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71.
Glycogen synthase kinase 3 (GSK3), a key component of the insulin and wnt signaling pathways, is unusual, as it is constitutively active and is inhibited in response to upstream signals. Kinase activity is thought to be increased by intramolecular phosphorylation of a tyrosine in the activation loop (Y216 in GSK3beta), whose timing and mechanism is undefined. We show that GSK3beta autophosphorylates Y216 as a chaperone-dependent transitional intermediate possessing intramolecular tyrosine kinase activity and displaying different sensitivity to small-molecule inhibitors compared to mature GSK3beta. After autophosphorylation, mature GSK3beta is then an intermolecular serine/threonine kinase no longer requiring a chaperone. This shows that autoactivating kinases have adopted different molecular mechanisms for autophosphorylation; and for kinases such as GSK3, inhibitors that affect only the transitional intermediate would be missed in conventional drug screens. 相似文献
72.
JJ Malemba JM Mbuyi-Muamba J Mukaya X Bossuyt MP Emonds K Deiteren R Westhovens P Verschueren 《Arthritis research & therapy》2013,15(4):R89
Introduction
Little is known about rheumatoid arthritis in the black, particularly in Congolese, populations. Our objective was to describe the phenotype and genotype of rheumatoid arthritis (RA) in Congolese.Methods
All consecutive rheumatoid arthritis (RA) patients attending Kinshasa University Hospital in a three-year time period were included. Demographics, clinical features and tobacco consumption were noted. Disease Activity Score (DAS)-28 based on the erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire (HAQ), anti-citrullinated peptide antibodies (CCP) antibodies and rheumatoid factor (RF) were determined. Radiographs were scored according to Sharp-van der Heijde. On a subset of patients and controls HLA-DRB1 typing was performed.Results
A total of 114 females and 14 males aged 51.2 ± 14.9 were included. Mean duration of symptoms was four years. Moderate tobacco consumption was reported in a minority of patients. DAS-28 at first visit was >5.1 and HAQ ≥0.5 in all patients. X-rays showed joint erosions and/or joint space narrowing, mostly of a moderate grade in 55.8% of patients. Anti-CCP and/or RF were present in 48.6% of patients with available data (n = 72) and in 3.0% of controls (n = 67). Radiographic changes and nodules were more frequent in RF or anti-CCP positive patients. One copy of the shared epitope was found in 13 patients (35.1%) and 3 controls (12.5%). Two copies were found in one patient (2.7%) and in one control (4.2%).Conclusion
Congolese patients with RA consult long after disease onset. Despite this delay, the majority presents without major damage and is RF, anti-CCP and SE negative. We put forward the hypothesis that besides different environmental factors there is probably also a particular genetic risk profile in Congolese patients, different from the HLA-DRB1 shared epitope. 相似文献73.
C Smith P Lochhead U Basavaraju GL Hold N Fyfe GI Murray EM El-Omar 《BMC research notes》2012,5(1):371
ABSTRACT: BACKGROUND: Prostate stem cell antigen (PSCA) has been implicated in the pathogenesis of several solid tumours, either due to changes in protein expression, or through association with the rs2294008 polymorphism in the PSCA gene. To our knowledge, the role of PSCA in the development of colorectal neoplasia has not been explored. We performed a genotyping study to assess for associations between the rs2294008 polymorphism and risk of adenomatous polyps and colorectal cancer. DNA samples were available from 388 individuals with colorectal neoplasia and 496 controls, all of whom had undergone screening colonoscopy. In addition, we performed immunohistochemical staining for PSCA in colonic tissue representing all stages of the adenoma-carcinoma sequence. RESULTS: No genotypic associations were found between the rs2294008 polymorphism and the risk of colorectal adenomata or cancer. Immunohistochemical staining did not reveal any alteration in PSCA expression accompanying the adenoma-carcinoma sequence. CONCLUSION: From these data it seems unlikely that PSCA has a role in the initiation or progression of colorectal neoplasia. 相似文献
74.
The MEK5 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5]/ERK5 pathway is the least well studied MAPK signalling module. It has been proposed to play a role in the pathology of cancer. In the present paper, we review the role of the MEK5/ERK5 pathway using the 'hallmarks of cancer' as a framework and consider how this pathway is deregulated. As well as playing a key role in endothelial cell survival and tubular morphogenesis during tumour neovascularization, ERK5 is also emerging as a regulator of tumour cell invasion and migration. Several oncogenes can stimulate ERK5 activity, and protein levels are increased by a novel amplification at chromosome locus 17p11 and by down-regulation of the microRNAs miR-143 and miR-145. Together, these finding underscore the case for further investigation into understanding the role of ERK5 in cancer. 相似文献
75.
76.
77.
Glycosylation sites and site-specific glycosylation in human Tamm- Horsfall glycoprotein 总被引:4,自引:1,他引:3
The N-glycosylation sites of human Tamm-Horsfall glycoprotein from one
healthy male donor have been characterized, based on an approach using
endoproteinase Glu-C (V-8 protease, Staphylococcus aureus ) digestion and a
combination of chromatographic techniques, automated Edman sequencing, and
fast atom bombardment mass spectrometry. Seven out of the eight potential
N-glycosylation sites, namely, Asn52, Asn56, Asn208, Asn251, Asn298,
Asn372, and Asn489, turned out to be glycosylated, and the potential
glycosylation site at Asn14, being close to the N-terminus, is not used.
The carbohydrate microheterogeneity on three of the glycosylation sites was
studied in more detail by high-pH anion-exchange chromatographic profiling
and 500 MHz1H-NMR spectroscopy. Glycosylation site Asn489 contains mainly
di- and tri-charged oligosaccharides which comprise, among others, the
GalNAc4 S (beta1-4)GlcNAc terminal sequence. Only glycosylation site Asn251
bears oligomannose-type carbohydrate chains ranging from Man5GlcNAc2to
Man8GlcNAc2, in addition to a small amount of complex- type structures.
Profiling of the carbohydrate moieties of Asn208 indicates a large
heterogeneity, similar to that established for native human Tamm-Horsfall
glycoprotein, namely, multiply charged complex-type carbohydrate
structures, terminated by sulfate groups, sialic acid residues, and/or the
Sda-determinant.
相似文献
78.
Leo AB Joosten Erik Lubberts Monique MA Helsen Tore Saxne Christina JJ Coenen-de Roo Dick Heinegård Wim B van den Berg 《Arthritis research & therapy》1999,1(1):81-11
Destruction of cartilage and bone are hallmarks of human rheumatoid arthritis (RA), and controlling these erosive processes
is the most challenging objective in the treatment of RA. Systemic interleukin-4 treatment of established murine collagen-induced
arthritis suppressed disease activity and protected against cartilage and bone destruction. Reduced cartilage pathology was
confirmed by both decreased serum cartilage oligomeric matrix protein (COMP) and histological examination. In addition, radiological
analysis revealed that bone destruction was also partially prevented. Improved suppression of joint swelling was achieved
when interleukin-4 treatment was combined with low-dose prednisolone treatment. Interestingly, synergistic reduction of both
serum COMP and inflammatory parameters was noted when low-dose interleukin-4 was combined with prednisolone. Systemic treatment
with interleukin-4 appeared to be a protective therapy for cartilage and bone in arthritis, and in combination with prednisolone
at low dosages may offer an alternative therapy in RA. 相似文献
79.
80.
A. G. Lochhead 《Microbiological reviews》1958,22(3):145-153