RESUMO
Receptor activator of nuclear factor (NF)-κB (RANK) signaling promotes pregnancy-dependent epithelial cell differentiation and expansion for mammary gland development, which requires NF-κB pathway-dependent Cyclin D1 induction and inhibitor of DNA binding 2 (Id2) pathway-dependent anti-apoptotic gene induction. However, the roles of tumor necrosis factor receptor-associated factor 6 (TRAF6) remain unclear despite its requirement in RANK signaling. Here we show that TRAF6 is crucial for both mammary stem cell maintenance and pregnancy-induced epithelial cell expansion. TRAF6 deficiency impairs phosphoinositide 3-kinase (PI3K)/AKT and canonical NF-κB pathways, whereas noncanonical NF-κB signaling remains functional. Therefore, we propose that TRAF6 promotes cell proliferation by activating PI3K/AKT signaling to induce retinoblastoma phosphorylation in concert with noncanonical NF-κB pathway-dependent Cyclin D1 induction. Furthermore, TRAF6 inhibits apoptosis by activating canonical NF-κB signaling to induce anti-apoptotic genes with the Id2 pathway. Therefore, proper orchestration of TRAF6-dependent and -independent RANK signals likely establishes mammary gland formation.
Assuntos
Proliferação de Células , Células Epiteliais/metabolismo , Glândulas Mamárias Animais/metabolismo , Células-Tronco/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/transplante , Animais , Apoptose , Linhagem Celular , Ciclina D1/metabolismo , Feminino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos Endogâmicos BALB C , Camundongos Knockout , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/deficiência , Fator 6 Associado a Receptor de TNF/genéticaRESUMO
Feline calicivirus (FCV) is an important veterinary pathogen that causes acute upper respiratory tract diseases and, occasionally, highly contagious febrile hemorrhagic syndrome in cats. Many viruses have adopted mechanisms for evading IFN-α/ß signaling, particularly by directly or indirectly suppressing activation of IRF-3. In this study, we investigated whether nonstructural proteins of FCV possess these mechanisms. When p39, a nonstructural protein of FCV, was transiently expressed in 293T cells, it suppressed IFN-ß and ISG15 mRNA production induced by dsRNA. Expression of p39 also suppressed phosphorylation and dimerization of IRF-3 induced by dsRNA. These results suggest that p39 suppresses type 1 IFN production by preventing IRF-3 activation. This may become an important factor in understanding the pathogenesis and virulence of FCV.