Signal Activator Of Transcription Research Articles

Perturbed IFN-γ-Jak-Signal Transducers and Activators of Transcription Signaling in Tuberous Sclerosis Mouse Models

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by widespread development of hamartomas, which is caused by mutations in either TSC1 or TSC2. We demonstrate a dramatic decrease of IFN-gamma expression in tumors and mouse embryo fibroblast cell lines that lack either Tsc1 or Tsc2, which is reversed by rapamycin (mammalian target of rapamycin inhibitor) therapy. Increased signal transducers and activators of transcription (STAT) 1 expression and phosphorylation at Ser 727 and increased pSTAT3 Tyr705 levels also are seen in Tsc1 null and Tsc2 null cells and in tumors. Treatment of Tsc1 or Tsc2 null cells with IFN-gamma induces apoptosis, in contrast to control cell lines, with reduction in pSTAT3 Tyr705 levels and major increases in pSTAT1 Tyr701, bax, and caspase-1 and -9 levels. A combination of IFN-gamma and rapamycin is markedly synergistic in induction of apoptosis in Tsc1 or Tsc2 null cells because pSTAT3 Tyr705 phosphorylation is abolished completely and the other effects of IFN-gamma are maintained or enhanced. Rapamycin-IFN-gamma has unique potential therapeutic benefit for management of TSC tumors.

Endostatin's Signaling Network

Endostatin is an endogenous antiangiogenic peptide that inhibits endothelial cell proliferation, migration, and tube formation. Abdollahi et al. performed cDNA and antibody microarray analysis along with selected Western blotting and immunocytochemistry to show that endostatin regulates multiple pathways in human dermal microvascular endothelial cells that converge to produce the antiangiogenic effect. At the level of gene expression, endostatin regulated ~12% of the genome, with genes associated with promotion of angiogenesis generally being down-regulated and genes associated with stress responses being up-regulated. The antibody arrays showed that for many of the pathways, the phosphorylation status of individual proteins was altered by endostatin treatment. Eight signaling cascades that were down-regulated by endostatin treatment were investigated in more detail: Id signaling and activator protein 1 signaling (cell proliferation), hypoxia inducible factor 1α signaling (low oxygen and metabolic adaptation), ephrin and tumor necrosis factor α signaling (cell migration), nuclear factor κB (proliferation and antiapoptosis), signal transducer and activator of transcription signaling (regulator of proliferation and migration), Ets (migration and antiapoptosis), coagulation cascades, and adhesion molecules pathways. These results identify several new pathways regulated by endostatin and present a picture of a complex network of responses that contribute to the antiangiogenic activity of a single ligand. A, Abdollahi, P. Hahnfeldt, C. Maercker, H.-J. Gröne, J. Debus, W. Ansorge, J. Folkman, L. Hlatky, P. E. Huber, Endostatin's antiangiogenic signaling network. Mol. Cell 13 , 649-663 (2004). [Online Journal]

Distinct components of Janus kinase/signal transducer and activator of transcription signaling pathway mediate the regulation of systemic and tissue localized renin-angiotensin system.

In an attempt to demonstrate the linkage between the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) signaling and the activity of the systemic or local renin-angiotensin system in vivo, we produced transgenic mice harboring angiotensinogen (ANG) promoter containing the wild-type or mutant STAT target site (St-domain) fused to the luciferase reporter. The ANG-promoter-driven luciferase expression was dependent upon phosphorylation of Jak2, as administration of tyrphostin AG490, a potent inhibitor of Jak2, down-regulated the ANG promoter activity and abolished the stimulated endogenous ANG mRNA level in the liver. Administration of angiotensin II peptide to the mice resulted in prominent expression of luciferase in the liver and heart of animals containing wild type St-domain, but not in transgenes with mutant St-domain. Angiotensin II-induced signaling caused activation of STAT proteins in the liver (systemic), the pattern of which was distinct from that in the heart (local). The inducible expression of ANG promoter appears to be mediated by physical association of p300 with STAT 5B in liver and STAT 3 and STAT 5A in heart. Taken together, these results point to the differences in signaling mechanisms in the circulating and localized renin-angiotensin system and identify at least two molecular steps, the tyrosyl phosphorylation of Jak2 and the STAT/St-domain interaction, as pivotal in the regulation of ANG gene transcription.

A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production.

Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3+/− mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon γ and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.