RESUMEN
S100A7 has been suggested to interact with Ran-binding protein 9. Both proteins are nowadays considered key effectors in immune response. Functional interaction between proteins is ensured by coevolution. The mechanisms of vertebrate coevolution between S100A7 and RanBP9 remain unclear. Several approaches for studying coevolution have been developed. Protein coevolution was inferred by calculating the linear correlation coefficients between inter-protein distance matrices using Mirrortree. We found an overall moderate correlation value (R = 0.53, p < 1e-06). Moreover, owing to the high conservation of RanBP9 protein among vertebrates, we chose to utilize a recent version of Blocks in Sequences (BIS2) algorithm implemented in BIS2Analyzer webserver. A coevolution cluster was identified between the two proteins (p < 8.10e-05). In conclusion, our coevolutionary analysis suggests that amino acid variations may modulate S100A7/RanBP9 interaction with potential pathogenic effects. Such findings could guide further analysis to better elucidate the function of S100A7 and RanBP9 and to design drugs targeting for these molecules in diseases.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Coevolución Biológica/genética , Proteínas del Citoesqueleto/metabolismo , Proteínas Nucleares/metabolismo , Proteína A7 de Unión a Calcio de la Familia S100/metabolismo , Proteínas Adaptadoras Transductoras de Señales/inmunología , Secuencia de Aminoácidos/genética , Animales , Evolución Biológica , Proteínas del Citoesqueleto/inmunología , Bases de Datos Genéticas , Evolución Molecular , Humanos , Mamíferos/genética , Proteínas Nucleares/inmunología , Proteína A7 de Unión a Calcio de la Familia S100/inmunologíaRESUMEN
Within the tumor, malignant and stromal cells support each other by secreting a wide variety of growth factors and cytokines, allowing tumor growth and disease progression. The identification and regulation of those key factors in this crosstalk has opened the opportunity to develop new therapeutic strategies that not only act on the tumor cells but also on the stroma. Among these factors, S100A7 protein has gained interest in the last years. With key roles in cell motility its expression correlates with increased tumor growth, angiogenesis and metastatic potential. This work aims to deepen in the role played by extracellular S100A7 in the tumor microenvironment, offering a new integrative insight of its mechanism of action on each cellular compartment (tumor, endothelial, immune and fibroblast). As a result, we demonstrate its implication in cell migration and invasion, and its important contribution to the formation of a proinflammatory and proangiogenic environment that favors tumor progression and metastasis. Furthermore, we define its possible role in the pre-metastatic niche formation. Considering the relevance of S100A7 in cancer progression, we have developed neutralizing monoclonal antibodies, reporting for the first time the proof of principle of this promising therapeutic strategy for cancer treatment.
Asunto(s)
Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Proteína A7 de Unión a Calcio de la Familia S100/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Proteínas Recombinantes/farmacología , Proteína A7 de Unión a Calcio de la Familia S100/genética , Proteína A7 de Unión a Calcio de la Familia S100/inmunología , Microambiente Tumoral/efectos de los fármacosRESUMEN
Psoriasis is a common chronic inflammatory and immune-mediated skin disease. Antagonists of TNF-α and, recently, IL-17 have proven to be highly effective in the treatment for psoriasis; however, the molecular mechanisms involved in the pathogenesis of psoriasis are poorly understood. Recently, we presented evidence that IκBζ is a key regulator in the development of psoriasis through its role in mediating IL-17A-driven effects. Like IL-17A, IL-17F is produced by a variety of immune cells, and the expression of IL-17F is increased in psoriatic skin. The purpose of this study was to characterize the role of IL-17F in the regulation of IκBζ expression and to investigate whether IL-17F regulates psoriasis-associated genes in human keratinocytes through IκBζ. Here, we demonstrate that IL-17F stimulation induces IκBζ expression at both the mRNA and the protein levels in normal human keratinocytes. Moreover, silencing IκBζ by siRNA revealed that IκBζ is a key regulator of specific IL-17F-inducible psoriasis-associated genes and proteins, including DEFB4/hBD2, S100A7, CCL20, IL-8 and CHI3L1. In addition, IL-17F-induced IκBζ expression is mediated by a mechanism involving the p38 MAPK and NF-κB signalling pathways, as shown by the clear reduction in IL-17F-mediated expression of IκBζ during chemical inhibition of these two signalling pathways. In summary, we present IκBζ as a novel key regulator of IL-17F-driven effects in psoriasis. Thus, antagonists to IκBζ could potentially provide a more targeted approach for treating psoriasis as well as for treating the other inflammatory and immune-mediated diseases for which IL-17-targeting drugs have recently been approved.
Asunto(s)
Expresión Génica/efectos de los fármacos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Interleucina-17/farmacología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Psoriasis/genética , Psoriasis/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Anticuerpos Neutralizantes/farmacología , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo , Proteína 1 Similar a Quitinasa-3/genética , Proteína 1 Similar a Quitinasa-3/metabolismo , Humanos , Proteínas I-kappa B/inmunología , Interleucina-8/genética , Interleucina-8/metabolismo , Queratinocitos , Sistema de Señalización de MAP Quinasas , FN-kappa B/metabolismo , Proteínas Nucleares/inmunología , ARN Mensajero/metabolismo , ARN Interferente Pequeño , Proteína A7 de Unión a Calcio de la Familia S100/genética , Proteína A7 de Unión a Calcio de la Familia S100/inmunología , Transfección , Factor de Necrosis Tumoral alfa/farmacología , beta-Defensinas/genética , beta-Defensinas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
S100A7 (psoriasin), an EF-hand type calcium binding protein localized in epithelial cells, regulates cell proliferation and differentiation. An S100A7 overexpression may occur in response to inflammatory stimuli, such in psoriasis, a chronic inflammatory autoimmune-mediated skin disease. Increasing evidence suggests that S100A7 plays critical roles in amplifying the inflammatory process in psoriatic skin, perpetuating the disease phenotype. This review will discuss the interactions between S100A7 and cytokines in psoriatic skin. Furthermore, we will focus our discussion on regulation and functions of S100A7 in psoriasis. Finally, we will discuss the possible use of S100A7 as therapeutic target in psoriasis.
