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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have indicated that serine phosphorylation regulates the activities of STAT1 and STAT3. However, the kinase(s) responsible and the role of serine phosphorylation in STAT function remain unresolved. In the present studies, we examined the growth factor-dependent serine phosphorylation of STAT1 and STAT3. We provide in vitro and in vivo evidence that the ERK family of mitogen-activated protein (MAP) kinases, but not JNK or p38, specifically phosphorylate STAT3 at serine 727 in response to growth factors. Evidence for additional mitogen-regulated serine phosphorylation is also provided. STAT1 is a relatively poor substrate for all MAP kinases tested both in vitro and in vivo. STAT3 serine phosphorylation, not its tyrosine phosphorylation, results in retarded mobility of the STAT3 protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Importantly, serine 727 phosphorylation negatively modulates STAT3 tyrosine phosphorylation, which is required for dimer formation, nuclear translocation, and the DNA binding activity of this transcriptional regulator. Interestingly, the cytokine interleukin-6 also stimulates STAT3 serine phosphorylation, but in contrast to growth factors, this occurs by an ERK-independent process.
Mol Cell Biol 1997 Nov
PMID:STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. 934 14

Local oestrogen biosynthesis within the breast can be highly variable, in vitro aromatase activity both in breast cancers and mammary adipose tissue displaying over a 40-fold range between the highest and lowest levels. Evidence is presented to show that: (i) transcriptional activity may influence oestrogen biosynthesis within breast cancers in that both aromatase mRNA and STAT nuclear binding are correlated positively to in vitro aromatase activity; (ii) the local presence of cancer may enhance aromatase activity in particulate fractions and primary fibroblast cultures from mammary adipose tissue; (iii) tumour extracts and breast cyst fluids may induce aromatase in cultured fibroblasts, the active principles responsible for these effects being incompletely defined (although the combination of interleukin (IL)-6 and its soluble receptor dramatically enhances aromatase activity, it is unclear whether this particular cytokine system can account for the stimulatory effects of breast extracts and fluids); (iv) the aromatase activities in both breast cancer and adipose tissues are susceptible to classical aromatase inhibitors such as aminoglutethimide and 4-hydroxyandrostenedione (and to newer inhibitors such as CGS16949 and CGS20267 at low nanomolar concentrations) but reduced sensitivity to 4-hydroxyandrostenedione may be observed in certain breast cancers. These findings may have important implications for the development and progression of hormone-dependent cancers within the breast.
J Steroid Biochem Mol Biol 1997 Apr
PMID:Regulation of aromatase activity within the breast. 936 90

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular cellular growth in humans and other species. This system, which has been conserved throughout evolution, plays an important role in cardiac and vascular pathology associated with hypertension, coronary heart disease, myocarditis and congestive heart failure. The traditional RAS is viewed as a system in which circulating Ang II is delivered to target organs and cells. However, in the past decade, a local RAS has been described in cardiac cells, providing evidence for autocrine and paracrine pathways by which biological actions of Ang II could be mediated. The critical actions of Ang II are mediated primarily through the AT1, G-protein (guanylyl nucleotide binding protein) coupled receptor. In addition to coupling to conventional G-protein signal transduction pathways, the AT1 receptor was recently shown to increase the tyrosine phosphorylation of several intracellular substrates, including the STAT (Signal Transducers and Activators of Transcription) family of novel transcription factors, in rat cardiac fibroblasts, myocytes and vascular smooth muscle cells, and AT1 receptor transfected CHO cells. It has been shown that Ang II stimulates the tyrosine phosphorylation and nuclear translocation of Stat1 (Stat 91) and Stat3 (Stat 92). Angiotensin II acting directly through the AT1 receptor, induces the formation of a complex of STAT proteins termed SIF (sis-inducing factor) which binds the DNA sequence, SIE (sis-inducing element) present in the promotor element of many genes. This provides evidence for a direct role of Ang II in mediating inflammatory and remodeling responses through the JAK-STAT pathway. Thus, it is likely that the JAK-STAT pathway has an important role in Ang II-mediated effects on gene transcription, cardiac and vascular cellular growth/development, and inflammatory responses.
J Mol Cell Cardiol 1997 Nov
PMID:Molecular mechanisms of angiotensin II in modulating cardiac function: intracardiac effects and signal transduction pathways. 940 64

Guinea pig bone marrow megakaryocytes were isolated and cultured on collagen gels to promote proplatelet formation. In control cultures 15.6% of the cells formed proplatelets. Both IL6 and TPO stimulated dose dependent increases in the percent of proplatelet forming cells up to 26.7% at 100ng/mal IL6 and 26.8% at 100 ng/ml TPO. IL1 and IL3 had no effect on proplatelet formation. IL3 in combination with IL6 and TPO blocked the increase in proplatelet formation observed with IL6 or TPO alone. IL3 was also found to stimulate thymidine incorporation in megakaryocytes. The role of phosphorylation in proplatelet formation was studied using certain inhibitors. The tyrosine kinase inhibitor genestien had no effect on proplatelet formation at concentrations up to 100 microg/ml. The phosphatase inhibitors calyculin A and okadaic acid both inhibited proplatelet formation. Studies on protein phosphorylation revealed that IL6, but not TPO, stimulated phosphorylation of JAK1, JAK2 and MAP kinase. TPO did stimulate tyrosine phosphorylation of Tyk-2. Although IBMX stimulated proplatelet formation, it inhibited phosphorylation of JAK1 and MAP kinase. Adhesion of megakaryocytes to collagen gel also inhibited phosphorylation of JAK1 and JAK2, while MAP kinase phosphorylation was unaffected. These data show that IL6 and TPO stimulate megakaryocyte proplatelet formation. In addition, although these cytokines increase phosphorylation of signal transduction proteins in the JAK/STAT pathway, it appears that a different signal transduction pathway regulated by a combination of phosphatase activity and cAMP levels, leads to proplatelet formation.
Blood Cells Mol Dis 1997 Aug
PMID:Effect of recombinant interleukin-6 and thrombopoietin on isolated guinea pig bone marrow megakaryocyte protein phosphorylation and proplatelet formation. 941 Apr 69

Eosinophils are potent effector cells contributing to allergic inflammation and asthma. The differentiation, recruitment, and effector functions of eosinophils are greatly affected by interleukin (IL)-5. In the eosinophil, signal transduction pathways including Jak-STAT and Ras-Raf-MAP kinase are stimulated by IL-5 and enzymatic activation of tyrosine kinases Jak-2 and Lyn has been demonstrated. The participation of adapter proteins in the responses of the Ras-Raf-MAP kinase pathway has been documented in many cytokine family receptors but the expression and activation of these proteins have not been demonstrated in eosinophils. In these studies, we have found three isoforms of the adapter protein, Shc, to be expressed in eosinophils. One of these isoforms, p52 Shc, was tyrosine phosphorylated following IL-5 treatment of eosinophils. A second adapter protein, Grb2, coimmunoprecipitated with Shc following IL-5 stimulation of eosinophils. Furthermore, p52 Shc was increasingly associated with a cell fraction resistant to detergent solubilization, following IL-5 administration. This cell fraction of limited detergent solubility is a complex mixture of proteins and the adapter protein Grb2, the tyrosine kinases Jak-2 and Lyn, the nucleotide exchange factor Vav, and the serine-threonine kinases p45 MAP kinase, Raf-1, and PKCbeta, were distributed either wholly or partially in the same fraction, as were the cytoskeletal proteins actin and vimentin. Only p52 Shc, however, demonstrated discernibly increased association with this fraction following IL-5 stimulation of eosinophils. These data suggest that IL-5 activates a signal transduction pathway utilizing the adapter proteins Shc and Grb2 in the human eosinophil.
Am J Respir Cell Mol Biol 1998 Jan
PMID:Interleukin 5 signals through Shc and Grb2 in human eosinophils. 944 48

Although peripheral blood and bone marrow are usually readily available from patients, present techniques of RNA extraction are tedious, require millilitres of starting material and removal of red blood cells before RNA purification. Further, successful reverse transcriptase polymerase chain reaction (RT-PCR) amplification requires the removal of haemoglobin derivatives which interfere with the PCR process. Recently, one step rapid use reagents have become available, claiming to be useful for obtaining high quality RNA from microlitre quantities of whole blood drawn directly from the patient. Their use to date in clinical samples appears limited with little information in the literature documented. In an attempt to overcome this, we tested the Trizol-LS, RNA-STAT-50 and Ultraspec-3 reagents upon a statistically significant number of clinical isolates of fresh and cryopreserved peripheral blood, bone marrow, blood apheresis products and a breast cancer cell line (MCF7) in order to evaluate whether these methods could be applied to routine laboratory use in an RT-PCR method capable of detecting rare gene expression. Our findings showed that there was some variation in the quality of RNA extracted which was indicated by absorbance spectrophotometry at 260 and 280 nm. 1% agarose gel electrophoresis showed that each of these methods could yield total RNA capable of generating the signature 18S and 28S rRNA bands. Using the Kruskal-Wallis non-parametric anova test combined with Dunn's multiple comparison test, the only statistically significant difference (p<0.05) indicated that Trizol-LS was more reliable than RNA-STAT-50-LS and Ultraspec-3 at extracting RNA from fresh peripheral blood. RNA extracted with the Trizol-LS and RNA STAT-50 reagents was successfully amplified in a multiplex RT-PCR reaction for detection of the multi-drug resistance related genes MDR1, the multi-drug resistance related protein (MRP) and topoisomerase IIalpha. Low level MDR1 gene expression could be detected in frozen whole blood. However, PCR products were only seen when the anti-coagulant heparin was removed from all samples prior to cDNA production. RT-PCR amplification was not 100% successful with RNA extracted with Ultraspec-3 reagent. In conclusion, we found that the RNA extracted from whole blood with the Trizol-LS and the RNA-STAT-50 are suitable for use in clinically relevant molecular biology protocols that analyze rare event genes without further purification. Our results indicated that the Trizol-LS reagent was generally more consistent in obtaining a pure and sufficient quantity of RNA from patient material as shown by the mean result of purity and quantity in comparison to either Ultraspec-3 or RNA-STAT-50-LS reagents. Ultraspec-3 is not easily suited for direct use with whole blood products.
Cell Mol Biol (Noisy-le-grand) 1997 Dec
PMID:Evaluation of three rapid RNA extraction reagents: relevance for use in RT-PCR's and measurement of low level gene expression in clinical samples. 948 49

The characterization of the c-Mpl receptor resulted from studies on a murine retrovirus, and proved an important step in the identification of a key hemopoietic regulator. First proposed and named in 1958, the ultimate characterization of the long-awaited 'thrombopoietin' (TPO) came with the molecular cloning and characterization of the in vitro and in vivo properties of the c-Mpl ligand. Gene targeting experiments have demonstrated that the TPO/Mpl receptor signalling pathway is the principal physiological regulator of megakaryocytes and platelets. Analysis of signalling through c-Mpl has provided important insights into the function of this pathway, which, as with other members of the hemopoietin receptor family, involves activation of the JAK/STAT and Ras signalling cascades. Preclinical studies have documented a role for this molecule in overcoming thrombocytopenia following chemo/radiotherapy in several animal models. Clinical studies have demonstrated the safety and efficacy of Mpl ligand in elevating platelet counts. The identification of thrombopoietin has provided an important impetus in understanding megakaryocyte and platelet physiology, and provided a new therapeutic that will find application in a variety of clinical contexts.
Cytokines Cell Mol Ther 1998 Mar
PMID:Thrombopoietin in vitro and in vivo. 955 14

While signal transducers and activators of transcription (STATs) were originally discovered as intracellular effectors of normal signaling by cytokines, increasing evidence also points to a role for STAT transcription factors in oncogenesis. Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein. To determine if this Stat3 activation by Src could induce Stat3-mediated gene expression, luciferase reporter constructs based on synthetic and authentic promoters were transfected into NIH 3T3 cells. Activation of endogenous cellular Stat3 by the Src oncoprotein induced gene expression through a Stat3-specific binding element (TTCCCGAA) of the C-reactive protein gene promoter. A naturally occurring splice variant of human Stat3 protein, Stat3beta, with a deletion in the C-terminal transactivation domain abolished this gene induction in a dominant negative manner. Expression of Stat3beta did not have any effect on a reporter construct based on the c-fos serum response element, which is not dependent on Stat3 signaling, indicating that Stat3beta does not nonspecifically inhibit other signaling pathways or Src function. Transfection of vectors expressing Stat3beta together with Src blocked cell transformation by Src as measured in a quantitative focus formation assay using NIH 3T3 cells. By contrast, Stat3beta had a much less pronounced effect on focus formation induced by the Ras oncoprotein, which does not activate Stat3 signaling. In addition, three independent clones of NIH 3T3 cells stably overexpressing Stat3beta were generated and characterized, demonstrating that Stat3beta overexpression does not have a toxic effect on cell viability. These Stat3beta-overexpressing clones were shown to be deficient in Stat3-mediated signaling and refractory to Src-induced cell transformation. We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis. Our findings provide evidence that oncogenesis-associated activation of Stat3 signaling is part of the process of malignant transformation.
Mol Cell Biol 1998 May
PMID:Stat3 activation by Src induces specific gene regulation and is required for cell transformation. 956 74

The transcription factor TFII-I was initially isolated as a factor that can bind to initiator elements in core promoters. Recent evidence suggests that TFII-I may also have a role in signal transduction. We have found that overexpression of TFII-I can enhance the response of the wild-type c-fos promoter to a variety of stimuli. This effect depends on the c-fos c-sis-platelet-derived growth factor-inducible factor binding element (SIE) and serum response element (SRE). There is no effect of cotransfected TFII-I on the TATA box containing the c-fos basal promoter. Three TFII-I binding sites can be found in c-fos promoter. Two of these overlap the c-fos SIE and SRE, and another is located just upstream of the TATA box. Mutations that distinguish between serum response factor (SRF), STAT, and TFII-I binding to the c-fos SIE and SRE suggest that the binding of TFII-I to these elements is important for c-fos induction in conjunction with the SRF and STAT transcription factors. Moreover, TFII-I can form in vivo protein-protein complexes with the c-fos upstream activators SRF, STAT1, and STAT3. These results suggest that TFII-I may mediate the functional interdependence of the c-fos SIE and SRE elements. In addition, the ras pathway is required for TFII-I to exert its effects on the c-fos promoter, and growth factor stimulation enhances tyrosine phosphorylation of TFII-I. These results indicate that TFII-I is involved in signal transduction as well as transcriptional activation of the c-fos promoter.
Mol Cell Biol 1998 Jun
PMID:TFII-I enhances activation of the c-fos promoter through interactions with upstream elements. 958 71

Angiotensin II (Ang II) treatment was recently shown to activate Jak2, Stat1, and Stat3 proteins in cardiac myocytes. Angiotensin-converting enzyme (ACE) inhibitors have been shown to be an effective clinical treatment following myocardial infarction, implying that inhibition of Ang II production is beneficial in this pathological condition. Some of the effects of Ang II in cardiac myocytes may be mediated by the JAK-STAT signaling pathway. The AT1 receptor was the first G-protein-coupled-receptor reported to activate the JAK-STAT pathway. Recently, however, another G-protein-coupled-receptor (i.e. serotonin) was also shown to signal through the JaK2 and STAT proteins in myoblasts. We hypothesized that Ang II treatment might also activate Stat5 transcription factors in cardiac myocytes. In this study, we provide evidence that the G-protein-coupled, Ang II type I (AT1) receptor couples to activation of Stat5 through Jak2 kinase in neonatal rat ventricular myocytes. Angiotensin II induces a 1.5- to 10-fold increase in a Stat5 transcription complex, which binds to the prolactin-inducing element (PIE). By Western analysis, Stat5 protein levels were shown to be tyrosine phosphorylated two- to three-fold over control, following. Ang II treatment of cardiac myocytes. Phosphorylation of Stat5a and Stat5b proteins was rapid and sustained (30-60 min), and Jak2 kinase co-immunoprecipitated with activated Stat5 proteins. In cardiac myocytes, Stat5 proteins co-immunoprecipitated with the AT1 receptor. Selective inhibition of Jak2 kinase with AG-490 blocked formation of prolactin-inducing factor (PIF) complexes by Ang II, suggesting that Jak2 kinase was required for the tyrosine phosphorylation of Stat5 in cardiac myocytes.
J Mol Cell Cardiol 1998 Apr
PMID:Angiotensin II activates Stat5 through Jak2 kinase in cardiac myocytes. 960 24


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