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1.
2.
Dependence receptors: between life and death 总被引:2,自引:0,他引:2
The recently described family of dependence receptors is a new family of functionally related receptors.
These proteins have little sequence similarity but display the common feature of inducing two completely opposite
intracellular signals depending on ligand availability: in the presence of ligand, these receptors transduce a
positive signal leading to survival, differentiation or migration, while in the absence of ligand, the receptors
initiate or amplify a negative signal for apoptosis. Thus, cells that express these proteins manifest a state of
dependence on their respective ligands. The mechanisms that trigger cell death induction in the absence of ligand
are in large part unknown, but typically require cleavage by specific caspases. In this review we will present the
proposed mechanisms for cell death induction by these receptors and their potential function in nervous system
development and regulation of tumorigenesis.Received 19 December 2003; received after revision 19 February 2004; accepted 26 February 2004 相似文献
3.
Mammalian aldehyde oxidases are a small group of proteins belonging to the larger family of molybdo-flavoenzymes along with
xanthine oxidoreductase and other bacterial enzymes. The two general types of reactions catalyzed by aldehyde oxidases are
the hydroxylation of heterocycles and the oxidation of aldehydes into the corresponding carboxylic acids. Different animal
species are characterized by a different complement of aldehyde oxidase genes. Humans contain a single active gene, while
marsupials and rodents are characterized by four such genes clustering at a short distance on the same chromosome. At present,
little is known about the physiological relevance of aldehyde oxidases in humans and other mammals, although these enzymes
are known to play a role in the metabolism of drugs and compounds of toxicological importance in the liver. The present article
provides an overview of the current knowledge of genetics, evolution, structure, enzymology, tissue distribution and regulation
of mammalian aldehyde oxidases.
Received 30 August 2007; received after revision 2 November 2007; accepted 8 November 2007 相似文献
4.
Polyphenolic phytochemicals are ubiquitous in plants, in which they function in various protective roles. A ‘recommended’
human diet contains significant quantities of polyphenolics, as they have long been assumed to be ‘antioxidants’ that scavenge
excessive, damaging, free radicals arising from normal metabolic processes. There is recent evidence that polyphenolics also
have ‘indirect’ antioxidant effects through induction of endogenous protective enzymes. There is also increasing evidence
for many potential benefits through polyphenolic-mediated regulation of cellular processes such as inflammation. Inductive
or signalling effects may occur at concentrations much lower than required for effective radical scavenging. Over the last
2 – 3 years, there have been many exciting new developments in the elucidation of the in vivo mechanisms of the health benefits of polyphenolics. We summarise the current knowledge of the intake, bio-availability and
metabolism of polyphenolics, their antioxidant effects, regulatory effects on signalling pathways, neuro-protective effects
and regulatory effects on energy metabolism and gut health.
Received 14 May 2007; received after revision 27 June 2007; accepted 24 July 2007 相似文献
5.
L. Fesus A. Madi Z. Balajthy Z. Nemes Z. Szondy 《Cellular and molecular life sciences : CMLS》1996,52(10-11):942-949
Clarification of the molecular details of forms of natural cell death, including apoptosis, has become one of the most challenging issues of contemporary biomedical sciences. One of the effector elements of various cell death pathways is the covalent cross-linking of cellular proteins by transglutaminases. This review will discuss the accumulating data related to the induction and regulation of these enzymes, particularly of tissue type transglutaminase, in the molecular program of cell death. A wide range of signalling pathways can lead to the parallel induction of apoptosis and transglutaminase, providing a handle for better understanding the exact molecular interactions responsible for the mechanism of regulated cell death. 相似文献
6.
Trevor W. Stone L. Gail Darlington 《Cellular and molecular life sciences : CMLS》2017,74(14):2627-2643
Several toxins are known which account for the ability of some bacteria to initiate or promote carcinogenesis. These ideas are summarised and evidence is discussed for more specific mechanisms involving chymotrypsin and the bacterial chymotryptic enzyme subtilisin. Subtilisin and Bacillus subtilis are present in the gut and environment and both are used commercially in agriculture, livestock rearing and meat processing. The enzymes deplete cells of tumour suppressors such as deleted in colorectal cancer (DCC) and neogenin, so their potential presence in the food chain might represent an important link between diet and cancer. Over-eating increases secretion of chymotrypsin which is absorbed from the gut and could contribute to several forms of cancer linked to obesity. Inhibition of these serine proteases by Bowman–Birk inhibitors in fruit and vegetables could account for some of the protective effects of a plant-rich diet. These interactions represent previously unknown non-genetic mechanisms for the modification of tumour suppressor proteins and provide a plausible explanation contributing to both the pro-oncogenic effects of meat products and the protective activity of a plant-rich diet. The data suggest that changes to farming husbandry and food processing methods to remove these sources of extrinsic proteases might significantly reduce the incidence of several cancers. 相似文献
7.
Daniela Corda Pasquale Zizza Alessia Varone Beatrice Maria Filippi Stefania Mariggiò 《Cellular and molecular life sciences : CMLS》2009,66(21):3449-3467
The glycerophosphoinositols are cellular products of phospholipase A2 and lysolipase activities on the membrane phosphoinositides. Their intracellular concentrations can vary upon oncogenic transformation,
cell differentiation and hormonal stimulation. Specific glycerophosphodiester phosphodiesterases are involved in their catabolism,
which, as with their formation, is under hormonal regulation. With their mechanisms of action including modulation of adenylyl
cyclase, intracellular calcium levels, and Rho-GTPases, the glycerophosphoinositols have diverse effects in multiple cell
types: induction of cell proliferation in thyroid cells; modulation of actin cytoskeleton organisation in fibroblasts; and
reduction of the invasive potential of tumour cell lines. More recent investigations include their effects in inflammatory
and immune responses. Indeed, the glycerophosphoinositols enhance cytokine-dependent chemotaxis in T-lymphocytes induced by
SDF-1α-receptor activation, indicating roles for these compounds as modulators of T-cell signalling and T-cell responses. 相似文献
8.
Hippocrates’ assertion that ‘what the lance does not heal, fire will’ underscores the fact that for thousands of years heat
has been used to treat a variety of diseases, including cancer. Indeed, spontaneous tumor remission has been observed in patients
following feverish infection [1], and expression of activated oncogenes, such as Ras, can render tumor cells sensitive to
heat compared with normal cells [2, 3]. In the past, a primary drawback to the use of heat as a clinical therapy was the inability
to selectively focus heat to tumors in situ. Of late, however, several approaches have been devised to deliver heat more precisely, including the use of heated nanoparticles,
making hyperthermia a more clinically tractable treatment option [4, 5]. Despite these practical advances, the mechanisms
responsible for heat shock-induced cell death remain controversial and ill-defined. In this Visions and Reflections we discuss recent findings surrounding the initiation of heat shock-induced apoptosis, and propose future areas of research.
Received 17 March 2007; received after revision 25 April 2007; accepted 22 May 2007 相似文献
9.
Cifuentes-Pagano E Csanyi G Pagano PJ 《Cellular and molecular life sciences : CMLS》2012,69(14):2315-2325
NADPH oxidases (Nox) are established as major sources of reactive oxygen species (ROS). Over the past two decades, Nox-derived ROS have emerged as pivotal in the development of myriad diseases involving oxidative stress. In contrast, Nox are also involved in signaling mechanisms necessary for normal cell function. The study of these enzymes in physiological and pathophysiological conditions is made considerably more complex by the discovery of 7 isoforms: Nox1 through 5 as well as Duox1 and 2, each with its own specific cytosolic components, regulatory control mechanisms, subcellular localization and/or tissue distribution. A clear understanding of the role individual isoforms play in a given system is hindered by the lack of isoform-specific inhibitors. In animal models, knockdown or knockout methodologies are providing definitive answers to perplexing questions of the complex interplay of multiple Nox isoforms in cell and tissue signaling. However, the complex structures and interactions of these heteromeric isozymes predict pleiotropic actions of the Nox subunits and thus suppression of these proteins is almost certain to have untoward effects. Thus, as both therapies and pharmacological tools, molecule-based inhibitors continue to prove extremely useful and rational in design. Unfortunately, many of the available inhibitors have proven non-specific, falling into the category of scavengers or inhibitors of more than one source of ROS. Here, we will review some of the efforts that have been undertaken to develop specific inhibitors of NADPH oxidase over the past decade, from the peptidic inhibitor Nox2ds-tat to more recent small molecule inhibitors that have emerged from high-throughput screening campaigns. 相似文献
10.
Sphingolipids and glycosphingolipids are emerging as major players in many facets of cell physiology and pathophysiology.
We now present an overview of sphingolipid biochemistry and physiology, followed by a brief presentation of recent advances
in translational research related to sphingolipids. In discussing sphingolipid biochemistry, we focus on the structure of
sphingolipids, and their biosynthetic pathways – the recent identification of most of the enzymes in this pathway has led
to significant advances and better characterization of a number of the biosynthetic steps, and the relationship between them.
We then discuss some roles of sphingolipids in cell physiology, particularly those of ceramide and sphingosine-1-phosphate,
and mention current views about how these lipids act in signal transduction pathways. We end with a discussion of sphingolipids
and glycosphingolipids in the etiology and pathology of a number of diseases, such as cancer, immunity, cystic fibrosis, emphysema,
diabetes, and sepsis, areas in which sphingolipids are beginning to take a central position, even though many of the details
remain to be elucidated.
Received 13 February 2007; received after revision 19 April 2007; accepted 26 April 2007 相似文献
11.
Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action 总被引:3,自引:0,他引:3
Montecucco C Gutiérrez JM Lomonte B 《Cellular and molecular life sciences : CMLS》2008,65(18):2897-2912
A large variety of snake toxins evolved from PLA2 digestive enzymes through a process of ‘accelerated evolution’. These toxins have different tissue targets, membrane receptors
and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA2s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which
is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation
which promotes a large increase of the cytosolic Ca2+ concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular
junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms
of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.
Received 05 March 2008; received after revision 08 April 2008; accepted 29 April 2008 相似文献
12.
Isakovic A Harhaji L Stevanovic D Markovic Z Sumarac-Dumanovic M Starcevic V Micic D Trajkovic V 《Cellular and molecular life sciences : CMLS》2007,64(10):1290-1302
The present study reports for the first time a dual antiglioma effect of the well-known antidiabetic drug metformin. In low-density
cultures of the C6 rat glioma cell line, metformin blocked the cell cycle progression in G0/G1 phase without inducing significant cell death. In confluent C6 cultures, on the other hand, metformin caused massive induction
of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation, mitochondrial depolarization and
oxidative stress. Metformin-triggered apoptosis was completely prevented by agents that block mitochondrial permeability transition
(cyclosporin A) and oxygen radical production (N-acetylcisteine), while the inhibitors of JNK activation (SP600125) or glycolysis
(sodium fluoride, iodoacetate) provided partial protection. The antiglioma effect of metformin was reduced by compound C,
an inhibitor of AMP-activated protein kinase (AMPK), and was mimicked by the AMPK agonist AICAR. Similar effects were observed
in the human glioma cell line U251, while rat primary astrocytes were completely resistant to the antiproliferative and proapoptotic
action of metformin.
Received 14 February 2007; received after revision 26 March 2007; accepted 3 April 2007 相似文献
13.
Higgins GC Devenish RJ Beart PM Nagley P 《Cellular and molecular life sciences : CMLS》2011,68(22):3725-3740
Primary neurons undergo insult-dependent programmed cell death. We examined autophagy as a process contributing to cell death
in cortical neurons after treatment with either hydrogen peroxide (H2O2) or staurosporine. Although caspase-9 activation and cleavage of procaspase-3 were significant following staurosporine treatment,
neither was observed following H2O2 treatment, indicating a non-apoptotic death. Autophagic activity increased rapidly with H2O2, but slowly with staurosporine, as quantified by processing of endogenous LC3. Autophagic induction by both stressors increased
the abundance of fluorescent puncta formed by GFP-LC3, which could be blocked by 3-methyladenine. Significantly, such inhibition
of autophagy blocked cell death induced by H2O2 but not staurosporine. Suppression of Atg7 inhibited cell death by H2O2, but not staurosporine, whereas suppression of Beclin 1 prevented cell death by both treatments, suggesting it has a complex
role regulating both apoptosis and autophagy. We conclude that autophagic mechanisms are activated in an insult-dependent
manner and that H2O2 induces autophagic cell death. 相似文献
14.
The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified as a key regulator of insulin-dependent
glycogen synthesis. GSK-3 was subsequently shown to function in a wide range of cellular processes including differentiation,
growth, motility and apoptosis. Aberrant regulation of GSK-3 has been implicated in a range of human pathologies including
Alzheimer’s disease, non-insulin-dependent diabetes mellitus (NIDDM) and cancer. As a consequence, the regulation of GSK-3
and the therapeutic potential of GSK-3 inhibitors have become key areas of investigation. This review will focus on the mechanisms
of GSK-3 regulation, with emphasis on modulation by upstream signals, control of substrate specificity and GSK-3 localisation.
The details of these mechanisms will be discussed in the context of specific signalling pathways.
Received 30 January 2007; received after revision 5 March 2007; accepted 16 April 2007 相似文献
15.
The highly conserved Notch signaling pathway plays pleiotropic roles during embryonic development and is important for the
regulation of selfrenewing tissues. The physiological functions of this signaling cascade range from stem cell maintenance
and influencing cell fate decisions of barely differentiated progenitor cells, to the induction of terminal differentiation
processes, all of which have been found to be recapitulated in different forms of cancers. Although Notch signaling has mostly
been associated with oncogenic and growth-promoting roles, depending on the tissue type it can also function as a tumor suppressor.
Here we describe recent findings on Notch signaling in cancer and tumor angiogenesis, and highlight some of the therapeutic
approaches that are currently being developed to interfere with tumor growth and progression.
Received 2 April 2007; received after revision 29 June 2007; accepted 2 July 2007 相似文献
16.
Regulation of insulin receptor function 总被引:1,自引:0,他引:1
Youngren JF 《Cellular and molecular life sciences : CMLS》2007,64(7-8):873-891
Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular
disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation
events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin
resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase
activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation
of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding
to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational
changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human
disease, is reviewed in this article.
Received 3 August 2006; received after revision 1 December 2006; accepted 8 January 2007 相似文献
17.
Cohausz O Blenn C Malanga M Althaus FR 《Cellular and molecular life sciences : CMLS》2008,65(4):644-655
Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor
(AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR
molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we
determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG),
the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2
and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems
to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved.
Received 7 November 2007; received after revision 19 December 2007; accepted 21 December 2007
O. Cohausz, C. Blenn: These two authors contributed equally to this work. 相似文献
18.
Fernández MR Porté S Crosas E Barberà N Farrés J Biosca JA Parés X 《Cellular and molecular life sciences : CMLS》2007,64(11):1419-1427
ζ-crystallins constitute a family of proteins with NADPH:quinone reductase activity found initially in mammalian lenses but
now known to be present in many other organisms and tissues. Few proteins from this family have been characterized, and their
function remains unclear. In the present work, ζ-crystallins from human and yeast (Zta1p) were expressed, purified and characterized.
Both enzymes are able to reduce ortho-quinones in the presence of NADPH but are not active with 2-alkenals. Deletion of the ZTA1 gene makes yeast more sensitive to menadione and hydrogen peroxide, suggesting a role in the oxidative stress response. The
human and yeast enzymes specifically bind to adenine-uracil rich elements (ARE) in RNA, indicating that both enzymes are ARE-binding
proteins and that this property has been conserved in ζ-crystallins throughout evolution. This supports a role for ζ-crystallins
as trans-acting factors that could regulate the turnover of certain mRNAs.
Received 21 February 2007; received after revision 16 April 2007; accepted 23 April 2007
M. R. Fernández, S. Porté: These authors contributed equally to this work. 相似文献
19.
Infection of bacteria triggers innate immune defense reactions in Drosophila. So far, the only bacterial component known to be recognized by the insect innate immune system is peptidoglycan, one of
the most abundant constituents of the bacterial cell wall. Insects use peptidoglycan recognition proteins to detect peptidoglycan
and to activate innate immune responses. Such specialized peptidoglycan receptors appear to have evolved from phage enzymes
that hydrolyze bacterial cell walls. They are able to bind specific peptidoglycan molecules with distinct chemical moieties
and activate innate immune pathways by interacting with other signaling proteins. Recent X-ray crystallographic studies of
the peptidoglycan recognition proteins LCa, and LCx bound to peptidoglycan have provided structural insights into recognition
of peptidoglycan and activation of innate immunity in insects.
Received 28 December 2006; received after revision 2 February 2007; accepted 21 February 2007 相似文献
20.
Edouard T Montagner A Dance M Conte F Yart A Parfait B Tauber M Salles JP Raynal P 《Cellular and molecular life sciences : CMLS》2007,64(13):1585-1590
Activating and inactivating mutations of SHP-2 are responsible, respectively, for the Noonan (NS) and the LEOPARD (LS) syndromes.
Clinically, these developmental disorders overlap greatly, resulting in the apparent paradox of similar diseases caused by
mutations that oppositely influence SHP-2 phosphatase activity. While the mechanisms remain unclear, recent functional analysis
of SHP-2, along with the identification of other genes involved in NS and in other related syndromes (neurofibromatosis-1,
Costello and cardio-facio-cutaneous syndromes), strongly suggest that Ras/MAPK represents the major signaling pathway deregulated
by SHP-2 mutants. We discuss the idea that, with the exception of LS mutations that have been shown to exert a dominant negative
effect, all disease-causing mutations involved in Ras/MAPK-mediated signaling, including SHP-2, might lead to enhanced MAPK
activation. This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the
possibility that LS mutations may not simply exhibit dominant negative activity.
Received 30 November 2006; received after revision 8 February 2007; accepted 13 March 2007 相似文献