RESUMO
Studies of SOCS-1-deficient mice have implicated Socs-1 in the suppression of JAK-STAT (Janus tyrosine kinase-signal transducers and activators of transcription) signaling and T cell development. It has been suggested that the levels of Socs-1 protein may be regulated through the proteasome pathway. Here we show that Socs-1 interacts with members of the Pim family of serine/threonine kinases in thymocytes. Coexpression of the Pim kinases with Socs-1 results in phosphorylation and stabilization of the Socs-1 protein. The protein levels of Socs-1 are significantly reduced in the Pim-1(-/-), Pim-2(-/-) mice as compared with wild-type mice. Similar to Socs-1(-/-) mice, thymocytes from Pim-1(-/-), Pim-2(-/-) mice showed prolonged Stat6 phosphorylation upon IL-4 stimulation. These data suggest that the Pim kinases may regulate cytokine-induced JAK-STAT signaling through modulation of Socs-1 protein levels.
Assuntos
Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Repressoras , Animais , Linhagem Celular , Clonagem Molecular , DNA Complementar/metabolismo , Biblioteca Gênica , Glutationa Transferase/metabolismo , Humanos , Interleucina-4/metabolismo , Luciferases/metabolismo , Camundongos , Fosforilação , Plasmídeos , Testes de Precipitina , Ligação Proteica , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-pim-1 , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Fator de Transcrição STAT6 , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina , Timo/citologia , Timo/metabolismo , Fatores de Tempo , Transativadores/metabolismo , Transfecção , Técnicas do Sistema de Duplo-HíbridoRESUMO
STAT6 plays an important role in IL-4-mediated B cell activation and differentiation. To identify primary and secondary target genes of STAT6, gene expression profiles of IL-4-stimulated B cells from STAT6+/+ vs STAT6-/- mice were compared. Statistical analysis revealed that 106 distinct probe sets including 70 known genes were differentially expressed between the 2 genotypes. These genes include transcription factors, kinases, and other enzymes, cell surface receptors, and Ig H chains. Surprisingly, although 31 genes were expressed at higher levels in STAT6+/+ B cells, 39 genes were expressed at higher abundance in STAT6-/- B cells. This result implies both positive and negative regulatory functions of STAT6 in IL-4-mediated gene expression. Furthermore, IL-4 induces expression of the transcription factor Krox20, which is required for maximal IL-4-induced transcription.