TGFbeta, activina e sinalização SMAD em câncer de tiróide

Abstract

RESUMOTGFβ e activina são membros da superfamília TGFβ e desempenham um amplo papel no desenvolvimento, proliferação e apoptose. Estes fatores de crescimento exercem seus efeitos biológicos ligando-se a receptores de membrana do tipo I e do tipo II que transduzem a sinalização até o núcleo através da fosforilação das proteínas R-SMADs (SMAD 2/3) e co-SMADs (SMAD4). O controle apropriado da via de TGFβ/activina ainda depende da regulação negativa exercida pelo SMAD inibitório (SMAD7) e pelas enzimas E3 de ubiquitinação (Smurfs). Fisiologicamente, TGFβ e activina atuam como potentes inibidores da proliferação na célula folicular tiroidiana. Desta forma, alterações de receptores e componentes da via de sinalização SMAD estão associadas a diferentes tipos de tumores. Desde que TGFβ e activina geram sua sinalização intracelular utilizando os mesmos componentes da via SMAD, o desequilíbrio desta via prejudica dois processos antimitogênicos da célula. Nesta revisão, enfocamos aspectos que indicam o mecanismo de resistência ao efeito inibitório de TGFβ e activina ocasionado pelo desequilíbrio da via de sinalização SMAD nas neoplasias da tiróide. TGFβ and activin are members of the TGFβ superfamily and play a wide role in development, proliferation and apoptosis. These growth factors exert their biological effects by binding to the type I and II membrane receptors to transduce their signalling through the nucleus by phosphorylation of R-SMADs (SMAD 2/3) and co-SMADs (Smad 4). The proper control of TGFβ/activin pathway is negatively regulated by inhibitory SMAD (SMAD7) and by E3 ubiquitination enzymes (Smurfs). Physiologically, TGFβ and activin act as potent growth inhibitors in thyroid follicular cell. Thus, alterations in the receptors and components of SMAD signalling pathway are associated with several types of tumors. Since TGFβ and activin generate their intracellular signalling through the same components of the SMAD pathway, the unbalance of this pathway impairs both of anti-mitogenic signals in the cell. This review addresses aspects of the molecular mechanisms in the understanding of resistance to the growth inhibitory effects of TGFβ and activin due to the disequilibrium in the SMAD inhibitory pathway in thyroid neoplasia.

Cross platform analysis of transcriptomic data identifies ageing has distinct and opposite effects on tendon in males and females

“…Antigen processing and presentation (MHCII) was increased resulting in the identification of a variety of pathways involved in infections and immune responses (Table M1 S5 ). Reductions in the expression of SMAD3, high expression of TGF- β as well as reduced p53 signalling, MAPK signalling and sonic hedgehog signalling are indicative of a reduced cell cycle in females (Table M2 S4 , Table 4 ) 45 , 46 . Cell cycle reductions are further supported by reduced DNA replication, RNA transport, base excision repair (Tables M1 S5 and M2 S4 ) glucose, fructose, mannose and galactose metabolism (Table M1 S5 ), digestion and absorption of B vitamins, oxidative phosphorylation, and ether lipid metabolism (Table M2 S4 ).…”

MiRNA-146b-5p upregulates migration and invasion of different Papillary Thyroid Carcinoma cells

“…Additionally, the TGF-β pathway plays important roles in other cellular functions, i.e. apoptosis and cell motility [ 15 , 44 , 45 ].…”

“…These mutations constitutively activate the same signaling pathway, and rarely overlap. The growth factor TGF-β is a negative regulator of thyroid follicular cell growth, and the evasion of TGF-β signaling by follicular thyroid cells results in increased proliferation, the acquisition of an invasive phenotype and tumor progression [ 14 , 15 ].…”

Expression of SMAD proteins, TGF-beta/activin signaling mediators, in human thyroid tissues

“…The activation of SMAD2/ SMAD3 allows their interaction with common-mediator SMAD (co-SMAD), SMAD4, and then this complex moves to the nucleus where it regulates gene transcription. Although activin binds to its own specific receptors, the same set of SMADs is recruited for its signal transduction (6)(7)(8)(9)(10). This TGF-β/activin signaling is attenuated by SMAD7, an inhibitory SMAD (I-SMAD) that prevents phosphorylation of SMAD2/3 and interferes with the formation of complex SMAD2/3 and SMAD4 (11,12).…”