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1.
Eur Radiol ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34549326

RESUMO

OBJECTIVES: In multiple sclerosis (MS), iron rim lesions (IRLs) are indicators of chronic low-grade inflammation and ongoing tissue destruction. The aim of this study was to assess the relationship of IRLs with clinical measures and magnetic resonance imaging (MRI) markers, in particular brain and cervical cord volume. METHODS: Clinical and MRI parameters from 102 relapsing MS patients (no relapses for at least 6 months, no contrast-enhancing lesions) were included; follow-up data obtained after 12 months was available in 49 patients. IRLs were identified on susceptibility-weighted images (SWIs). In addition to standard brain and spinal cord MRI parameters, normalised cross-sectional area (nCSA) of the upper cervical cord was calculated. RESULTS: Thirty-eight patients had at least one IRL on SWI MRI. At baseline, patients with IRLs had higher EDSS scores, higher lesion loads (brain and spinal cord), and lower cortical grey matter volumes and a lower nCSA. At follow-up, brain atrophy rates were higher in patients with IRLs. IRLs correlated spatially with T1-hypointense lesions. CONCLUSIONS: Relapsing MS patients with IRLs showed more aggressive MRI disease characteristics in both the cross-sectional and longitudinal analyses. KEY POINTS: • Multiple sclerosis patients with iron rim lesions had higher EDSS scores, higher brain and spinal cord lesion loads, lower cortical grey matter volumes, and a lower normalised cross-sectional area of the upper cervical spinal cord. • Iron rim lesions are a new lesion descriptor obtained from susceptibility-weighted MRI. Our data suggests that further exploration of this lesion characteristic in regard to a poorer prognosis in multiple sclerosis patients is warranted.

2.
J Neuroimaging ; 31(3): 471-474, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33793026

RESUMO

BACKGROUND AND PURPOSE: Internuclear ophthalmoplegia is a dysfunction of conjugate eye movements, caused by lesions affecting the medial longitudinal fasciculus (MLF). Multiple sclerosis (MS) and ischemic stroke represent the most common pathophysiologies. While magnetic resonance imaging (MRI) allows for localizing lesions affecting the MLF, comprehensive comparative studies exploring potential different spatial characteristics of lesions affecting the MLF are missing until now. METHODS: We retrospectively investigated MRI examinations of 82 patients (40 patients with MS and 42 patients with ischemic stroke). For lesion localization, the brainstem was segmented into (1) ponto-medullary junction, (2) mid pons, (3) upper pons, and (4) mesencephalon. RESULTS: Corresponding lesions affecting the MLF were observed in 29/40 (72.5%) MS and 38/42 (90.5%) stroke patients. Compared to stroke patients, MS patients had significantly more lesions in multiple locations (P < .001). Stroke patients showed more lesions at the level of the mesencephalon (P < .001), while lesions at the level of the ponto-medullary junction, mid, and upper pons did not statistically differ between the groups. CONCLUSION: Our results demonstrate that multiple lesions affecting the MLF make inflammatory-demyelination due to MS more likely, while lesion localization at the level of the mesencephalon favors ischemia.


Assuntos
Isquemia Encefálica/patologia , AVC Isquêmico/patologia , Esclerose Múltipla/patologia , Transtornos da Motilidade Ocular/diagnóstico por imagem , Transtornos da Motilidade Ocular/patologia , Adulto , Idoso , Isquemia Encefálica/diagnóstico por imagem , Tronco Encefálico/patologia , Feminino , Humanos , AVC Isquêmico/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Mesencéfalo/patologia , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Ponte/patologia , Estudos Retrospectivos
3.
Eur J Neurol ; 28(7): 2392-2395, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33864730

RESUMO

BACKGROUND AND PURPOSE: There has been an increasing interest in chronic active multiple sclerosis (MS) lesions as a new magnetic resonance imaging (MRI) marker of disease progression. Chronic active lesions are characterized by progressive tissue matrix damage, axonal loss and chronic inflammation. Sodium (23 Na) MRI provides a biochemical marker of cell integrity and tissue viability in a quantitative manner. The aim of this study was to investigate with 23 Na MRI tissue abnormalities in chronic active lesions as indicators of tissue destruction. METHODS: To identify chronic active lesions, two 3D magnetization-prepared rapid acquisition gradient-echo datasets obtained 12 months apart were processed using the voxel-guided morphometry algorithm. Cross-sectional 23 Na MRI was performed during the 12-month follow-up period. Total sodium concentration was calculated in chronic active lesions compared to shrinking, chronic stable and acute contrast-enhancing lesions. RESULTS: Overall, 70 MS lesions (21 chronic active, 10 shrinking, 29 chronic stable lesions, 10 acute contrast-enhancing lesions) in 12 patients were included. Total sodium concentration in chronic active lesions (49.57 ± 8.47 mM) was significantly higher than in shrinking (42.16 ± 3.9 mM; p = 0.03) and chronic stable lesions (39.92 ± 4.82 mM; p < 0.001). Chronic active lesions showed similar sodium values compared to acute contrast-enhancing lesions (48.06 ± 6.65 mM; p = 0.97). No differences between shrinking and chronic stable lesions were observed (p = 0.89). CONCLUSION: High sodium values in chronic active MS lesions may be an indicator of ongoing inflammation and tissue damage.


Assuntos
Esclerose Múltipla , Sódio , Encéfalo/diagnóstico por imagem , Estudos Transversais , Progressão da Doença , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem
4.
Magn Reson Imaging ; 79: 97-102, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33771609

RESUMO

OBJECTIVE: Recently, there has been an increasing interest in "chronic enlarging" or "chronic active" multiple sclerosis (MS) lesions that are associated with clinical disability. However, investigation of dynamic lesion volume changes requires longitudinal MRI data from two or more time points. The aim of this study was to investigate the application of texture analysis (TA) on baseline T1-weighted 3D magnetization-prepared rapid acquisition gradient-echo (MPRAGE) images to differentiate chronic active from chronic stable MS lesions. MATERIAL AND METHODS: To identify chronic active lesions as compared to non-enhancing stable lesions, two MPRAGE datasets acquired on a 3 T MRI at baseline and after 12 months follow-up were applied to the Voxel-Guided Morphometry (VGM) algorithm. TA was performed on the baseline MPRAGE images, 36 texture features were extracted for each lesion. RESULTS: Overall, 374 chronic MS lesions (155 chronic active and 219 chronic stable lesions) from 60 MS patients were included in the final analysis. Multiple texture features including "DISCRETIZED_HISTO_Energy", "GLCM_Energy", "GLCM_Contrast" and "GLCM_Dissimilarity" were significantly higher in chronic active as compared to chronic stable lesions. Partial least squares regression yielded an area under the curve of 0.7 to differentiate both lesion types. CONCLUSION: Our results suggest that multiple texture features extracted from MPRAGE images indicate higher intralesional heterogeneity, however they demonstrate only a fair accuracy to differentiate chronic active from chronic stable MS lesions.


Assuntos
Esclerose Múltipla , Algoritmos , Encéfalo/diagnóstico por imagem , Humanos , Imageamento Tridimensional , Análise dos Mínimos Quadrados , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem
5.
Mult Scler Relat Disord ; 49: 102752, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33486402

RESUMO

BACKGROUND: In multiple sclerosis (MS), magnetic resonance imaging (MRI) frequently shows ill-defined areas with intermediate signal intensity between the normal appearing white matter (NAWM) and focal T2-hyperintense lesions, termed "diffusely appearing white matter" (DAWM). Even though several advanced MRI techniques have shown the potential to detect and quantify subtle commonly not visible microscopic tissue changes, to date only a few advanced MRI studies investigated DAWM changes in a quantitative manner. The aim of this study was to detect and quantify tissue abnormalities in the DAWM in comparison to focal lesions and the NAWM in MS patients by sodium (23Na) MRI. METHODS: 23Na and conventional MRI were performed in 25 MS patients with DAWM (DAWM+) and in 25 sex- and age matched MS patients without DAWM (DAWM-), as well as in ten healthy controls (HC). Mean total sodium concentrations (TSC) were quantified in the DAWM, NAWM, normal appearing grey matter (NAGM) and in focal MS lesions. RESULTS: In MS DAWM+and DAWM-, TSC values were increased in the NAGM (DAWM+: 44.61 ± 4.09 mM; DAWM-: 45.37 ± 3.8 mM) and in the NAWM (DAWM+: 39.85 ± 3.89 mM; DAWM-: 39.82 ± 4.25 mM) compared to normal grey and white matter in HC (GM 40.87 ± 3.25 mM, WM 35.9 ± 1.81 mM; p < 0.05 for all comparisons). Interestingly, the DAWM showed similar sodium concentrations (39.32 ± 4.59 mM) to the NAWM (39.85 ± 3.89 mM), whereas TSC values in T1 hypointense (46.53 ± 7.87 mM) and T1 isointense (41.99 ± 6.10 mM) lesions were significantly higher than in the DAWM (p < 0.001 and 0.017 respectively). CONCLUSION: 23Na MRI is confirmed as a sensitive marker of even subtle tissue abnormalities. DAWM sodium levels are increased and comparable to the abnormalities in NAWM, suggesting pathological changes less severe than in focal lesions comparable to what is expected in the NAWM.


Assuntos
Esclerose Múltipla , Substância Branca , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Sódio , Substância Branca/diagnóstico por imagem
6.
J Neuroimaging ; 31(2): 394-400, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33270952

RESUMO

BACKGROUND AND PURPOSE: To investigate the temporal evolution of venous diameter in chronic active and nonenhancing shrinking multiple sclerosis (MS) lesions in a longitudinal magnetic resonance imaging (MRI) study including susceptibility-weighted images (SWI). METHODS: We compared the venous diameter in chronic active and nonenhancing shrinking lesions to the venous diameter in nonenhancing stable lesions on two 3 T MRI data sets obtained 12 months apart. Chronic active and nonenhancing shrinking lesions were identified by Voxel-Guided Morphometry. Coregistered, overlaid fluid-attenuated inversion recovery/SWI were analyzed for the presence of a central vein. Quantitative calculation of the venous diameter for each time point was performed on the reconstructed veins. RESULTS: Sixty-two relapsing-remitting MS patients (50 women; mean age: 36 ± 11 years; mean disease duration: 4 ± 7 years) were included in the study. Overall, we identified 222 chronic MS lesions (48 chronic active, 48 shrinking, 126 stable) with a corresponding intralesional central vein. On baseline MRI, the mean venous diameter did not statistically differ between all subgroups, whereas on follow-up MRI, the mean intralesional venous diameter was smaller in chronic active (0.92 ± 0.15 mm) and shrinking lesions (0.90 ± 0.19 mm) compared to stable lesions (1.10 ± 0.18 mm; P < .001). CONCLUSION: Our findings demonstrate venous narrowing in chronic active and nonenhancing shrinking MS lesions. The smaller diameter of intralesional veins during follow up in these lesions may reflect structural, degenerative, and metabolic changes due to chronic inflammation, (perivascular) fibrosis, collagenous thickening, and increased levels of oxygenated hemoglobin.


Assuntos
Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/patologia , Veias/patologia , Adulto , Doença Crônica , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Veias/diagnóstico por imagem
7.
J Neuroimaging ; 30(6): 766-768, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32857891

RESUMO

BACKGROUND AND PURPOSE: The swallow tail sign describes the physiological appearance of nigrosome-1 within the substantia nigra on high-resolution transverse susceptibility-weighted imaging (SWI). Previous studies demonstrated its absence in Parkinson's disease due to increasing iron content. In multiple sclerosis (MS), increased iron accumulation can be found in the brain tissue including the substantia nigra. METHODS: We investigated the swallow tail sign on high-resolution SWI MRI in 46 MS and 23 age- and sex-matched controls. RESULTS: MS patients demonstrated significantly more often an abnormal swallow tail sign (28/46; 60%) compared to controls (4/23; 17%; P = .001). In MS patients, we found no correlation between an abnormal swallow tail sign and age, disease duration or Expanded Disability Status Scale scores. CONCLUSION: The finding of an abnormal swallow tail sign in MS patients may provide an additional imaging marker even in early MS development.


Assuntos
Esclerose Múltipla/diagnóstico por imagem , Substância Negra/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
8.
Mult Scler Relat Disord ; 45: 102409, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32711298

RESUMO

BACKGROUND: Recently there has been an increasing interest in the "central vein sign" (CVS) in multiple sclerosis (MS) lesions. Infratentorial brain regions represent typical predilection sites for MS lesion development and are part of the current McDonald criteria to demonstrate dissemination in space, but only a few studies investigated the presence of the CVS in infratentorial MS lesions. The aim of this study was to investigate the CVS in infratentorial MS lesions. METHODS: 3T MRI data sets from 119 patients with relapsing MS were analysed. Chronic lesions were identified on T2-weighted images. Co-registered T2 / susceptibility-weighted images (SWI) were analysed for the presence of the CVS. RESULTS: A total of 527 lesions were analysed. A CVS was present in the majority of infratentorial lesions (62/88, 70%). There was no difference in the frequencies of the CVS of infratentorial lesions compared to paraventricular lesions (67/81, 83%; p = 0.06) or subcortical (150/209; 72%; p = 0.82) lesions. Infratentorial lesions showed a CVS more often than juxtacortical lesions (16/34; 47%; p = 0.02), while periventricular lesions showed a CVS more often than infratentorial lesions (97/115; 84%, p = 0.02). CONCLUSION: CVS is a frequent finding in infratentorial MS lesions that may increase the diagnostic value in MS.


Assuntos
Esclerose Múltipla , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Recidiva , Veias
9.
Oncotarget ; 9(65): 32507-32522, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30197759

RESUMO

In cancer cells, microRNAs (miRNAs) are often aberrantly expressed resulting in impaired mRNA translation. In this study we show that miR-193b and miR-30c-1* inhibit, whereas miR-576-5p accelerates invasion of various human melanoma cell lines. Using Boyden chamber invasion assays the effect of selected miRNAs on the invasive capacity of various human melanoma cell lines was analyzed. Upon gene expression profiling performed on transfected A375 cells, CTGF, THBS1, STMN1, BCL9, RAC1 and MCL1 were identified as potential targets. For target validation, qPCR, Western blot analyses or luciferase reporter assays were applied. This study reveals opposed effects of miR-193b / miR-30c-1* and miR-576-5p, respectively, on melanoma cell invasion and on expression of BCL9 and MCL1, possibly accounting for the contrasting invasive phenotypes observed in A375 cells transfected with these miRNAs. The miRNAs studied and their targets identified fit well into a model proposed by us explaining the regulation of invasion associated genes and the observed opposed phenotypes as a result of networked direct and indirect miRNA / target interactions. The results of this study suggest miR-193b and miR-30c-1* as tumor-suppressive miRNAs, whereas miR-576-5p appears as potential tumor-promoting oncomiR. Thus, miR-193b and miR-30c-1* mimics as well as antagomiRs directed against miR-576-5p might become useful tools in future therapy approaches against advanced melanoma.

10.
Cancer Res ; 76(12): 3562-71, 2016 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-27197185

RESUMO

Determinants of invasion and metastasis in cancer remain of great interest to define. Here, we report the definition of miR-339-3p as a novel tumor suppressive microRNA that blocks melanoma cell invasion without affecting cell survival. miR-339-3p was identified by a comprehensive functional screen of a human miRNA mimetic library in a cell-based assay for invasion by the melanoma cell line A375. miR-339-3p was determined as a strong inhibitor of invasion differentially expressed in melanoma cells and healthy melanocytes. MCL1 was defined as a target for downregulation by miR-339-3p, functioning through direct interaction with the 3' untranslated region of MCL1 mRNA. Blocking miR-339-3p by an antagomiR was sufficient to increase melanoma cell invasion, an effect that could be phenocopied by RNAi-mediated silencing of MCL1. In vivo studies established that miR-339-3p overexpression was sufficient to decrease lung colonization by A375 melanoma cells in NSG mice, relative to control cells. Overall, our results defined miR-339-3p as a melanoma tumor suppressor, the levels of which contributes to invasive aggressiveness. Cancer Res; 76(12); 3562-71. ©2016 AACR.


Assuntos
Genes Supressores de Tumor/fisiologia , Melanoma/prevenção & controle , MicroRNAs/fisiologia , Animais , Linhagem Celular Tumoral , Melanoma/genética , Melanoma/patologia , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Invasividade Neoplásica
11.
BMC Med Genomics ; 9: 10, 2016 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-26927636

RESUMO

BACKGROUND: Melanoma is a cancer with rising incidence and new therapeutics are needed. For this, it is necessary to understand the molecular mechanisms of melanoma development and progression. Melanoma differs from other cancers by its ability to produce the pigment melanin via melanogenesis; this biosynthesis is essentially regulated by microphthalmia-associated transcription factor (MITF). MITF regulates various processes such as cell cycling and differentiation. MITF shows an ambivalent role, since high levels inhibit cell proliferation and low levels promote invasion. Hence, well-balanced MITF homeostasis is important for the progression and spread of melanoma. Therefore, it is difficult to use MITF itself for targeted therapy, but elucidating its complex regulation may lead to a promising melanoma-cell specific therapy. METHOD: We systematically analyzed the regulation of MITF with a novel established transcription factor based gene regulatory network model. Starting from comparative transcriptomics analysis using data from cells originating from nine different tumors and a melanoma cell dataset, we predicted the transcriptional regulators of MITF employing ChIP binding information from a comprehensive set of databases. The most striking regulators were experimentally validated by functional assays and an MITF-promoter reporter assay. Finally, we analyzed the impact of the expression of the identified regulators on clinically relevant parameters of melanoma, i.e. the thickness of primary tumors and patient overall survival. RESULTS: Our model predictions identified SOX10 and SOX5 as regulators of MITF. We experimentally confirmed the role of the already well-known regulator SOX10. Additionally, we found that SOX5 knockdown led to MITF up-regulation in melanoma cells, while double knockdown with SOX10 showed a rescue effect; both effects were validated by reporter assays. Regarding clinical samples, SOX5 expression was distinctively up-regulated in metastatic compared to primary melanoma. In contrast, survival analysis of melanoma patients with predominantly metastatic disease revealed that low SOX5 levels were associated with a poor prognosis. CONCLUSION: MITF regulation by SOX5 has been shown only in murine cells, but not yet in human melanoma cells. SOX5 has a strong inhibitory effect on MITF expression and seems to have a decisive clinical impact on melanoma during tumor progression.


Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Melanoma/patologia , Fator de Transcrição Associado à Microftalmia/genética , Fatores de Transcrição SOXD/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Simulação por Computador , Fluorescência , Técnicas de Silenciamento de Genes , Proteínas de Fluorescência Verde/metabolismo , Humanos , Fator de Transcrição Associado à Microftalmia/metabolismo , Invasividade Neoplásica , Fenótipo , Programação Linear , RNA Interferente Pequeno/metabolismo , Reprodutibilidade dos Testes , Fatores de Transcrição SOXE/metabolismo , Análise de Sobrevida , Transfecção
12.
Exp Dermatol ; 24(12): 947-52, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26186482

RESUMO

MicroRNAs (miRNA) are key players in a variety of cancers including malignant melanoma. miR-137 has been reported to be a tumor suppressor in melanoma and several targets have been identified for this miRNA. We previously developed a novel proteomics technology, (35) S in vivo/vitro labelling analysis for dynamic proteomics (SiLAD). Because of its high sensitivity in analysing protein expression rates, SiLAD has the potential to unravel miRNA effects on mRNAs coding for proteins with long half-lives or high abundance. Using SiLAD, we discovered that miR-137 significantly downregulated the expression rate of p21-activated kinase 2 (PAK2) in melanoma cells. Bioinformatics analysis predicted PAK2 as a direct target of miR-137, which was confirmed by luciferase reporter assay and Western blot analysis. We found that overexpression of miR-137 inhibited the proliferation of melanoma cells, which could be phenocopied by knockdown of PAK2 using siRNAs. Furthermore, overexpression of PAK2 restored miR-137-mediated suppression of cell proliferation. These findings indicate that miR-137 could inhibit proliferation through targeting PAK2 in melanoma cells.


Assuntos
Melanoma/genética , Melanoma/patologia , MicroRNAs/genética , Quinases Ativadas por p21/antagonistas & inibidores , Quinases Ativadas por p21/genética , Apoptose/genética , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Melanoma/metabolismo , MicroRNAs/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA Interferente Pequeno/genética , Transfecção , Quinases Ativadas por p21/metabolismo
13.
Eur J Cell Biol ; 93(1-2): 11-22, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24602414

RESUMO

Melanoma is the most dangerous form of skin cancer, being largely resistant to conventional therapies at advanced stages. Understanding the molecular mechanisms behind this disease might be the key for the development of novel therapeutic strategies. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control gene expression, thereby regulating various cellular signaling pathways involved in the initiation and progression of different cancer types, including melanoma. In this review, we summarize approaches for the identification of candidate miRNAs and their target genes and review the functions of miRNAs in melanoma. Finally, we highlight the recent progress in pre-clinical use of miRNAs as prognostic markers and therapeutic targets.


Assuntos
Biomarcadores Tumorais/metabolismo , Melanoma/genética , MicroRNAs/metabolismo , Neoplasias Cutâneas/genética , Animais , Antineoplásicos/uso terapêutico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Melanoma/metabolismo , MicroRNAs/genética , Oncogenes , Prognóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo
14.
PLoS One ; 6(5): e19927, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21625644

RESUMO

Protein modifications of death receptor pathways play a central role in the regulation of apoptosis. It has been demonstrated that O-glycosylation of TRAIL-receptor (R) is essential for sensitivity and resistance towards TRAIL-mediated apoptosis. In this study we ask whether and how glycosylation of CD95 (Fas/APO-1), another death receptor, influences DISC formation and procaspase-8 activation at the CD95 DISC and thereby the onset of apoptosis. We concentrated on N-glycostructure since O-glycosylation of CD95 was not found. We applied different approaches to analyze the role of CD95 N-glycosylation on the signal transduction: in silico modeling of CD95 DISC, generation of CD95 glycosylation mutants (at N136 and N118), modulation of N-glycosylation by deoxymannojirimycin (DMM) and sialidase from Vibrio cholerae (VCN). We demonstrate that N-deglycosylation of CD95 does not block DISC formation and results only in the reduction of the procaspase-8 activation at the DISC. These findings are important for the better understanding of CD95 apoptosis regulation and reveal differences between apoptotic signaling pathways of the TRAIL and CD95 systems.


Assuntos
Apoptose , Caspase 8/metabolismo , Linfócitos/metabolismo , Mutação/genética , Receptor fas/genética , Western Blotting , Células Cultivadas , Biologia Computacional , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glicosilação , Humanos , Imunoprecipitação , Linfócitos/citologia , Conformação Proteica , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptor fas/química , Receptor fas/metabolismo
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