Signal Transducers And Activators Of Transcription Transcription Factors Research Articles

Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation.

Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics.

Predicting gene-level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway integrates complex cytokine signals via a limited number of molecular components, inspiring numerous efforts to clarify the diversity and specificity of STAT transcription factor function. We developed a computational framework to make global cytokine-induced gene predictions from STAT phosphorylation dynamics, modeling macrophage responses to interleukin (IL)-6 and IL-10, which signal through common STATs, but with distinct temporal dynamics and contrasting functions. Our mechanistic-to-machine learning model identified cytokine-specific genes associated with late pSTAT3 time frames and a preferential pSTAT1 reduction upon JAK2 inhibition. We predicted and validated the impact of JAK2 inhibition on gene expression, identifying genes that were sensitive or insensitive to JAK2 variation. Thus, we successfully linked STAT signaling dynamics to gene expression to support future efforts targeting pathology-associated STAT-driven gene sets. This serves as a first step in developing multi-level prediction models to understand and perturb gene expression outputs from signaling systems. A record of this paper's transparent peer review process is included in the supplemental information.

Lung cancer treatment potential and limits associated with the STAT family of transcription factors

Lung cancer is one of the mortal cancers and the leading cause of cancer-related mortality, with a cancer survival rate of fewer than 5% in developing nations. This low survival rate can be linked to things like late-stage detection, quick postoperative recurrences in patients receiving therapy, and chemoresistance developing against various lung cancer treatments. Signal transducer and activator of transcription (STAT) family of transcription factors are involved in lung cancer cell proliferation, metastasis, immunological control, and treatment resistance. By interacting with specific DNA sequences, STAT proteins trigger the production of particular genes, which in turn result in adaptive and incredibly specific biological responses. In the human genome, seven STAT proteins have been discovered (STAT1 to STAT6, including STAT5a and STAT5b). Many external signaling proteins can activate unphosphorylated STATs (uSTATs), which are found inactively in the cytoplasm. When STAT proteins are activated, they can increase the transcription of several target genes, which leads to unchecked cellular proliferation, anti-apoptotic reactions, and angiogenesis. The effects of STAT transcription factors on lung cancer are variable; some are either pro- or anti-tumorigenic, while others maintain dual, context-dependent activities. Here, we give a succinct summary of the various functions that each member of the STAT family plays in lung cancer and go into more detail about the advantages and disadvantages of pharmacologically targeting STAT proteins and their upstream activators in the context of lung cancer treatment.

JAK inhibition in the treatment of inflammatory rheumatic diseases.

The most common immune-mediated inflammatory rheumatic diseases, rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis and have reached significant advances in recent years with the introduction of biological therapies against cytokines and immune cells, but also against intracellular enzymes, specifically Janus kinases (JAKs). Intracellular JAK signalling is activated by binding of various cytokines or growth factors to the respective cellular receptors, allowing the activation of STAT (Signal Transducers and Activators of Transcription) transcription factors and ultimately the transcription of genes with important roles during the innate and adaptive immune response. Four Janus kinases have been described: JAK1, JAK2, JAK3 and tyrosine kinase-2 (TYK2). Four JAK inhibitors (tofacitinib, baricitinib, upadacitinib and filgotinib) are currently approved for the treatment of rheumatoid arthritis, and some for the treatment of psoriatic arthritis and axial spondyloarthritis. JAK inhibitors have varying selectivity against individual kinases. Some JAK inhibitors are being tested in other rarer systemic connective tissue diseases. The general advantages of JAK inhibitors are oral administration, rapid onset of action, and efficacy in monotherapy. The safety profile of JAK inhibitors compared with biologic therapy appears to be comparable, with a higher incidence of herpes zoster, and an increased incidence of major cardiovascular disease, thromboembolic complications, and cancer in at-risk patients is discussed. The aim of this paper will be to summarize the latest findings on JAK inhibitors in approved indications for the most common rheumatic diseases.

Characterization and bioinformatics analysis of ptc-miR396g-5p in response to drought stress of Paeonia ostii.

Drought is one of the main abiotic stress factors affecting yield of Paeonia ostii. In this study, we conducted bioinformatics and differential expression analyses of P. ostii ‘Feng Dan’ ptc-miR396g-5p in leaf samples under different drought stress. ptc-miR396g-5p belongs to the miR396 family. Among the 271 plant species registered in the miRBase database, at least one miR396 member was found in 48 Angiospermae species, 3 in Gymnospermae species, and 1 in Pteridophy. Mature sequence alignment showed that P. ostii ‘Feng Dan’ ptc-miR396g-5p had high sequence similarity with miR396 from other species. Secondary structure prediction showed that the precursor sequence of ‘Feng Dan’ ptc-miR396g-5p could form a stable stem-loop structure, and the mature sequence was located on the 5′ arm of the secondary structure. Phylogenetic tree analysis showed that ‘Feng Dan’ was closely related to 20 species such as Glycine max, Medicago truncatula, Populus trichocarpa, Citrus sinensis, Vitis vinifera, and Theobroma cacao. The predicted target gene of the ‘Feng Dan’ ptc-miR396g-5p encodes a Signal Transducer and Activator of Transcription (STAT) transcription factor. The negative correlation of expression between the miRNA and its target gene was confirmed by qRT-PCR. Our data indicate that ‘Feng Dan’ ptc-miR396g-5p′s expression decreases under drought, leading to an expression increase of the STAT transcription factor.

The role of understudied post-translational modifications for the behavior and function of Signal Transducer and Activator of Transcription 3.

The Signal Transducer and Activator of Transcription (STAT) family of transcription factors is involved in inflammation, immunity, development, cancer, and response to injury, among other biological phenomena. Canonical STAT signaling is often represented as a 3-step pathway involving the sequential activation of a membrane receptor, an intermediate kinase, and a STAT transcription factor. The rate-limiting phosphorylation at a highly conserved C-terminal tyrosine residue determines the nuclear translocation and transcriptional activity of STATs. This apparent simplicity is actually misleading and can hardly explain the pleiotropic nature of STATs, the existence of various noncanonical STAT pathways, or the key role of the N-terminal domain in STAT functions. More than 80 post-translational modifications (PTMs) have been identified for STAT3, but their functions remain barely understood. Here, we provide a brief but comprehensive overview of these underexplored PTMs and their role on STAT3 canonical and noncanonical functions. A less tyrosine-centric point of view may be required to advance our understanding of STAT signaling.

Transcriptome analysis reveals modulation of the STAT family in PEDV-infected IPEC-J2 cells

BackgroundPorcine epidemic diarrhea virus (PEDV) is a causative agent of serious viral enteric disease in suckling pigs. Such diseases cause considerable economic losses in the global swine industry. Enhancing our knowledge of PEDV-induced transcriptomic responses in host cells is imperative to understanding the molecular mechanisms involved in the immune response. Here, we analyzed the transcriptomic profile of intestinal porcine epithelial cell line J2 (IPEC-J2) after infection with a classical strain of PEDV to explore the host response.ResultsIn total, 854 genes were significantly differentially expressed after PEDV infection, including 716 upregulated and 138 downregulated genes. Functional annotation analysis revealed that the differentially expressed genes were mainly enriched in the influenza A, TNF signaling, inflammatory response, cytokine receptor interaction, and other immune-related pathways. Next, the putative promoter regions of the 854 differentially expressed genes were examined for the presence of transcription factor binding sites using the MEME tool. As a result, 504 sequences (59.02%) were identified as possessing at least one binding site of signal transducer and activator of transcription (STAT), and five STAT transcription factors were significantly induced by PEDV infection. Furthermore, we revealed the regulatory network induced by STAT members in the process of PEDV infection.ConclusionOur transcriptomic analysis described the host genetic response to PEDV infection in detail in IPEC-J2 cells, and suggested that STAT transcription factors may serve as key regulators in the response to PEDV infection. These results further our understanding of the pathogenesis of PEDV.

Activation of STAT transcription factors by the Rho-family GTPases.

The Rho-family of small GTPases are biological molecular switches that are best known for their regulation of the actin cytoskeleton. Through their activation and stimulation of downstream effectors, the Rho-family control pathways involved in cellular morphology, which are commonly activated in cancer cell invasion and metastasis. While this makes them excellent potential therapeutic targets, a deeper understanding of the downstream signalling pathways they influence will be required for successful drug targeting. Signal transducers and activators of transcription (STATs) are a family of transcription factors that are hyper-activated in most cancer types and while STATs are widely understood to be activated by the JAK family of kinases, many additional activators have been discovered. A growing number of examples of Rho-family driven STAT activation, largely of the oncogenic family members, STAT3 and STAT5, are being identified. Cdc42, Rac1, RhoA, RhoC and RhoH have all been implicated in STAT activation, contributing to Rho GTPase-driven changes in cellular morphology that lead to cell proliferation, invasion and metastasis. This highlights the importance and therapeutic potential of the Rho-family as regulators of non-canonical activation of STAT signalling.

Assessing Phosphorylation of STAT Transcription Factors in Mouse Innate Lymphoid Cells.

Innate lymphoid cells (ILCs) ensure protection against pathogens by quickly reacting to the alterations of the cytokine milieu taking place upon infection. More than 50 cytokines and growth factors activate the Janus kinases (JAKs), leading to phosphorylation of members of the signal transducer and activator of transcription (STAT) family. Activation of STATs induces specific transcriptional programs which are associated with distinct cellular outcomes. Thus, an efficient measurement of rapid STAT phosphorylation enables not only to dissect the spectrum of cytokine sensitivity among ILC subsets but also to pinpoint specific transcriptional programs and cellular functions initiated after activation. Using this method, we have previously dissected the downstream events of Interleukin (IL)-23 and IL-12 signaling in ILCs, shedding light on the differential usage of STATs among ILC subsets. Here, we provide an optimized and detailed protocol describing how to analyze phosphorylation of STAT transcription factors in murine NK and ILC subsets isolated from different tissues.

Effect of pyruvate peritoneal resuscitation on JAK/STAT signaling pathway in intestinal tissues of rats with hemorrhagic shock

Objective To evaluate the effect of pyruvate peritoneal resuscitation on Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway in intestinal tissues of rats with hemorrhagic shock. Methods Twenty-four healthy male Sprague-Dawley rats, weighing 200-300 g, were divided into 3 groups (n=8 each) using a random number table method: sham operation group (S group), intravenous resuscitation group (VR group), and peritoneal resuscitation with pyruvate group (PY group). Hemorrhagic shock was induced by blood-letting and infusing blood withdrawn with mean arterial pressure reduced to 30-40 mmHg for 60 min in pentobarbital-anesthetized rats.Hemorrhagic shock was resuscitated with autologous blood and normal saline 2 times the volume of blood withdrawn at the end of hemorrhagic shock in group VR.Pyruvate was intraperitoneally infused for 30 min using a micro-perfusion pump simultaneously with the intravenous resuscitation in group PY.The animals were sacrificed at 2 h after resuscitation, and intestinal tissues were obtained for determination of malondialdehyde (MDA) content (by thiobarbituric acid method), superoxide dismutase (SOD) activity (using xanthine oxidase method), myeloperoxidase (MPO) activity (using chemical colorimetry), and expression of phosphorylated STAT3 (p-STAT3), phosphorylated JAK2 (p-JAK2) and caspase-3 expression (by Western blot). Results Compared with group S, the MDA content and MPO activity were significantly increased, the SOD activity was decreased, and the expression of p-STAT3, p-JAK2 and caspase-3 was up-regulated in the other two groups (P<0.05). Compared with group VR, the MDA content and MPO activity were significantly decreased, the SOD activity was increased, and the expression of p-STAT3, p-JAK2 and caspase-3 was down-regulated in group PY (P<0.05). Conclusion The mechanism by which peritoneal resuscitation with pyruvate mitigates intestinal damage may be related to inhibiting activation of JAK/STAT signaling pathway in the rats with hemorrhagic shock. Key words: Pyruvic acid; Resuscitation; Shock, hemorrhagic; Intestines; Janus kinases; STAT transcription factors

Ikaros zinc finger transcription factors as novel regulators of STAT factor activity

Abstract Cytokine signaling is important for the differentiation and function of a number of cell types, including lymphocyte populations. One mechanism by which cytokine signals are propagated is via phosphorylation-mediated activation of Signal Transducer and Activator of Transcription (STAT) factors, which directly regulate cell type-specific gene programs. We recently identified novel regulatory modules composed of STAT and Ikaros Zinc Finger (IkZF) transcription factors in CD4+ T cell populations. Specifically, we found that IkZF/STAT modules composed of Aiolos/STAT3 and Eos/STAT5 directly activate genes associated with T follicular helper (TFH) and T helper 1 (TH1) gene programs, respectively. Here, we extend these findings and show that IkZF factor expression correlates with STAT activation, suggesting that IkZF proteins may regulate STAT factor activity in CD4+ T cells. We find that overexpression of Aiolos, but not the IkZF factors Ikaros and Eos, results in increased STAT3 activation. Conversely, overexpression of Eos, but not Ikaros or Aiolos, results in increased activation of STAT5. Importantly, when we performed these studies using IkZF protein mutants incapable of interacting with STAT factors, the observed increase in STAT factor phosphorylation was lost. We also find that in CD4+ T cells, Eos deficiency correlates with reduced STAT5 activation, while Aiolos-deficient cells display reduced STAT3 activation. Finally, we observe differential IkZF factor expression across CD4+ T cell subsets. When coupled with known differences in STAT factor activation, these findings suggest that IkZF/STAT regulatory modules may broadly regulate T helper cell differentiation.

IRF and STAT Transcription Factors - From Basic Biology to Roles in Infection, Protective Immunity, and Primary Immunodeficiencies.

The induction and action of type I interferon (IFN) is of fundamental importance in human immune defenses toward microbial pathogens, particularly viruses. Basic discoveries within the molecular and cellular signaling pathways regulating type I IFN induction and downstream actions have shown the essential role of the IFN regulatory factor (IRF) and the signal transducer and activator of transcription (STAT) families, respectively. However, the exact biological and immunological functions of these factors have been most clearly revealed through the study of inborn errors of immunity and the resultant infectious phenotypes in humans. The spectrum of human inborn errors of immunity caused by mutations in IRFs and STATs has proven very diverse. These diseases encompass herpes simplex encephalitis (HSE) and severe influenza in IRF3- and IRF7/IRF9 deficiency, respectively. They also include Mendelian susceptibility to mycobacterial infection (MSMD) in STAT1 deficiency, through disseminated measles infection associated with STAT2 deficiency, and finally staphylococcal abscesses and chronic mucocutaneous candidiasis (CMC) classically described with Hyper-IgE syndrome (HIES) in the case of STAT3 deficiency. More recently, increasing focus has been on aspects of autoimmunity and autoinflammation playing an important part in many primary immunodeficiency diseases (PID)s, as exemplified by STAT1 gain-of-function causing CMC and autoimmune thyroiditis, as well as a recently described autoinflammatory syndrome with hypogammaglobulinemia and lymphoproliferation as a result of STAT3 gain-of-function. Here I review the infectious, inflammatory, and autoimmune disorders arising from mutations in IRF and STAT transcription factors in humans, highlightning the underlying molecular mechanisms and immunopathogenesis as well as the clinical/therapeutic perspectives of these new insights.

The Activity of JAK/STAT and NF-κB in Patients with Rheumatoid Arthritis.

Research is still being conducted in order to determine the mechanisms responsible for the initiation of rheumatoid arthritis (RA) as well as for its persistence and progression. The aim of this work was to establish the expression of the signal transducer and activator of transcription (STAT) transcription factors and the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) transcription factor in peripheral blood leukocytes and synovial fluid cells. The correlations between the activation level of the transcription factors and the activity of the disease were also analyzed. In total, the study included 34 RA patients and 19 healthy individuals as controls. The expression of NFκB, STAT1, STAT3, STAT4, STAT5 and STAT6 in peripheral blood leukocytes and synovial fluid cells was established. The immunocytochemistry method was used to determine the degree of activation of STAT and NF-κB transcription factors. For the location of the factors, primary polyclonal anti-STATs and monoclonal anti-NF-κB antibodies were used. The expression of STAT1, STAT3, STAT4, STAT5, STAT6 and NFκB was significantly higher in the group of RA patients than in the controls. No statistically significant differences were found between the expression of STATs in peripheral blood leukocytes and synovial fluid cells. In comparison with the control group, the expression of the STAT and NFκB transcription factors in RA patients was higher, which may be helpful in better understanding the etiopathogenesis of the disease in the future, and may potentially have important therapeutic implications.

GPx2 Induction Is Mediated Through STAT Transcription Factors During Acute Colitis.

The selenoprotein glutathione peroxidase 2 (GPx2) is highly expressed in the gastrointestinal epithelium. During inflammatory bowel disease and colorectal cancer, GPx2 expression is enhanced. We analyzed GPx2 expression and transcriptional regulation during the different phases of dextran sulfate sodium (DSS)-induced colitis in mice and in cytokine-treated colorectal cancer cells. In the colon of DSS-treated mice, GPx2 was upregulated during the acute and recovery phase. In the latter, it was specifically localized in regenerating ki67-positive crypts next to ulcerations. In cultured cells, endogenous GPx2 expression and GPx2 promoter activity were enhanced by the anti-inflammatory mediators 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) and interleukin-22 (IL-22), while it was unaffected by classical proinflammatory cytokines like IL-1β. Induction of GPx2 expression by 15d-PGJ2 was mediated through Nrf2. In contrast, in DSS-treated Nrf2-KO mice GPx2 expression remained upregulated during recovery, which appeared to be independent of Nrf2. IL-22 activates transcription factors of the signal transducers and activators of transcription (STAT) family. Therefore, we analyzed the GPx2 promoter for putative STAT-responsive elements and identified 4 of them. Point mutation of the binding element next to the transcription start completely abolished promoter activation after IL-22 treatment and after cotransfection of STAT expression plasmids. To show in vivo relevance of the obtained results, we performed immunohistochemistry for phospho-STAT3 and GPx2. Especially during acute colitis, GPx2 and nuclear STAT3 colocalized in inflamed areas. GPx2 is a novel target of STAT transcription factors. The upregulation of GPx2 by IL-22 indicates that GPx2 might be important for the resolution of inflammation.

Mutations leading to constitutive active gp130/JAK1/STAT3 pathway

Constitutive activation of STAT (Signal Transducer and Activator of Transcription) transcription factors is a common feature identified in numerous tumors. Inflammatory hepatocellular adenomas (IHCA) are benign liver tumors characterized by an inflammatory phenotype and an overexpression of STAT3 target genes. Recurrent somatic mutations in major actors belonging to the IL6/JAK/STAT3 pathway have been identified in these tumors. (1) 60% of IHCA show IL-6 signal transducer (IL6ST; gp130) mutations; (2) 10% harbor mutations of the Fyn-related kinase FRK; (3) 5% harbor mutations in STAT3; (4) 5% harbor somatic mutations in the GNAS complex locus; and (5) 1% of IHCA harbor mutations in the Janus kinase 1 (JAK1). All these IHCA-associated mutations promote the constitutive activation of STAT3. In this review, we discuss the role of these mutated genes in IHCA and other tumors.

Mechanism of activation of protein kinase JAK2 by the growth hormone receptor.

Signaling from JAK (Janus kinase) protein kinases to STAT (signal transducers and activators of transcription) transcription factors is key to many aspects of biology and medicine, yet the mechanism by which cytokine receptors initiate signaling is enigmatic. We present a complete mechanistic model for activation of receptor-bound JAK2, based on an archetypal cytokine receptor, the growth hormone receptor. For this, we used fluorescence resonance energy transfer to monitor positioning of the JAK2 binding motif in the receptor dimer, substitution of the receptor extracellular domains with Jun zippers to control the position of its transmembrane (TM) helices, atomistic modeling of TM helix movements, and docking of the crystal structures of the JAK2 kinase and its inhibitory pseudokinase domain with an opposing kinase-pseudokinase domain pair. Activation of the receptor dimer induced a separation of its JAK2 binding motifs, driven by a ligand-induced transition from a parallel TM helix pair to a left-handed crossover arrangement. This separation leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation. This model may well generalize to other class I cytokine receptors.

Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation

STAT (Signal Transducer and Activator of Transcription) transcription factors are constitutively activated in most hematopoietic cancers. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. miR-28 exerts negative effects on thrombopoietin receptor signaling and platelet formation. Here, we demonstrate that, in transformed hematopoietic cells, STAT5 and p53 must be synergistically bound to chromatin for induction of LPP/miR-28 transcription. Genome-wide association studies show that both STAT5 and p53 are co-localized on the chromatin at 463 genomic positions in proximal promoters. Chromatin binding of p53 is dependent on persistent STAT5 activation at these proximal promoters. The transcriptional activity of selected promoters bound by STAT5 and p53 was significantly changed upon STAT5 or p53 inhibition. Abnormal expression of several STAT5-p53 target genes (LEP, ATP5J, GTF2A2, VEGFC, NPY1R and NPY5R) is frequently detected in platelets of myeloproliferative neoplasm (MPN) patients, but not in platelets from healthy controls. In conclusion, persistently active STAT5 can recruit normal p53, like in the case of MPN cells, but also p53 mutants, such as p53 M133K in human erythroleukemia cells, leading to pathologic gene expression that differs from canonical STAT5 or p53 transcriptional programs.

The effects of erythropoietin on STAT1 and STAT3 levels following cerebral ischemia-reperfusion in rats

Objective To explore the effects of erythropoietin （EPO） on the expression of signal transducer and activator of transcription （STAT） 1, phosphorylated STAT1 （ P-STAT1 ）, STAT3, P-STAT3 and cell apoptosis in rat models of focal cerebral ischemia-reperfusion. Methods Eighty male Sprague- Dawley rats were randomly and evenly divided into four groups by completely random design method： shamoperation （group A ）, cerebral isehemia-reperfusion （group B ）, cerebral ischemia-reperfusion ＋ saline （group C） and cerebral ischemia-reperfusion ＋ EPO （group D）. The model of focal cerebral ischemiareperfusion injury was established by blocking the left middle cerebral artery. All rats underwent MRI for the detection of the changes of infarct area between 2 h post ischemia and 24 h of reperfusion. Western blot was used to observe the expression of STAT1, P-STAT1, STAT3, P-STAT3. Terminal oxynucleotidyl transferase mediated dUTP biotin nick end labeling （TUNEL） was used to evaluate the cell apoptosis including the relative area （ ROI area/whole brain area of the same layer x 100% ） of abnormal signal region, relative optical density （rOD） and apoptotic index. One-way analysis of variance and q test were used to analyze the data. Results On T2WI imaging, rats in group B and group C presented large hyperintense areas in the cortex and subcortex of left hemispheric （ （28.00±4.60） % and （29.70±4.80） % respectively）. Group D presented less hyperintense areas in the cortex and subcortex of left hemispheric compared with group B and group C （（21.10±2. 40）%; F= 11.285, P〈0.01 ）. The expression of STAT1 and STAT3 proteins was not significandy affected by ischemia-reperfusion and EPO intervention compared with normal brain tissue （ F= 0.806, 1.558, both P〉0.05）. However, the level of P-STAT1 was low in group A （rOD = 0.75±0.13） but increased after cerebral ischemia-reperfusion. Compared with group B and group C, P-STAT1 expression was lower in group D （B-D： 2. 08±0.15, 2.05±0.16, 1.92±0.05; F= 3.274, P〉0.05）. The level of P-STAT3 was also low in group A （rOD= 1.02＋0.09）. Compared with group B and group C, P-STAT3 expression in group D was significantly higher （ B- D ： 2.22 ± 0.13, 2.04 ± 0.14, 4.21± 0.21 ; F = 40.719, P 〈 0.01 ）. The apoptotic index of group B and group C was （42.00±1.30）% and （41.20±2.50）%, respectively, which was significantly higher than that of group D （ （20. 90±1.46）%; F= 378.704, P〈0.01 ）. Conclusion Intraperitoneal injection of EPO can reduce the cerebral ischemic area and the number of apoptotic cells in the ischemic penumbra in rat ischemia-reperfusion models through increasing P-STAT3 and decreasing P-STAT1 levels. Key words: Cerebral ischemia; Reperfusion; STAT transcription factors; Erythropoietin; Magnetic resonance imaging; Rats

The role of a non-canonical JAK-STAT pathway in IFN therapy of poxvirus infection and multiple sclerosis: An example of Occam's Broom?

Signaling by cytokines such as the interferons (IFNs) involves Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) transcription factors. The beauty of the classical model of JAK-STAT signaling is its simplicity in that JAK-activated STATs in the nucleus are responsible for specific gene activation. The fact that many ligands, growth factors, and hormones use the same STAT transcription factors, but exert different functions at the level of the cell, tissue, and organ would suggest significant shortcomings in the classical model. Our studies have resulted in the development of a non-canonical, more complex model of IFN signaling that bears a striking resemblance to that of steroid hormone (SH)/steroid receptor (SR) signaling. Thus, both types I and II IFN signaling involves nuclear translocation of complexed ligand, receptor, activated JAKs, and activated STATs to the promoters of the genes that are specifically activated by the IFNs, where they are involved in specific gene activation and epigenetic remodeling. Receptor intracellular domains play an important role in binding the C-terminus of the IFNs, which is the basis for our development of IFN mimetics. The IFN mimetics are not recognized by poxvirus decoy receptors, since the decoy receptors compete for extracellular binding and not intracellular binding. Further, the type I IFN mimetics provide therapeutic protection against experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis, without the side effects. Extracellular receptor binding by intact IFN is the primary reason for undesirable side effects of flu-like symptoms, bone-marrow suppression, and weight loss. The non-canonical model of IFN signaling thus provides insight into the specificity of such signaling and a mechanism for development of IFN mimetics. It is our contention that this model applies to other cytokines.

STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

Signal transducer and activator of transcription (STAT) proteins comprise a family of transcription factors that are activated by cytokines, hormones and growth factors. The activation of STAT proteins plays a key role in the production of mature hematopoietic cells via effects on cellular proliferation, survival and lineage-specific differentiation. Emerging evidence also demonstrates frequent, constitutive activation of STATs in primary leukemia specimens. Moreover, roles for STATs in promoting leukemia development have been delineated in numerous preclinical studies. This review summarizes our current understanding of STAT protein involvement in normal hematopoiesis and leukemogenesis, as well as recent advances in the development and testing of novel STAT inhibitors.