RESUMEN
Functional classification of proteins from sequences alone has become a critical bottleneck in understanding the myriad of protein sequences that accumulate in our databases. The great diversity of homologous sequences hides, in many cases, a variety of functional activities that cannot be anticipated. Their identification appears critical for a fundamental understanding of the evolution of living organisms and for biotechnological applications. ProfileView is a sequence-based computational method, designed to functionally classify sets of homologous sequences. It relies on two main ideas: the use of multiple profile models whose construction explores evolutionary information in available databases, and a novel definition of a representation space in which to analyze sequences with multiple profile models combined together. ProfileView classifies protein families by enriching known functional groups with new sequences and discovering new groups and subgroups. We validate ProfileView on seven classes of widespread proteins involved in the interaction with nucleic acids, amino acids and small molecules, and in a large variety of functions and enzymatic reactions. ProfileView agrees with the large set of functional data collected for these proteins from the literature regarding the organization into functional subgroups and residues that characterize the functions. In addition, ProfileView resolves undefined functional classifications and extracts the molecular determinants underlying protein functional diversity, showing its potential to select sequences towards accurate experimental design and discovery of novel biological functions. On protein families with complex domain architecture, ProfileView functional classification reconciles domain combinations, unlike phylogenetic reconstruction. ProfileView proves to outperform the functional classification approach PANTHER, the two k-mer-based methods CUPP and eCAMI and a neural network approach based on Restricted Boltzmann Machines. It overcomes time complexity limitations of the latter.
Asunto(s)
Evolución Molecular , Proteínas , Secuencia de Aminoácidos , Bases de Datos de Proteínas , Filogenia , Extractos Vegetales , Proteínas/química , Proteínas/genéticaRESUMEN
Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2.
Asunto(s)
Vía de Señalización Hippo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Transactivadores/metabolismo , Variaciones en el Número de Copia de ADN/genética , Humanos , Modelos Biológicos , Medicina de PrecisiónAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/metabolismo , Núcleo Celular/metabolismo , Resistencia a Antineoplásicos , Proteínas Serina-Treonina Quinasas/metabolismo , Tamoxifeno/uso terapéutico , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Oxidorreductasa que Contiene Dominios WW/metabolismo , Transporte Activo de Núcleo Celular/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias de la Mama/genética , Núcleo Celular/genética , Núcleo Celular/patología , Femenino , Vía de Señalización Hippo , Humanos , Células MCF-7 , Fosforilación/genética , Proteínas Serina-Treonina Quinasas/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Oxidorreductasa que Contiene Dominios WW/genética , Proteínas Señalizadoras YAPRESUMEN
Evodiamine is one of the main components isolated from Evodia rutaecarpa, and it has been reported to exert inhibitory effects on cancers by anti-proliferative and apoptosis-inducing activities. Although the anti-cancer activity of evodiamine has been identified, the precise mechanisms of this action remain obscure. While previous studies indicated that evodiamine exerts anti-tumor effects through inhibiting ß-catenin activity, and WW domain-containing oxidoreductase (WWOX) regulates ß-catenin accumulation in cytoplasm, the effects of evodiamine on the expression of WWOX are still unknown. In this study, we provide evidence that evodiamine dose- and time-dependently inhibits both Mus musculus and Homo sapiens hepatocellular carcinoma (HCC) cells, as well as Hepa1-6 and HepG2 cell proliferation. We further tested the therapeutic effects of evodiamine in Hepa1-6 hepatoma-bearing mice, and we found that treatment of evodiamine by oral gavage significantly decreased the tumor size of the mice. Moreover, the expressions of WWOX were dose-dependently increased in HCC cell lines as well as in Hepa1-6 hepatoma-bearing mice after the treatment with evodiamine. Knockdown of WWOX in HepG2 and Hepa1-6 cells diminished the effects of evodiamine on the inhibitory effect of cancer cell growth, indicating that evodiamine induced anti-cancer activity through a WWOX-dependent pathway. As such, evodiamine activated WWOX to exert an anti-HCC activity, and might be a potential therapeutic or preventive candidate for HCC treatment.