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711.
Inhibiting the production of amyloid-β by antagonising γ-secretase activity is currently being pursued as a therapeutic strategy
for Alzheimer’s disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent
γ-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently,
transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial
knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive
to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if γ-secretase
is to be pursued as a therapeutic target. Herein we review the current understanding of γ-secretase complexes; their regulation,
abundance of interacting partners and diversity of substrates. We also discuss regulation of the γ-secretase complexes, with
an emphasis on the functional role of presenilins in cell biology.
Received 25 July 2008; received after revision 24 November 2008; accepted 10 December 2008 相似文献
712.
713.
Roth L Koncina E Satkauskas S Crémel G Aunis D Bagnard D 《Cellular and molecular life sciences : CMLS》2009,66(4):649-666
The semaphorin family is a large group of proteins controlling cell migration and axonal growth cone guidance. These proteins
are bi-functional signals capable of growth promotion or growth inhibition. Initially described in the nervous system, the
majority of studies related to semaphorins and semaphorin signalling are nowadays performed in model systems outside the nervous
system. Here, we provide an exhaustive review of the many faces of semaphorins both during developmental, regulatory and pathological
processes. Indeed, because of their crucial fundamental roles, the semaphorins and their receptors represent important targets
for the development of drugs directed at a variety of diseases.
Received 22 August 2008; received after revision 22 September 2008; accepted 24 September 2008
L. Roth, E. Koncina, S. Satkauskas: These authors contributed equally to this work. 相似文献
714.
R. George H.-L. Chan Z. Ahmed K. M. Suen C. N. Stevens J. A. Levitt K. Suhling J. Timms J. E. Ladbury 《Cellular and molecular life sciences : CMLS》2009,66(4):711-720
The three isoforms of the adaptor protein Shc play diverse roles in cell signalling. For example, the observation of p46 Shc
in the nuclei of hepatocellular carcinoma cells suggests a function quite distinct from the better characterised cytoplasmic
role. Ligands responsible for the transport of various Shc isoforms into organelles such as the nucleus have yet to be reported.
To identify such ligands a far western approach was used to determine the p52 Shc interactome. The Ran-GTPase nuclear transport
protein was identified and found to bind to p52 Shc in vitro with low micromolar affinity. Co-immunoprecipitation, pull down and fluorescence lifetime imaging microscopy experiments
in stable cells confirmed cellular interaction and nuclear localisation. The nuclear transport factor protein NTF2, which
functions in cohort with Ran, was shown to form a complex with both RAN and Shc, suggesting a mechanism for Shc entry into
the nucleus as part of a tertiary complex.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 20 October 2008; received after revision 04 December 2008; accepted 15 December 2008 相似文献
715.
D. Parolini M. Meregalli M. Belicchi P. Razini R. Lopa B. Del Carlo A. Farini S. Maciotta N. Bresolin L. Porretti M. Pellegrino Y. Torrente 《Cellular and molecular life sciences : CMLS》2009,66(4):697-710
Among the heterogeneous population of circulating hematopoietic and endothelial progenitors, we identified a subpopulation
of CD133+ cells displaying myogenic properties. Unexpectedly, we observed the expression of the B-cell marker CD20 in blood-derived
CD133+ stem cells. The CD20 antigen plays a role in the modulation of intracellular calcium homeostasis through signaling pathways
activation. Several observations suggest that an increase in intracellular calcium concentration ([Ca2+]i) could be involved in the etiology of the Duchenne muscular dystrophy (DMD). Here, we show that a CD20-related signaling
pathway able to induce an increase in [Ca2+]i is differently activated after brain derived neurotrophic factor (BDNF) stimulation of normal and dystrophic blood-derived
CD133+ stem cells, supporting the assumption of a “CD20-related calcium impairment-affecting dystrophic cells. Presented findings
represent the starting point toward the expansion of knowledge on pathways involved in the pathology of DMD and in the behavior
of dystrophic blood-derived CD133+ stem cells.
Received 15 October 2008; received after revision 27 November 2008; accepted 05 December 2008 相似文献
716.
A. Deshmukh F. Salehzadeh S. Metayer-Coustard R. Fahlman K. S. Nair L. Al-Khalili 《Cellular and molecular life sciences : CMLS》2009,66(8):1457-1466
Excessive nutrients, especially amino acids, impair insulin action on glucose metabolism in skeletal muscle. We tested the
hypothesis that the branched-chain amino acid leucine reduces acute insulin action in primary myotubes via a negative feedback mechanism involving ribosomal protein S6 kinase 1 (S6K1). The effect of S6K1 on glucose metabolism was
determined by applying RNA interference (siRNA). Leucine (5 mM) reduced glucose uptake and incorporation to glycogen by 13%
and 22%, respectively, compared to the scramble siRNA-transfected control at the basal level. Leucine also reduced insulin-stimulated
Akt phosphorylation, glucose uptake and glucose incorporation to glycogen (39%, 39% and 37%, respectively), and this reduction
was restored after S6K1 silencing. Depletion of S6K1 enhanced basal glucose utilization and protected against the development
of impaired insulin action, in response to excessive leucine. In conclusion, S6K1 plays an important role in the regulation
of insulin action on glucose metabolism in skeletal muscle.
Received 22 December 2008; received after revision 19 February 2009; accepted 23 February 2009 相似文献
717.
The bugs that came in from the cold: molecular adaptations to low temperatures in insects 总被引:2,自引:0,他引:2
The widespread distribution of insects over many ecological niches is a testimony to their evolutionary success. The colonization
of environments at high latitudes or altitudes required the evolution of biochemical strategies that reduced the impact of
cold or freezing stress. This review focuses on our current interests in some of the genes and proteins involved in low temperature
survival in insects. Although the most widespread form of protection is the synthesis of low molecular weight polyol cryoprotectants,
proteins with intrinsic protective properties, such as the thermal hysteresis or antifreeze proteins are also important. These
have been cloned and characterized in certain moths and beetles. Molecular techniques allowing the isolation of genes differentially
regulated by low temperatures have revealed that heat shock proteins, cold stress proteins, membrane protectants, as well
as ice nucleators and other less well characterized proteins likely also play a role in cold hardiness.
Received 10 June 2008; received after revision 17 November 2008; accepted 18 November 2008 相似文献
718.
Epidemiological studies establish a link between Type 2 diabetes (T2DM) and Alzheimer’s disease (AD), both leading causes
of morbidity and mortality in the elderly. These diseases also share clinical and biochemical features suggesting common pathogenic
mechanisms. Specifically, both are amyloidoses as they are characterized by fibrillar protein aggregates – amylin in T2DM
pancreatic islets, and β-amyloid (Aβ) and neurofibrillary tangles (NFTs) in AD brain. Amylin aggregation is associated with
pancreatic β-cell loss, and Aβ and NFT formation with neuronal cell loss. We discuss the possibility that amylin and Aβ exert
their toxicity by similar mechanisms, with components of the pathocascades shared, and that therapies based on amyloidogenic
properties are beneficial for both T2DM and AD.
Received 27 January 2009; received after revision 17 February 2009; accepted 23 February 2009 相似文献
719.
Methionine adenosyltransferases (MATs) are the family of enzymes that synthesize the main biological methyl donor, S-adenosylmethionine. The high sequence conservation among catalytic subunits from bacteria and eukarya preserves key residues
that control activity and oligomerization, which is reflected in the protein structure. However, structural differences among
complexes with substrates and products have led to proposals of several reaction mechanisms. In parallel, folding studies
begin to explain how the three intertwined domains of the catalytic subunit are produced, and to highlight the importance
of certain intermediates in attaining the active final conformation. This review analyzes the available structural data and
proposes a consensus interpretation that facilitates an understanding of the pathological problems derived from impairment
of MAT function. In addition, new research opportunities directed toward clarification of aspects that remain obscure are
also identified.
Received 22 August 2008; received after revision 22 September 2008; accepted 26 September 2008 相似文献
720.
Epigenetic mechanisms in mammals 总被引:11,自引:1,他引:10
DNA and histone methylation are linked and subjected to mitotic inheritance in mammals. Yet how methylation is propagated
and maintained between successive cell divisions is not fully understood. A series of enzyme families that can add methylation
marks to cytosine nucleobases, and lysine and arginine amino acid residues has been discovered. Apart from methyltransferases,
there are also histone modification enzymes and accessory proteins, which can facilitate and/or target epigenetic marks. Several
lysine and arginine demethylases have been discovered recently, and the presence of an active DNA demethylase is speculated
in mammalian cells. A mammalian methyl DNA binding protein MBD2 and de novo DNA methyltransferase DNMT3A and DNMT3B are shown experimentally to possess DNA demethylase activity. Thus, complex mammalian
epigenetic mechanisms appear to be dynamic yet reversible along with a well-choreographed set of events that take place during
mammalian development. 相似文献