Signal Transducer And Activator Of Transcription Inhibitor Research Articles

Cloning and analysis of a murine PIAS family member, PIASgamma, in developing skin and neurons.

Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic transcription factors that become activated in response to stimulation by various cytokines. Recently a new family of five structurally related proteins, called PIAS (Protein Inhibitor of Activated STAT) has been identified as potentially important downregulators of this pathway. Members of the PIAS family of STAT inhibitors may play a prominent role in the downregulation of STAT-mediated signaling processes. In this article we describe the isolation of the cDNA and expression of the gene for the murine homologue of the human STAT inhibitor family member PIASgamma. The cDNA for mPIASgamma encodes a protein of 507 amino acids that is highly homologous to the human protein and is expressed in the mouse as early as d 7.5 of gestation. In situ hybridizations of staged mouse embryos localized the transcript for the PIASgamma gene to the limbs, neuroepithelium, and the inner root sheath of the hair follicle, suggesting a role in the development of these structures. Immunostaining studies with a polyclonal antibody (PAb) recognizing human PIASgamma localized the protein in the hair follicle of human scalp hair and in monkey neuronal cells. Thus PIASgamma exhibits a highly selective pattern of expression, suggesting that it modulates the response of cells to developmental cues.

The Jak-Stat Pathway: Cytokine Signalling from the Receptor to the Nucleus

The Jak-STAT pathway was originally discovered through the study of interferon induced intracellular signal transduction. Meanwhile, a large number of cytokines, hormones and growth factors have been found to activate Jaks and STATs. Jaks (Janus Kinases) are a unique class of tyrosine kinases that associate with cytokine receptors. Upon ligand binding, they activate members of the Signal Transducers and Activators of Transcription (STAT) family through phosphorylation on a single tyrosine. Activated STATs form dimers, translocate to the nucleus, bind to specific response elements in promotors of target genes, and transcriptionally activate these genes. Both positive and negative regulations of the Jak-STAT pathway have been identified. In a positive feedback loop, interferons transcriptionally activate the genes for components of the interferon stimulated gene factor 3 (ISGF3). A number of cytokines that activate the Jak-STAT pathway, e.g. IL-6, IL-4, LIF, G-CSF, have been shown to upregulate the expression of SOCS-JABs-SSIs, a recently discovered class of STAT inhibitors. Targeted disruption of genes for a number of Jaks and STATs in mice have revealed specific biological functions for many of them. Although most of the STATs are activated in cell culture by many different ligands, STAT knockout mice mostly show defects in a single or a few cytokine dependent processes. STAT1 knockout mice have an impaired interferon signalling, STAT4 knockouts impaired IL-12 signalling, STAT5a knockouts impaired prolactin signalling, STAT5b knockouts impaired growth hormone signalling, and STAT6 knockout impaired IL-4 and IL-13 signalling. Defects in the Jak-STAT pathway have already been identified in a number of human diseases. Prominent amongst them are leukaemias, lymphomas and inherited immunodeficiency syndromes. It can be expected that additional Jak-STAT related diseases will be identified over the next years. To date, specific STAT inhibitory drugs are not known, but a number of specific protein-protein interactions in the Jak-STAT pathway are potential targets for pharmaceutical interventions.

Three distinct domains of SSI-1/SOCS-1/JAB protein are required for its suppression of interleukin 6 signaling.

Cytokine-inducible protein SSI-1 [signal transducers and activators of transcription (STAT)-induced STAT inhibitor 1, also referred to as SOCS-1 (suppressor of cytokine signaling 1) or JAB (Janus kinase-binding protein)] negatively regulates cytokine receptor signaling by inhibition of JAK kinases. The SSI family of proteins includes eight members that are structurally characterized by an SH2 domain and a C-terminal conserved region that we have called the SC-motif. In this study, we investigated the roles of these domains in the function of SSI-1. Results of reporter assays demonstrated that the pre-SH2 domain (24 aa in front of the SH2 domain) and the SH2 domain of SSI-1 were required for the suppression by SSI-1 of interleukin 6 signaling. Coexpression studies of COS7 cells revealed that these domains also were required for inhibition of three JAKs (JAK1, JAK2, and TYK2). Furthermore, deletion of the SH2 domain, but not the pre-SH2 domain, resulted in loss of association of SSI-1 with TYK2. Thus, SSI-1 associates with JAK family kinase via its SH2 domain, and the pre-SH2 domain is required for the function of SSI-1. Deletion of the SC-motif markedly reduced expression of SSI-1 protein in M1 cells, and this reduction was reversed by treatment with proteasome inhibitors, suggesting that this motif is required to protect the SSI-1 molecule from proteolytic degradation. Based on these findings, we concluded that three distinct domains of SSI-1 (the pre-SH2 domain, the SH2 domain, and the SC-motif) cooperate in the suppression of interleukin 6 signaling.