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Results for “STAT5 Transcription Factor”

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At least 19 recordsLinked to original sources

PubMed2002

Interleukin-2 family cytokines stimulate phosphorylation of the Pro-Ser-Pro motif of Stat5 transcription factors in human T cells: resistance to suppression of multiple serine kinase pathways.

Signal transducer and activator of transcription (Stat)5a and Stat5b are critical for normal immune function. Progression of T cells through G(1)-S phase of cell cycle requires T cell receptor (TCR)- and/or cytokine-inducible tyrosine phosphorylation of Stat5a/b. Stat5a/b may also, in a cell-dependent manner, be constitutively or cytokine-inducibly phosphorylated on a Pro-Ser-Pro (PSP) motif located within the transcriptional activation domain. Phosphorylation of the PSP motif is needed for maximal transcriptional activation by Stat5, at least in certain promoter contexts. The basal and cytokine-inducible serine phosphorylation state of Stat5a/b has not been determined in T cells. Using primary human T cells and T lymphocytic cell lines coupled with novel phospho-specific antibodies to this conserved phosphoserine motif in Stat5a or Stat5b, we report that: Stat5a and Stat5b were unphosphorylated on the PSP motif under basal conditions and became markedly phosphorylated in response to several T cell growth factor stimuli, including interleukin (IL)-2, -7, -9, and -15 and phorbol ester 12-myristate 13-acetate but not TCR engagement; inducible Stat5a/b serine phosphorylation differed quantitatively and temporally; and Stat5a/b serine phosphorylation was, in contrast to inducible Stat3 serine phosphorylation, insensitive to inhibitors of mitogen-activated protein kinase, phosphatidylinositol-3 kinase, and mammalian target of rapamycin or deletion of Raf-A, -B, or -C by antisense oligonucleotides. We conclude that IL-2 family cytokines tightly control Stat5 serine phosphorylation through a kinase distinct from the Stat3 serine kinase.

Amino Acid Motifs↗

PubMed1998

Transcription factor Stat5 is an early marker of differentiation of murine embryonic stem cells.

Embryonic stem (ES) cells are pluripotent descendants of the inner cell mass of blastocysts capable of differentiating into progenitor cells of most if not all tissues. The pluripotency of ES cells is maintained by leukemia inhibitory factor (LIF), a member of the family of interleukin-6-type cytokines. These cytokines activate Janus tyrosine kinases and signal transducer and activator of transcription factors (Stat) via the signalling receptor component gp130. Pluripotent ES1 cells proliferating in the presence of LIF were known from previous studies to contain Stat3 and Stat1 capable of transcriptional activation. Here we report that the level of tyrosine-phosphorylated Stat3 decreases rapidly during differentiation induced by treatment of ES1 cells either with retinoic acid (RA) or by withdrawal of LIF. In line with this finding, the DNA-binding activity of Stat3 decreased during differentiation. In contrast, Stat5 was absent from pluripotent proliferating ES cells, but appeared early after induction of differentiation. The positive correlation between induction of differentiation and expression of Stat5 mRNA was confirmed for three independent ES cell lines. Stat5 transcripts were detectable in ES1 cells as early as 12 h after treatment with RA and 36 h after withdrawal of LIF. Stat5 protein was detectable 2 days after the onset of differentiation. These results establish Stat5 as a novel marker of very early stages of differentiation of ES cells.

Animals↗

PubMed2000

The activity of transcription factor Stat5 responds to prolactin, growth hormone, and IGF-I in rat and bovine mammary explant culture.

Signal transducer and activator of transcription-5 (Stat5) is known to play a critical role in prolactin-induced beta-casein gene transcription in rodents. In nonmammary cells, Stat5 is activated by multiple hormones and cytokines, including growth hormone. We hypothesized that Stat5 may serve as a common point in the signal transduction pathways of hormones that promote milk protein gene expression in bovine mammary cells, which are regulated by GH and IGF-I in addition to prolactin. Assays for Stat5 DNA binding activity and protein were validated in mammary explant culture. The Stat5 protein abundance was not changed by any of the short-term hormonal treatments used in our study, suggesting that short-term regulation of Stat5 is predominantly at the level of protein activation. Both rat and bovine explant culture showed a rapid stimulation of Stat5 DNA binding activity by prolactin, GH, and IGF-I at the high concentrations typically used in explant cultures as well as at levels within physiologic ranges. Growth hormone stimulated Stat5 activity at a lower concentration in bovine than in rat cultures, but in both species the presence of GH increased the response of Stat5 activity to prolactin. These results suggest that transcription factor Stat5 may represent part of a common route by which different extracellular signals converge and are transduced intracellularly to coordinately regulate cell function in the mammary gland.

Animals↗

PubMed2005

Regulation of interleukin 7-dependent immunoglobulin heavy-chain variable gene rearrangements by transcription factor STAT5.

Rearrangement of immunoglobulin heavy-chain variable (V(H)) gene segments has been suggested to be regulated by interleukin 7 signaling in pro-B cells. However, the genetic evidence for this recombination pathway has been challenged. Furthermore, no molecular components that directly control V(H) gene rearrangement have been elucidated. Using mice deficient in the interleukin 7-activated transcription factor STAT5, we demonstrate here that STAT5 regulated germline transcription, histone acetylation and DNA recombination of distal V(H) gene segments. STAT5 associated with V(H) gene segments in vivo and was recruited as a coactivator with the transcription factor Oct-1. STAT5 did not affect the nuclear repositioning or compaction of the immunoglobulin heavy-chain locus. Therefore, STAT5 functions at a distinct step in regulating distal V(H) recombination in relation to the transcription factor Pax5 and histone methyltransferase Ezh2.

Animals↗

PubMed2003

Inhibition of transcription factor Stat5 induces cell death of human prostate cancer cells.

Identifying regulators of prostate cancer cell survival may lead to new therapeutic strategies for prostate cancer. We now report prevalent activation of transcription factor Stat5 in human prostate cancer and provide novel evidence that blocking activation of Stat5 in human prostate cancer cells leads to extensive cell death. Specifically, Stat5 was activated in 65% of human prostate cancer specimens examined based on nuclear location of tyrosine phosphorylated Stat5. Adenoviral gene delivery of a dominant-negative Stat5 mutant (DNStat5), but not wild-type Stat5, induced cell death of both the androgen-independent human prostate cancer cell line CWR22Rv and the androgen-sensitive LnCap cell line. Endogenous Stat5 was active in both CWR22Rv and LnCap cells. In contrast, only low levels of inactive Stat5 proteins were detected in the PC-3 cell line, which correlated with resistance to DNStat5-induced cell death. In CWR22Rv and LnCap cells, inhibition of Stat5 by expression of DNStat5 induced apoptotic cell death as judged from morphological changes, DNA fragmentation, and caspase-3 activation with evidence of a caspase-9-dependent mechanism. We propose that blocking Stat5 function may represent a novel therapeutic approach for prostate cancer.

Adenoviridae↗

PubMed1996

Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor.

Members of the cytokine/growth hormone (GH)/prolactin receptor superfamily transduce signals by association and activation of JAK tyrosine kinases. For GH receptor (GHR), both JAK2 and the GHR undergo tyrosine phosphorylation upon GH stimulation. Also, GH has recently been shown to activate the transcription factor STAT5 by tyrosine phosphorylation. In the present study, we demonstrate that GH induces rapid tyrosine phosphorylation of different isoforms of STAT5 in mouse L cells stably transfected with a cDNA encoding porcine GHR (pGHR). In this cell system, STAT5 directly interacts with the GHR in a GH-dependent manner. Additionally, GH-induced tyrosine phosphorylation of STAT5 and the interaction of STAT5 with GHR can be observed in mouse 3T3-F442A cells which express endogenous mouse GHR. Interestingly, when cDNAs encoding the two mouse STAT5 homologs (STAT5A and STAT5B) were individually transfected into mouse L cells expressing pGHR, only STAT5A demonstrated the ability to interact with the pGHR and subsequently underwent GH-dependent tyrosine phosphorylation. STAT5B did not. Therefore, the GH-dependent interaction of a particular STAT5 with tyrosine-phosphorylated GHR may play an important role in GH-mediated signal transduction.

Animals↗

PubMed2006

[Activation of transcriptional factors stat5 and stat3 during human T-lymphocyte proliferation induced by different mitogenic stimuli].

The activation of closely related transcription factors STAT5alpha and STAT5beta is one of the key signalling events during interleukin-2-dependent stage of T-lymphocyte proliferation. Here, we investigate the activation of STAT5 and STAT3 family proteins on different stages of T-cell proliferative response to various mitogenic stimuli. The activation of STAT proteins was estimated according to their tyrosine phosphorylation. Isolated peripheral blood lymphocytes were stimulated by phytogemagglutinin (PHA), or by phorbol-12,13-dibutyrate (PDBu) with calcium ionophore--ionomycin, or by exogenous interleukin-2 (IL-2). After activation of T-cells by PHA as well as by PDBu with ionomycin we observed phosphorylation of STAT5 not earlier than in 5 h. The maximum phosphorylation (by 10 times and more, as compared to control resting lymphocytes) was detected following 24 h of mitogen stimulation. In the lymphocytes pretreated by PHA in submitogenic concentration, exogenous IL-2 induces a proliferative response. High phosphorylation level of STAT5 was determined 10 min after addition of IL-2 and kept for the next 24 h. In contrast to STAT5, some basal phosphorylation of STAT3 was found in resting and PHA-pretreated T-cells. The profile of phosphorylation STAT3 during mitogen-induced activation is more leveled. An immunosuppressant cyclosporine A taken at antiproliferative concentration decreased phosphorylation of both STAT5 and STAT3 by 1.5-2.0 times at early stages, as well as at late stages of activation. A correlation between alteration in tyrosine phosphorylation level of STAT5 and the expression of the high affinity IL-5 receptor was established. Taken together, we report that the increased STAT5 phosphorylation can serve as a marker of T-lymphocyte entrance into IL-2-dependent stage of proliferation after T-cell activation by different mitogens.

Carcinogens↗

PubMed1995

Interleukin 2 activates STAT5 transcription factor (mammary gland factor) and specific gene expression in T lymphocytes.

Although prolactin and interleukin 2 (IL-2) can elicit distinct physiological responses, we have found that their signal pathways share a common signal transducer and activator of transcription, STAT5. STAT5 was originally identified as a mammary gland factor induced by prolactin in lactating breast cells. Here we demonstrate that STAT5 is activated after IL-2 stimulation of two responsive lymphocyte cell lines, Nb2 and YT. Activation of STAT5 is measured both by IL-2-induced tyrosine phosphorylation and by IL-2-induced DNA binding. The STAT5 DNA recognition site is the same as the interferon gamma-activated site (GAS) in the interferon regulatory factor 1 gene. We demonstrate that the GAS element is necessary and sufficient for transcriptional induction by both IL-2 and prolactin in T lymphocytes. These results indicate that the role of STAT5 in the regulation of gene expression is not restricted to mammary cells or to prolactin, but is an integral part of the signal pathway of a critical immunomodulatory cytokine, IL-2.

Animals↗

PubMed2005

The gammac-cytokine regulated transcription factor, STAT5, increases HIV-1 production in primary CD4 T cells.

Although HIV-1 (HIV) replicates poorly in non-dividing CD4 lymphocytes, resting T cells contribute to the latent reservoir. The gammac-related cytokines reverse this block to HIV infection; however, the molecular mechanisms controlling this process are not understood. We asked whether the gammac-cytokine regulated transcription factor, signal transducer and activator of transcription 5 (STAT5), activates HIV transcription. We identified three regions in the long terminal repeat (LTR) as close matches to the STAT5 consensus-binding site and show that STAT5 binds the LTR during HIV infection. Expression of Janus kinase 3 (JAK3) or STAT5 in primary human CD4 T cells activated LTR transcription, while transactivation-incompetent dominant-negative STAT5 inhibited JAK3-induced LTR activity and infection of activated HIV-producing CD4 T-cells. In addition, overexpression of STAT5 increased virus production in unstimulated primary T cells - both the number of p24+ cells and their level of p24 production - suggesting that STAT5 promotes a permissive state for HIV infection. These data may have implications for regulation of latency and therapeutic strategies for control of HIV disease.

Binding Sites↗

PubMed2003

Hematopoietic cell survival signals are elicited through non-tyrosine-containing sequences in the membrane-proximal region of the erythropoietin receptor (EPOR) by a Stat5-dependent pathway.

OBJECTIVE: Erythropoietin is essential for red blood cell development in vivo and is also an important therapeutic agent to treat anemia resulting from kidney failure or bone marrow suppression. The erythropoietin receptor (EPOR) elicits both positive and negative regulatory signaling pathways, primarily through phosphorylated tyrosine residues in the cytoplasmic domain of the activated receptor complex. Surprisingly, however, EPOR tyrosine residues are dispensable for in vivo erythropoiesis under nonstress conditions. One of the key signaling molecules elicited by the EPOR is the Stat5 transcription factor. Stat5 activation has been mapped to tyrosines 343 and 401 in the EPOR cytoplasmic region, although non-tyrosine-containing sequences in the EPOR cytoplasmic region can also stimulate Stat5. To test the functional role of non-tyrosine-containing sequences in the EPOR, we analyzed a series of mutant EPOR isoforms in cell survival and proliferation assays. METHODS: The IL-3-dependent 32D cell line was stably transfected with cDNAs encoding the wild-type EPOR or mutant EPORs containing or lacking intracellular tyrosines, in the absence or presence of a dominant inhibitory Stat5 isoform. EPO-dependent cell signaling, survival, and proliferation were evaluated. RESULTS: EPOR isoforms lacking intracellular tyrosine residues elicit an important survival signal in 32D cells. Stat5 function is critical for EPO-dependent cell survival mediated by these non-tyrosine-containing receptor sequences. Interestingly, EPO-dependent survival does not require the presence of fetal calf serum (FCS) in the culture medium, yet FCS is important for 32D cell proliferation in response to EPO. CONCLUSION: Our results elucidate a previously unrecognized survival pathway elicited by the EPOR. They demonstrate that this pathway requires Stat5 and is serum independent. These findings contribute significantly to our understanding of the complexity by which the EPOR functions in hematopoietic cells.

Amino Acid Sequence↗

PubMed1995

Prolactin and interleukin-2 receptors in T lymphocytes signal through a MGF-STAT5-like transcription factor.

The cell surface receptors for PRL and interleukin-2 (IL-2) are structurally distinct, but share regulatory tasks in T lymphocytes. They can stimulate proliferation and activate transcription of over-lapping sets of genes of T cells. PRL and IL-2 receptor activation are both linked to the Jak/Stat (signal transducer and activator of transcription) pathway. We investigated the ability of PRL and IL-2 to activate Stat proteins in different T cell lines. The DNA binding specificities, the reactivities toward Stat-specific antisera, and the mol wt of IL-2- and PRL-induced DNA-binding proteins in Nb2 and C196 T cell lines were investigated. A comparison with the Stat proteins induced by interferon-gamma, PRL, and IL-6 in T47D mammary tumor cells was made. We found that these parameters were indistinguishable for one of the PRL- and IL-2-induced factors. A transcription factor closely related to mammary gland factor-Stat5 is rapidly activated upon interaction of IL-2 and PRL with their respective receptors. Activation of a second protein related to Stat1 was also observed. Our results emphasize the role of PRL as a regulator of the immune response and indicate that the Stat factors mammary gland factor-Stat5 and Stat1 play a role in the regulation of gene expression during T cell development.

Animals↗

PubMed2003

Growth impairment in IL-6-overexpressing transgenic mice is associated with induction of SOCS3 mRNA.

MUP/hIL-6 transgenic mice overexpressing human interleukin-6 (IL-6) are growth-retarded. As documented here, the major transcriptional factor constitutively activated by IL-6 in the MUP/hIL6 transgenic mice was signal transducer and transactivator 3 (STAT3). Since STAT3 has been implicated in the expression of negative regulators of GH signaling, the suppressors of cytokine signaling (SOCS) genes, we have in this study examined the expression of SOCS1, SOCS2, SOCS3, and CIS genes. We found a large, 5-fold increase in SOCS3 mRNA in the liver, brain, skeletal muscle, and the lung of the MUP/hIL-6 transgenic mice. SOCS genes are thought to inhibit activation of transcriptional factor STAT5 by GH. Despite the induction of SOCS3 mRNA, STAT5 was activated in growth-retarded transgenic mice in response to elevated endogenous GH serum levels. The significance of activation of STAT3 and STAT5 transcription factors for cell proliferation and growth impairment in this mouse model is therefore discussed.

Alpha-Globulins↗

PubMed1999

Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1alpha.

Salmon insulin-like growth factor-I (sIGF-I) expression is, as in mammals, induced by growth hormone (GH). To elucidate the mechanism by which GH stimulates the transcription of the IGF-I gene, we transiently transfected Hep3B cells expressing the rat GH receptor with a sIGF-I promoter-luciferase reporter construct. Activation of the construct by GH added to the medium of the transfected cells was observed when two specific transcription factors, STAT5 and HNF-1alpha, were simultaneously overexpressed in these cells. This finding demonstrates for the first time a GH-dependent activation of an IGF-I promoter construct in an immortalized laboratory cell line.

Animals↗

PubMed1995

Growth hormone induction of hepatic serine protease inhibitor 2.1 transcription is mediated by a Stat5-related factor binding synergistically to two gamma-activated sites.

A growth hormone (GH)-inducible nuclear factor (GHINF) from rat liver has been purified to near homogeneity. On SDS-polyacrylamide gel electrophoresis and UV-cross-linking, a major band of mass approximately 93 kDa and a minor band of approximately 70 kDa are detected in the purified fraction. DNase I footprinting using purified GHINF yields a protected region of -149/-115 on the rat serine protease inhibitor 2.1 (Spi 2.1) promoter encompassed within the growth hormone response element (GHRE). Mutational analysis demonstrated that GHINF binds synergistically to two gamma-interferon-activated sites (GAS) within the GHRE, with the 3' element being the pivotal binding domain. Functional assays show that both GAS elements are necessary for full GH response. GHINF has no immunoreactivity with either a C-terminal Stat1 antibody or an N-terminal Stat3 antibody, while cross-reacting with a C-terminal Stat5 monoclonal antibody. GHINF will bind to two GAS elements from the Stat5 binding region of the beta-casein gene. These studies indicate that GHINF is a Stat5-related factor binding synergistically to two GAS elements to activate Spi 2.1 transcription.

Animals↗

PubMed2002

Basal activation of transcription factor signal transducer and activator of transcription (Stat5) in nonpregnant mouse and human breast epithelium.

Transcription factor Stat5 (signal transducer and activator of transcription) is essential for PRL-induced terminal differentiation of mouse mammary epithelial cells during pregnancy and lactation and has been implicated in mammary tumorigenesis. A new and sensitive immunological method to detect active, tyrosine phosphorylated Stat5 in situ revealed that Stat5 is continuously activated in luminal epithelial cells of mouse and human breast, not only during pregnancy and lactation, but also outside of pregnancy. Examination of virgin Stat5a or Stat5b null mice suggested that Stat5a was the primary isoform activated in mammary epithelial cells. Basal activation of Stat5 in mammary epithelium of virgin wild-type mice was continuous throughout estrous cycle and was also detected in 17 of 17 normal human breast tissue specimens analyzed. PRL was identified as the principal factor maintaining basal activation of Stat5 in mammary epithelium of nonpregnant mice based on several lines of evidence. First, administration of PRL, but not GH or epidermal growth factor, uniformly enhanced basal activation of Stat5 in luminal mammary epithelial cells. Second, hypophysectomy disrupted basal activation of Stat5, an effect that was completely reversed by administration of PRL, but only partially by GH. Third, knock-out of the PRL receptor gene markedly reduced basal activation of Stat5, an effect that was maintained in a normalized endocrine environment after transplanting PRL receptor null mammary epithelium into wild-type mice. Continuous activation of Stat5 indicates a role of this transcription factor in normal, nonpregnant breast epithelial cells, and may shed new light on Stat5 involvement in breast tumor promotion.

Animals↗

PubMed2003

Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3.

Cytokines may cause an acquired growth hormone (GH) resistance in patients with inflammatory diseases. Anabolic effects of GH are mediated through activation of STAT5 transcription factors. We have reported that TNF-alpha suppresses hepatic GH receptor (GHR) gene expression, whereas the cytokine-inducible SH2-containing protein 1 (Cis)/suppressors of cytokine signaling (Socs) genes are upregulated by TNF-alpha and IL-6 and inhibit GH activation of STAT5. However, the relative importance of these mechanisms in inflammatory GH resistance was not known. We hypothesized that IL-6 would prevent GH activation of STAT5 and that this would involve Cis/Socs protein upregulation. GH +/- LPS was administered to TNF receptor 1 (TNFR1) or IL-6 null mice and wild-type (WT) controls. STAT5, STAT3, GHR, Socs 1-3, and Cis phosphorylation and abundance were assessed by using immunoblots, EMSA, and/or real time RT-PCR. TNF-alpha and IL-6 abundance were assessed by using ELISA. GH activated STAT5 in WT and TNFR1 or IL-6 null mice. LPS pretreatment prevented STAT5 activation in WT and TNFR1 null mice; however, STAT5 activation was preserved in IL-6 null mice. GHR abundance did not change with LPS administration. Inhibition of STAT5 activation by LPS was temporally associated with phosphorylation of STAT3 and upregulation of Cis and Socs-3 protein in WT and TNFR1 null mice; STAT3, Cis, and Socs-3 were not induced in IL-6 null mice. IL-6 inhibits hepatic GH signaling by upregulating Cis and Socs-3, which may involve activation of STAT3. Therapies that block IL-6 may enhance GH signaling in inflammatory diseases.

Animals↗

PubMed2002

Role of tyrosine kinase Jak2 in prolactin-induced differentiation and growth of mammary epithelial cells.

Genetic studies in mice have established a critical role for prolactin receptors and transcription factor Stat5 in mammary gland differentiation. However, the enzymatic coupling between prolactin receptors and Stat5 in this process has not been established. In addition to Jak2, several other tyrosine kinases reportedly also are associated with prolactin receptors and may phosphorylate Stat5. Because Jak2 null mice die in utero, we targeted Jak2 in an ex vivo model of prolactin-induced mammary epithelial cell differentiation to determine the role of Jak2 in regulation of cell differentiation and growth. Two independent targeting strategies were used to suppress Jak2 in immortalized HC11 mouse mammary epithelial cells: 1) stable expression of a specific Jak2 antisense construct and 2) adenoviral delivery of a dominant-negative Jak2 gene. We now demonstrate that Jak2 is essential for prolactin-induced differentiation and activation of Stat5 in normal mouse mammary epithelial cells. Furthermore, suppression of Jak2 in HC11 cells was associated with constitutive activation of oncoprotein Stat3 and a hyperproliferative phenotype characterized by increased mitotic rate, reduced apoptosis, and reduced contact inhibition. Collectively, our data suggest that Jak2 is differentiation-inducing and growth-inhibitory in normal mammary epithelial cells, observations that may shed new light on the role of the Jak2-Stat5 pathway in breast cancer.

Adenoviridae↗

PubMed1997

Prolactin mediated intracellular signaling in mammary epithelial cells.

Prolactin binds to a member of the cytokine receptor superfamily. The cytoplasmic domain of the prolactin receptor (PrlR) displays no enzymatic activity yet prolactin treatment leads to the induction of protein tyrosine phosphorylation. PrlR is associated with JAK2, a protein tyrosine kinase whose activity is stimulated following receptor dimerization. JAK2 subsequently phosphorylates PrlR and other cellular proteins which are recruited to the activated receptor complex. Among the JAK2 substrates is the transcription factor Stat5 whose phosphorylation mediates the transcriptional activation of beta-casein gene expression. In this review we discuss the prolactin induced signaling pathways which mediate differentiation of the mammary gland.

Animals↗