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991.
Lindsay M. Steirer Eric I. Park R. Reid Townsend Jacques U. Baenziger 《The Journal of biological chemistry》2009,284(6):3777-3783
The asialoglycoprotein receptor (ASGP-R) is an abundant,
carbohydrate-specific, endocytic receptor expressed by parenchymal cells of
the liver. We recently demonstrated that the ASGP-R mediates the clearance of
glycoproteins bearing Siaα2,6GalNAc as well as those bearing terminal
Gal or GalNAc. We now report that glycoproteins such as haptoglobin, serum
amyloid protein (SAP), and carboxylesterase that bear oligosaccharides with
terminal Siaα2,6Gal are elevated in the plasma of ASGP-R-deficient mice.
Because of their abundance in plasma, glycoproteins bearing terminal
Siaα2,6Gal will saturate the ASGP-R and compete with each other on the
basis of their relative affinities for the ASGP-R and their relative
abundance. We propose that the ASGP-R mediates the clearance of glycoproteins
that bear oligosaccharides terminating with Siaα2,6Gal and thereby helps
maintain the relative concentrations of these glycoproteins in the blood.The asialoglycoprotein receptor
(ASGP-R)3 was
initially identified and characterized by Ashwell and co-workers
(1,
2) on the basis of its ability
to rapidly remove glycoproteins bearing oligosaccharides terminating with
β1,4-linked Gal from the circulation. The ASGP-R has been extensively
characterized since its initial discovery; however, its biologic function
in vivo has remained unclear. This endocytic receptor is highly
abundant with 500,000 receptors expressed at the plasma membrane of
hepatocytes
(3–5)
and is rapidly internalized (3,
6). The abundance of the ASGP-R
and its rapid rate of internalization in combination with the large number of
hepatocytes that are present in the liver, 1.35 × 108/g of
liver (7,
8), results in an enormous
potential capacity to remove glycoproteins from the circulation. Until
recently, mice that have had either subunit of the ASGP-R ablated, subunit 1
ASGP-R1(-/-) or subunit 2 ASGP-R2(-/-), have not been reported to have altered
levels of circulating glycoproteins in their blood or to have a physiologic
phenotype (9,
10). However, Grewal et
al. (11) have reported
that the ASGP-R plays a role in von Willebrand factor homeostasis and promotes
thrombocytopenia during Steptococcus pneumoniae sepsis by removing
platelets that have had their surface sialic acid removed by the bacterial
neuraminidase.We recently established that glycoproteins bearing Asn-linked
oligosaccharides terminating with the sequence
Siaα2,6GalNAcβ1,4GlcNAc are recognized by the ASGP-R and rapidly
removed from the blood (12,
13). Glycoproteins bearing
terminal Siaα2,6GalNAcβ1,4GlcNAc are the first examples of
endogenous glycoproteins that can be recognized by the ASGP-R without further
modification; i.e. removal of terminal Sia. Glycoproteins bearing
these structures, for example the prolactin-like proteins
(14), glycodelin
(15), urokinase
(16), and glycoprotein
hormones (17), are not highly
abundant, suggesting that the ASGP-R recognizes and clears additional more
abundant glycoproteins. The most likely candidates are glycoproteins bearing
Asn-linked oligosaccharides that terminate with the sequence
Siaα2,6Galβ1, 4GlcNAc. We have reported that the ASGP-R recognizes
these structures with an avidity that is in the micromolar range
(13). The avidity of the
ASGP-R for structures terminating with Siaα2,6Galβ1,4GlcNAc is
predicted to be sufficient to mediate binding and clearance of glycoproteins
bearing structures terminating with Siaα2,6Galβ1,4GlcNAc from the
blood. This concept is supported by indications that neo-glycoproteins bearing
structures terminating with Siaα2,6Galβ1,4GlcNAc are removed from
the blood at a faster rate than those bearing Siaα2,3Galβ1,4GlcNAc
(18). Slow clearance of
glycoproteins bearing Siaα2,6Galβ1,4GlcNAc, however, hampers
accurate measurement of their half-lives by injection of radiolabeled
ligands.We now report that multiple glycoproteins bearing oligosaccharides that
terminate with Siaα2,6Galβ1,4GlcNAc are elevated in the plasma of
ASGP-R-deficient ASGP-R2(-/-) mice as compared with wild-type (Wt) mice. The
elevation of multiple glycoproteins bearing terminal
Siaα2,6Galβ1,4GlcNAc supports our proposal that the ASGP-R accounts
for the clearance of these glycoproteins. This previously undiscerned role of
the ASGP-R now allows us to develop a model of how this receptor may
contribute to the regulation of the concentration of many different
glycoproteins in the blood. 相似文献
992.
Characterized as a peripheral metabolic disorder and a degenerative disease of the central nervous system respectively, it is now widely recognized that type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and amyloidogenesis. Several recent studies suggest that this is not an epiphenomenon, but rather these two diseases disrupt common molecular pathways and each disease compounds the progression of the other. For instance, in AD the accumulation of the amyloid-beta peptide (Aβ), which characterizes the disease and is thought to participate in the neurodegenerative process, may also induce neuronal insulin resistance. Conversely, disrupting normal glucose metabolism in transgenic animal models of AD that over-express the human amyloid precursor protein (hAPP) promotes amyloid-peptide aggregation and accelerates the disease progression. Studying these processes at a cellular level suggests that insulin resistance and Aβ aggregation may not only be the consequence of excitotoxicity, aberrant Ca2+ signals, and proinflammatory cytokines such as TNF-α, but may also promote these pathological effectors. At the molecular level, insulin resistance and Aβ disrupt common signal transduction cascades including the insulin receptor family/PI3 kinase/Akt/GSK3 pathway. Thus both disease processes contribute to overlapping pathology, thereby compounding disease symptoms and progression. 相似文献
993.
Bashar A. Zeidan Ramsey I. Cutress Claire Hastie Alex H. Mirnezami Graham Packham Paul A. Townsend 《Clinical proteomics》2009,5(3-4):133-147
Background
Proteomic profiling is a rapidly developing technology that may enable early disease screening and diagnosis. Surface-enhanced laser desorption ionization–time of flight mass spectrometry (SELDI-TOF MS) has demonstrated promising results in screening and early detection of many diseases. In particular, it has emerged as a high-throughput tool for detection and differentiation of several cancer types. This review aims to appraise published data on the impact of SELDI-TOF MS in breast cancer.Methods
A systematic literature search between 1965 and 2009 was conducted using the PubMed, EMBASE, and Cochrane Library databases. Studies covering different aspects of breast cancer proteomic profiling using SELDI-TOF MS technology were critically reviewed by researchers and specialists in the field.Results
Fourteen key studies involving breast cancer biomarker discovery using SELDI-TOF MS proteomic profiling were identified. The studies differed in their inclusion and exclusion criteria, biologic samples, preparation protocols, arrays used, and analytical settings. Taken together, the numerous studies suggest that SELDI-TOF MS methodology may be used as a fast and robust approach to study the breast cancer proteome and enable the analysis of the correlations between proteomic expression patterns and breast cancer.Conclusion
SELDI-TOF MS is a promising high-throughput technology with potential applications in breast cancer screening, detection, and prognostication. Further studies are needed to resolve current limitations and facilitate clinical utility. 相似文献994.
995.
A. Townsend B. G. Livett J.-P. Bingham H.-T. Truong J. A. Karas P. O’Donnell N. A. Williamson A. W. Purcell D. Scanlon 《International journal of peptide research and therapeutics》2009,15(3):195-203
Molluscs of the genus Conus (cone shells) are carnivorous, feeding on marine worms, small fish and other marine molluscs. They capture their prey by
injecting venom containing hundreds of neurally active peptide components. These peptides are classed as conotoxins and consist
of small disulfide-bonded peptides exhibiting a high degree of post-translational modifications (PTMs). The functional roles
of these modifications remain largely unknown. Two of the most frequently observed modifications are γ-carboxylation of glutamate
and hydroxylation of proline (Buczek et al. Cell Mol Life Sci 62:3067, 2005). Vc1.1 is an α-conotoxin from Conus victoriae (Sandall et al. Biochemistry 42(22):6904–6911, 2003) and the only form of this peptide which has been detected in the venom
is the γ-glutamate and hydroxyproline (Vc1.1.P6O:E14Gla) version of the molecule (Jakubowski et al. Toxicon 47(6):688–699,
2006). In order to investigate the role of PTMs, we did mass spectral profiling of the venom duct of C. victoriae looking at changes in mass and the number of peptides detected. We synthesised a number of predicted Vc1.1-PTM peptides together
with the three possible disulfide isoforms of Vc1.1 and assessed the possible functional role of the PTM conopeptides by measuring
the in vitro activity at the cognate neuronal nicotinic acetylcholine receptors (nAChRs). In addition we looked for their
presence Vc1.1 venom by mass spectrometry and by this approach we were able to detect unmodified Vc1.1 in C. victoriae venom for the first time. 相似文献
996.
PD Dr. rer. nat. et med. habil. D. Prawitt T. Enklaar B. Zabel 《Medizinische Genetik》2010,22(4):399-404
The Beckwith-Wiedemann syndrome (BWS) is a pediatric overgrowth syndrome with a variable clinical appearance. The phenotype normalizes with age but the diagnosis of BWS is important as syndrome-specific complications may develop, in particular as a result of a 400-fold increased risk of patients developing certain tumor entities, predominantly nephroblastomas (Wilms’ tumors) and hepatoblastomas, within the first years of life. BWS displays a clinical overlap with other syndromes so that an unambiguous molecular diagnostic is required for risk assessment and appropriate therapy. At the molecular level BWS is associated with the chromosomal region 11p15.5, where two clusters with imprinted genes are located. In patients both genetic mutations and in most cases aberrant DNA methylation can be observed, which pathogenically affect the gene dosage of functionally available monoallelically expressed 11p15.5 genes. Currently only a very incomplete genotype-phenotype correlation exists for BWS. Current research projects provide insights in the molecular etiopathogenesis of the syndrome by identifying interacting partners which modify the epigenetic regulation of imprinted 11p15.5-genes. 相似文献
997.
Sarah G. Bailey Tilman Sanchez-Elsner Anastasis Stephanou Mark S. Cragg Paul A. Townsend 《Apoptosis : an international journal on programmed cell death》2010,15(5):541-552
The p53 gene super family consists of three members; TP53, TP63 and TP73, encoding proteins p53, p63 and p73. Whilst p63 appears to have an essential role in embryonic development with a less clear role in carcinogenesis, irregularities
in p53 and p73 signalling are implicated in tumour formation. As such, p53 is a tumour suppressor which is mutated in over
50% cancers and p73 was recently formally classified as a tumour suppressor based on data showing p73 deficient mice generate
spontaneous tumours similar to those observed in p53 null mice. Dysregulation of both p53 and p73 has been correlated with
cancer progression in many cell types and although mutation of these genes is often observed, some form of p53/p73 deregulation
likely occurs in all tumour cells. The discovery that complementary micro RNAs (miRNAs) are able to target both of these genes
provides a potential new means of perturbing p53/p73 signalling networks in cancer cells. Here we summarise the current literature
regarding the involvement of miRNAs in the modulation of p53 family proteins and cancer development and detail the use of
in silico methods to reveal key miRNA targets. 相似文献
998.
Wiens JJ Kuczynski CA Townsend T Reeder TW Mulcahy DG Sites JW 《Systematic biology》2010,59(6):674-688
Molecular data offer great potential to resolve the phylogeny of living taxa but can molecular data improve our understanding of relationships of fossil taxa? Simulations suggest that this is possible, but few empirical examples have demonstrated the ability of molecular data to change the placement of fossil taxa. We offer such an example here. We analyze the placement of snakes among squamate reptiles, combining published morphological data (363 characters) and new DNA sequence data (15,794 characters, 22 nuclear loci) for 45 living and 19 fossil taxa. We find several intriguing results. First, some fossil taxa undergo major changes in their phylogenetic position when molecular data are added. Second, most fossil taxa are placed with strong support in the expected clades by the combined data Bayesian analyses, despite each having >98% missing cells and despite recent suggestions that extensive missing data are problematic for Bayesian phylogenetics. Third, morphological data can change the placement of living taxa in combined analyses, even when there is an overwhelming majority of molecular characters. Finally, we find strong but apparently misleading signal in the morphological data, seemingly associated with a burrowing lifestyle in snakes, amphisbaenians, and dibamids. Overall, our results suggest promise for an integrated and comprehensive Tree of Life by combining molecular and morphological data for living and fossil taxa. 相似文献
999.
Background
PABA/NO is a diazeniumdiolate that acts as a direct nitrogen monoxide (NO) donor and is in development as an anticancer drug. Its mechanism of action and effect on cells is not yet fully understood.Methodology/Principal Findings
We used HPLC and mass spectrometry to identify a primary nitroaromatic glutathione metabolite of PABA/NO and used fluorescent assays to characterize drug effects on calcium and NO homeostasis, relating these to endothelial nitric oxide synthase (eNOS) activity. Unexpectedly, the glutathione conjugate was found to be a competitive inhibitor of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) presumably at the same site as thapsigargin, increasing intracellular Ca2+ release and causing auto-regulation of eNOS through S-glutathionylation.Conclusions/Significance
The initial direct release of NO after PABA/NO was followed by an eNOS-mediated generation of NO as a consequence of drug-induced increase in Ca2+ flux and calmodulin (CaM) activation. PABA/NO has a unique dual mechanism of action with direct intracellular NO generation combined with metabolite driven regulation of eNOS activation. 相似文献1000.