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1.
PLoS One ; 12(5): e0177140, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28481943

RESUMO

It has been hypothesized that HLA class II alleles associated with rheumatoid arthritis (RA) preferentially present self-antigens altered by post-translational modification, such as citrullination. To understand the role of citrullination we tested four RA-associated citrullinated epitopes and their corresponding wild-type version for binding to 28 common HLA class II. Binding patterns were variable, and no consistent impact of citrullination was identified. Indeed, in one case citrullination significantly increased binding compared to the WT peptide, in another citrullination was associated with a reduction in promiscuity by 40%. For a more comprehensive analysis, we tested over 200 citrullinated peptides derived from vimentin and collagen II for their capacity to bind the RA-associated shared epitope alleles DRB1*01:01 and DRB1*04:01. The overall effect of citrullination on binding was found to be relatively minor, and only rarely associated with 3-fold increases or decreases in affinity. Previous studies have suggested that citrullination of MHC anchor residues, in particular P4, is associated with generation of novel RA-associated epitopes. However, analysis of the predicted MHC-binding cores of all peptides tested found that in modified peptides with increased binding affinity the citrullinated residue was predicted to occupy an anchor position in only a minority of cases. Finally, we also show that identification of citrullinated peptide binders could be facilitated by using the NetMHCIIpan 3.1 algorithm, representing citrullination as a wildcard. Our studies identify a total of 117 citrullinated peptides that bound RA-associated alleles with an affinity of 1000 nM or better.


Assuntos
Citrulina/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Peptídeos/metabolismo , Alelos , Epitopos/metabolismo , Humanos , Ligação Proteica
3.
Chem Biol ; 17(11): 1177-82, 2010 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-21095567

RESUMO

To identify new protein and pharmacological regulators of Wnt/ß-catenin signaling, we used a cell-based reporter assay to screen a collection of 1857 human-experienced compounds for their ability to enhance activation of the ß-catenin reporter by a low concentration of WNT3A. This identified 44 unique compounds, including the FDA-approved drug riluzole, which is presently in clinical trials for treating melanoma. We found that treating melanoma cells with riluzole in vitro enhances the ability of WNT3A to regulate gene expression, to promote pigmentation, and to decrease cell proliferation. Furthermore riluzole, like WNT3A, decreases metastases in a mouse melanoma model. Interestingly, siRNAs targeting the metabotropic glutamate receptor, GRM1, a reported indirect target of riluzole, enhance ß-catenin signaling. The unexpected regulation of ß-catenin signaling by both riluzole and GRM1 has implications for the future uses of this drug.


Assuntos
Antineoplásicos/uso terapêutico , Melanoma Experimental/metabolismo , Riluzol/uso terapêutico , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Proliferação de Células , Regulação da Expressão Gênica , Genes Reporter , Melanoma Experimental/tratamento farmacológico , Camundongos , Interferência de RNA , RNA Interferente Pequeno , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Transdução de Sinais , Pigmentação da Pele , Proteína Wnt3 , Proteína Wnt3A
4.
Proc Natl Acad Sci U S A ; 106(4): 1193-8, 2009 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-19144919

RESUMO

This study demonstrates that in malignant melanoma, elevated levels of nuclear beta-catenin in both primary tumors and metastases correlate with reduced expression of a marker of proliferation and with improved survival, in contrast to colorectal cancer. The reduction in proliferation observed in vivo is recapitulated in B16 murine melanoma cells and in human melanoma cell lines cultured in vitro with either WNT3A or small-molecule activators of beta-catenin signaling. Consistent with these results, B16 melanoma cells expressing WNT3A also exhibit decreased tumor size and decreased metastasis when implanted into mice. Genome-wide transcriptional profiling reveals that WNT3A up-regulates genes implicated in melanocyte differentiation, several of which are down-regulated with melanoma progression. These findings suggest that WNT3A can mediate transcriptional changes in melanoma cells in a manner reminiscent of the known role of Wnt/beta-catenin signaling in normal melanocyte development, thereby altering melanoma cell fate to one that may be less proliferative and potentially less aggressive. Our results may explain the observed loss of nuclear beta-catenin with melanoma progression in human tumors, which could reflect a dysregulation of cellular differentiation through a loss of homeostatic Wnt/beta-catenin signaling.


Assuntos
Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Biomarcadores/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Linhagem da Célula , Núcleo Celular/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Camundongos , Análise de Sobrevida , Regulação para Cima , Proteína Wnt3 , Proteína Wnt3A
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