
models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details
underlying mutations decreasing basal activity.
G. Kleinau, H. Jaeschke: These two authors contributed equally to this work.
Received 31 July 2008; received after revision 12 September 2008; accepted 19 September 2008 相似文献
15.
Wesch D Peters C Oberg HH Pietschmann K Kabelitz D 《Cellular and molecular life sciences : CMLS》2011,68(14):2357-2370
Toll-like receptors (TLR) are pattern-recognition receptors that recognize a broad variety of structurally conserved molecules
derived from microbes. The recognition of TLR ligands functions as a primary sensor of the innate immune system, leading to
subsequent indirect activation of the adaptive immunity as well as none-immune cells. However, TLR are also expressed by several
T cell subsets, and the respective ligands can directly modulate their effector functions. The present review summarizes the
recent findings of γδ T cell modulation by TLR ligands. TLR1/2/6, 3, and 5 ligands can act directly in combination with T
cell receptor (TCR) stimulation to enhance cytokine/chemokine production of freshly isolated human γδ T cells. In contrast
to human γδ T cells, murine and bovine γδ T cells can directly respond to TLR2 ligands with increased proliferation and cytokine
production in a TCR-independent manner. Indirect stimulatory effects on IFN-γ production of human and murine γδ T cells via
TLR-ligand activated dendritic cells have been described for TLR2, 3, 4, 7, and 9 ligands. In addition, TLR3 and 7 ligands
indirectly increase tumor cell lysis by human γδ T cells, whereas ligation of TLR8 abolishes the suppressive activity of human
tumor-infiltrating Vδ1 γδ T cells on αβ T cells and dendritic cells. Taken together, these data suggest that TLR-mediated
signals received by γδ T cells enhance the initiation of adaptive immune responses during bacterial and viral infection directly
or indirectly. Moreover, TLR ligands enhance cytotoxic tumor responses of γδ T cells and regulate the suppressive capacity
of γδ T cells. 相似文献
16.
Julie Patenaude Michele D’Elia Claudine Hamelin Jacques Bernier 《Cellular and molecular life sciences : CMLS》2010,67(8):1315-1329
Burn injury causes an immunosuppression associated with suppressed adaptive immune function. Dendritic cells (DCs) are APCs
for which signaling via their Toll-like receptors (TLRs) induces their maturation and activation, which is essential for the
adaptive immune response. In this study, we examined if burn injury alters the TLR activity of splenic DCs. After injury,
we noticed that DC functions were impaired, characterized by a suppressed capacity to prime naive T cells when triggering
the TLR4 signaling cascade using specific ligands (LPS or rHSP60). The observed perturbations on LPS-primed DCs isolated from
burned mice exhibited significantly diminished IL-12p40 production and enhanced IL-10 secretion-associated impairment in mitogen-activated
protein kinase activation. Interestingly, we observed a decrease of TLR4/MD-2 expression on the CD8α+ DC subset that persisted following LPS stimulation. The altered TLR4 expression on LPS-stimulated CD8α+ DCs was associated with reduced capacity to produce IL-12 after stimulation. Our results suggested that TLR4 reactivity on
DCs, especially CD8α+ DCs, is disturbed after burn injury. 相似文献
17.
18.
Franky Van Herreweghe Nele Festjens Wim Declercq Peter Vandenabeele 《Cellular and molecular life sciences : CMLS》2010,67(10):1567-1579
In this review, we discuss the signal-transduction pathways of three major cellular responses induced by tumor necrosis factor
(TNF): cell survival through NF-κB activation, apoptosis, and necrosis. Recruitment and activation of caspases plays a crucial
role in the initiation and execution of TNF-induced apoptosis. However, experimental inhibition of caspases reveals an alternative
cell death pathway, namely necrosis, also called necroptosis, suggesting that caspases actively suppress the latter outcome.
TNF-induced necrotic cell death crucially depends on the kinase activity of receptor interacting protein serine-threonine
kinase 1 (RIP1) and RIP3. It was recently demonstrated that ubiquitination of RIP1 determines whether it will function as
a pro-survival or pro-cell death molecule. Deeper insight into the mechanisms that control the molecular switches between
cell survival and cell death will help us to understand why TNF can exert so many different biological functions in the etiology
and pathogenesis of human diseases. 相似文献
19.
Guillaume Jacquemin Sarah Shirley Olivier Micheau 《Cellular and molecular life sciences : CMLS》2010,67(18):3115-3130
TNF-related apoptosis-inducing ligand (TRAIL) and its receptors are attractive targets for anticancer therapy owing to their
ability to trigger apoptosis selectively in cancer cells but not in normal cells. To date, many combinatorial strategies,
such as chemotherapy or radiotherapy, have given encouraging results for overcoming TRAIL resistance in preclinical models.
In this review, we provide an overview of the molecular mechanisms underlying sensitization to TRAIL-induced apoptosis by
polyphenols. These naturally occurring compounds can restore tumor cell sensitivity to TRAIL-induced cell death with no apparent
toxicity towards normal cells. Both extrinsic and intrinsic pathways can be modulated by polyphenols, the activation of which
largely depends on the cell type, the particular polyphenolic compound, and the conditions of treatment. The large variety
of polyphenol cellular targets could prove useful in circumventing TRAIL resistance. The relevance of these combined treatments
for cancer therapy is discussed in the light of recent preclinical studies. 相似文献