Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ciliary neurotrophic factor (CNTF) has been known to inhibit the differentiation of presumptive rod photoreceptor cells; however, the underlying mechanisms have remained to be elucidated. We demonstrated that STAT3 activation, but not SHP2 activation, is responsible for the CNTF/gp130 signaling that inhibits expression of Rhodopsin and its upstream activator, crx, in the retinal explants derived from P0 mice (P0 retinal explants), utilizing STAT3-deficient retina and electroporation of dominant-negative form of STAT3 (STAT3F). We also demonstrated that STAT3 activation in presumptive rod photoreceptor cells at E18.5 is rapidly downregulated at P0, when Rhodopsin expression starts during retinal development. Persistent STAT3 activation in the P0 retinal explants prevented Rhodopsin expression and rapid upregulation of crx expression. STAT3-deficient retinas did not exhibit precocious rod photoreceptor cell differentiation as a whole, although they occasionally exhibited precocious upregulation of crx mRNA. Thus, we conclude that downregulation of STAT3 activation is required, but insufficient, for rod photoreceptor cell differentiation in the postnatal retina.
Mol Cell Neurosci 2004 Jun
PMID:Downregulation of STAT3 activation is required for presumptive rod photoreceptor cells to differentiate in the postnatal retina. 1520 51

STRA13 is a pVHL-dependent bHLH transcription factor up-regulated on the mRNA level in multiple cancer cell lines and implicated recently in the regulation of immune cell homeostasis and autoimmunity. In searching for STRA13-interacting proteins with oncogenic potential by the yeast two-hybrid screening, we identified STAT3 beta as a STRA13-binding partner. We showed that STRA13 binds predominantly to phosphorylated (active) STAT3 alpha and beta isoforms via its HLH and C-terminal regions. We also found that STRA13 was able to activate transcription from STAT-dependent cis-elements. Expression of endogenous STRA13 was shown to be cytokine-inducible, consistent with STRA13 involvement in STAT-dependent transcription regulation. We demonstrated that the STAT3-regulated promoter of the pro-apoptotic Fas gene was activated upon STRA13 over-expression and that co-expression of STRA13 with STAT3 beta or STAT3 alpha modulated the transcriptional outcome. Forced expression of STRA13 induced apoptosis, in agreement with the STRA13 activation effect on the Fas promoter. Simultaneous expression of STRA13 and STAT3 beta resulted in alleviation of the STRA13 pro-apoptotic effect. Thus, for the first time, we identify STRA13 as a STAT3 partner and provide a consistent line of evidence for STRA13 involvement into regulation of apoptosis via the STAT pathways.
J Mol Biol 2004 Jul 16
PMID:STRA13 interacts with STAT3 and modulates transcription of STAT3-dependent targets. 1522 10

It is known that Notch activation promotes the self-renewal of hematopoietic cells. However, we have previously found that the growth of a myeloid leukemia cell line, OCI/AML-6, was suppressed by Notch activation induced by stimulation with a recombinant Notch ligand, Delta-1 protein. We recently found that the growth of another leukemia cell line, THP-1, was also suppressed by the ligands Delta-1 and Jagged-1. In this study, we tried to clarify the cellular and molecular mechanism of the growth suppression induced by Notch activation. Flow cytometric analysis showed that Delta-1 stimulation increased the expression of differentiation markers such as CD11b and CD13 while it decreased the expression of CD117 (c-KIT), a marker for primitive cells in THP-1 cells. In OCI/AML-6 cells, Delta-1 stimulation decreased the expression of CD11b and CD14 and increased CD34 expression. Namely, Delta-1 showed the opposite effects on the differentiation markers of each cell line. Delta-1 stimulation did not increase the binding of annexin V, a marker for apoptotic cells in either cell line. Since the growth of myeloid cells is regulated by MAP kinase and JAK/STAT pathways, we investigated the effects of the ligand stimulation on these pathways. Delta-1 stimulation did not induce the phosphorylation of ERK1/2 and STAT3 proteins in either cell line. Pre-exposure to Delta-1 did not affect the phosphorylation of ERK1/2 and STAT3 induced by G-CSF in OCI/AML-6 cells, either. Namely, it is thought that these pathways are not involved in the growth suppression caused by Notch ligands. Our study revealed several findings on Notch function. However, the precise mechanism remains to be elucidated.
Int J Mol Med 2004 Aug
PMID:Cellular analysis of growth suppression induced by the Notch ligands, Delta-1 and Jagged-1 in two myeloid leukemia cell lines. 1525 69

Chimeric RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncoproteins are constitutively active tyrosine kinases found in thyroid papillary carcinoma and nonneoplastic Hashimoto's thyroiditis. Although several proteins have been identified to be substrates of RET/PTC kinases, the pathogenic roles played by RET/PTC in malignant and benign thyroid diseases and the molecular mechanisms that are involved are not fully understood. We found that RET/PTC expression phosphorylates the Y701 residue of STAT1, a type II interferon (IFN)-responsive protein. RET/PTC-mediated signal transducer and activator of transcription 1 (STAT1) phosphorylation requires RET/PTC kinase activity to be intact but other tyrosine kinases, such as Janus kinases or c-Src, are not involved. RET/PTC-induced STAT1 transcriptional activation was not inhibited by suppressor of cytokine signaling-1 or -3, or protein inhibitors of activated STAT3 [(protein inhibitor of activated STAT (PIAS3)], but PIAS1 strongly repressed the RET/PTC-induced transcriptional activity of STAT1. RET/PTC-induced STAT1 activation caused IFN regulatory factor-1 expression. We found that STAT1 and IFN regulatory factor-1 cooperated to significantly increase transcription from type IV IFN-gamma responsive promoters of class II transactivator genes. Significantly, cells stably expressing RET/PTC expressed class II transactivator and showed enhanced de novo membrane expression of major histocompatibility complex (MHC) class II proteins. Furthermore, RET/PTC1-bearing papillary thyroid carcinoma cells strongly expressed MHC class II (human leukocyte-associated antigen-DR alpha) genes, whereas the surrounding normal tissues did not. Thus, RET/PTC is able to phosphorylate and activate STAT1. This may lead to enhanced MHC class II expression, which may explain why the tissues surrounding RET/PTC-positive cancers are infiltrated with lymphocytes. Such immune response-promoting activity of RET/PTC may also relate to the development of Hashimoto's thyroiditis.
Mol Endocrinol 2004 Nov
PMID:Regulation of signal transducer and activator of transcription 1 (STAT1) and STAT1-dependent genes by RET/PTC (rearranged in transformation/papillary thyroid carcinoma) oncogenic tyrosine kinases. 1529 6

Cytokines regulate numerous cell processes, including connexin expression and gap junctional coupling. In this study, we examined the effect of ciliary neurotrophic factor (CNTF) on connexin43 (Cx43) expression and intercellular coupling in astrocytes. Murine cortical astrocytes matured in vitro were treated with CNTF (20 ng/ml), soluble ciliary neurotrophic factor receptor alpha (CNTFRalpha) (200 ng/ml), or CNTF-CNTFRalpha. Although CNTF and CNTFRalpha alone had no effect on Cx43 expression, the heterodimer CNTF-CNTFRalpha significantly increased both Cx43 mRNA and protein levels. Cx43 immunostaining correlated with increased intercellular coupling as determined by dye transfer analysis. By using the pharmacological inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG490), the increase in Cx43 was found to be dependent on the Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Immunocytochemical analysis revealed that CNTF-CNTFRalpha treatment produced nuclear localization of phosphorylated STAT3, whereas CNTF treatment alone did not. Transient transfection of constructs containing various sequences of the Cx43 promoter tagged to a LacZ reporter into ROS 17/2.8 cells confirmed that the promoter region between -838 to -1693 was deemed necessary for CNTF-CNTFRalpha to induce heightened expression. CNTF-CNTFRalpha did not alter Cx30 mRNA levels, suggesting selectivity of CNTF-CNTFRalpha for connexin signaling. Together in the presence of soluble receptor, CNTF activates the JAK/STAT pathway leading to enhanced Cx43 expression and intercellular coupling.
Mol Biol Cell 2004 Nov
PMID:The complex of ciliary neurotrophic factor-ciliary neurotrophic factor receptor alpha up-regulates connexin43 and intercellular coupling in astrocytes via the Janus tyrosine kinase/signal transducer and activator of transcription pathway. 1534 87

Inflammatory pain is counteracted by a number of physiological processes. For example, opioid receptors, which are present on peripheral terminals of sensory neurons, are activated by endogenous opioids, which are released from immune cells migrating to the inflamed tissue. Earlier data demonstrated that interleukin-6 contributes to such inflammation-induced analgesia. In this report, we demonstrated that interleukin-6 strongly induces mu-opioid receptor mRNA in the human neuroblastoma cell line SH SY5Y, whereas delta-opioid receptor mRNA levels are not influenced. The mRNA increase in these cells is followed by an increase in mu-opioid receptor-specific binding. Using transcription factor decoy oligonucleotides, direct evidence was provided that the up-regulation of mu-opioid receptor mRNA in intact cells is dependent on the transcription factors signal transducers and activators of transcription 1 (STAT1) and STAT3, whereas other transcription factors, such as activator protein-1, nuclear factor (NF)-kappaB, or NF-interleukin-6 are not involved. STAT1 and STAT3 bound to a site located at nucleotide -1583 on the promoter of the human mu-opioid receptor gene, as shown by transient transfection experiments, electrophoretic mobility shift assays, and transcription factor decoy oligonucleotides. A mutation analysis of the 5'-TTCATGGAA-3' STAT1/3 element (palindrome underlined) was performed to determine nucleotide residues that are necessary for the binding of STAT1 and STAT3. It suggested that only the palindromic half sides and the two adjacent central nucleotides are required. Neither mutation of the nucleotides outside the palindrome nor mutation of the central nucleotide affected STAT1/3 binding.
Mol Pharmacol 2004 Dec
PMID:Transcriptional regulation of the human mu-opioid receptor gene by interleukin-6. 1544 91

The receptor tyrosine kinases (RTKs) RET, MET, and RON all carry the Met(p+1loop)-->Thr point mutation (i.e., 2B mutation), leading to the formation of tumors with high metastatic potential. Utilizing a novel antibody array, we identified constitutive phosphorylation of STAT3 in cells expressing the 2B mutation but not wild-type RET. MET or RON with the 2B mutation also constitutively phosphorylated STAT3. Members of the EPH, the only group of wild-type RTK that carry Thr(p+1loop) residue, are often expressed unexpectedly in different types of cancers. Ectopic expression of wild-type but not Thr(p+1loop)-->Met substituted EPH family members constitutively phosphorylated STAT3. In both RTK(Metp+1loop) with 2B mutation and wild-type EPH members the Thr(p+1loop) residue is required for constitutive kinase autophosphorylation and STAT3 recruitment. In multiple endocrine neoplasia 2B (MEN-2B) patients expressing RET(M918T), nuclear enrichment of STAT3 and elevated expression of CXCR4 was detected in metastatic thyroid C-cell carcinoma in the liver. In breast adenocarcinoma cell lines expressing multiple EPH members, STAT3 constitutively bound to the promoters of MUC1, MUC4, and MUC5B genes. Inhibiting STAT3 expression resulted in reduced expression of these metastasis-related genes and inhibited mobility. These findings provide insight into Thr(p+1loop) residue in RTK autophosphorylation and constitutive activation of STAT3 in metastatic cancer cells.
Mol Cell Biol 2004 Nov
PMID:Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. 1548 8

Signal transducers and activators of transcription (STAT) were originally discovered as components of cytokine signal transduction pathways. Persistent activation of one of these transcription factors, STAT3, is a feature of many malignancies, including hormone-resistant prostate cancer. In this regard, malignant cells expressing persistently activated STAT3 become dependent on it for survival, thus rendering STAT3 a potential molecular target for therapy of hormone-resistant prostate cancer. Previously, we reported that antisense oligonucleotides specific for STAT3 were better at inducing apoptosis than inhibitors of JAK1 or JAK2, the upstream activating kinases of STAT3. Here, we report that novel single-stranded oligonucleotides, which putatively block STAT3-DNA binding, were better at inducing hormone-resistant prostate cancer apoptosis than antisense STAT3 oligonucleotides. We observed that the novel STAT3-inhibiting oligonucleotides induced apoptosis by a mitochondrial-dependent pathway involving the activation of caspase-3. Prostate cell lines not expressing persistently activated STAT3 did not become apoptotic after treatment with these same oligonucleotides. Scrambled-sequence control oligonucleotides had none of the effects of the active sequence oligonucleotides on any variable measured. Furthermore, the novel STAT3-inhibiting oligonucleotides, but not scrambled-sequence control oligonucleotide, significantly reduced the volume of s.c. DU145 tumors in vivo. Histologic examination of the tumors revealed no infiltrate of mononuclear or granulocytic cells, which would be indicative of evocation of a nonspecific immune response by the oligonucleotides. We conclude that single-stranded oligonucleotides based on the binding sequences of STAT3 are an additional strategy to design inhibitors for this molecular target and that these inhibitors should be useful as experimental therapeutics for hormone-resistant prostate cancer.
Mol Cancer Ther 2004 Oct
PMID:Novel single-stranded oligonucleotides that inhibit signal transducer and activator of transcription 3 induce apoptosis in vitro and in vivo in prostate cancer cell lines. 1548 84

Here we examined the role of interferon (IFN)-gamma in regulating the Sonic hedgehog (Shh) pathway and cerebellar development in bigenic mice with temporal control of IFN-gamma gene expression driven by a tetracycline-controllable promoter. In IFN-gamma-expressing but not age-matched non-IFN-gamma-expressing bigenic or control mice, development of the cerebellum was severely affected with the persistence and extensive proliferation of the external granule neuron layer (EGL) and infiltration with modest numbers of T-lymphocytes. Following induction of IFN-gamma transgene expression, both total and tyrosine-phosphorylated signal transducer and activator of transcription (STAT)1 (the major transcriptional factor for IFN-gamma), phosphorylated STAT3 and STAT5, and expression of a number of IFN-gamma-regulated genes were significantly increased in cerebellum. In the cerebellum from IFN-gamma-expressing but not age-matched non-IFN-gamma-expressing mice, the level of Shh and Gli-1 but not Patched (Ptch) 1 RNA was increased as was the 19-kDa signaling product of the Shh precursor protein. In situ localization studies revealed ectopic expression of the Shh gene by the granule neurons. We conclude that IFN-gamma directly affects the proliferation and fate of EGL neurons in the cerebellum by activating the Shh pathway and stimulating an autocrine growth response by these cells.
Mol Cell Neurosci 2004 Dec
PMID:Inducible production of interferon-gamma in the developing brain causes cerebellar dysplasia with activation of the Sonic hedgehog pathway. 1555 26

The melanoma differentiation-associated gene-7 (mda-7/IL24) is a unique member of the IL-10 family of cytokines, with ubiquitous tumor cell proapoptotic activity. Transduction of tumor or normal cells with the mda-7 gene results in secretion of glycosylated MDA-7 protein. Recent data indicate that secreted MDA-7 protein functions as a pro-Th1 cytokine and as a potent antiangiogenic molecule. MDA-7 protein binds two distinct type II cytokine heterodimeric receptor complexes, IL-20R1/IL-20R2 (type 1 IL-20R) and IL-22R1/IL-20R2 (type 2 IL-20R). In this study we analyzed the activity of glycosylated secreted MDA-7 against human melanoma cells. MDA-7 protein induces phosphorylation and nuclear translocation of STAT3 in melanoma cells via both type 1 and type 2 IL-20R. MDA-7 induces dose-dependent cell death in melanoma tumor cells. MDA-7 receptor engagement results in up-regulation of BAX and subsequent apoptosis induction; this effect is mediated by STAT3-independent signaling. Additional IL-10 family members (IL-10, -19, -20, and -22) also activate STAT3; however, these ligands do not activate death pathways in melanoma. In normal cells, MDA-7 can bind to its cognate receptors and induce phosphorylation of STAT3, without cytotoxic sequelae. This study defines a tumor-selective cytotoxic bystander role for secreted MDA-7 protein and identifies a novel receptor-mediated, STAT3-independent, and PKR-independent death pathway.
Mol Ther 2004 Dec
PMID:Bystander activity of Ad-mda7: human MDA-7 protein kills melanoma cells via an IL-20 receptor-dependent but STAT3-independent mechanism. 1556 40


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