
IndraLab
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"In epidemiologic studies, the presence of prolactin and phosphorylated signal transducer and activator of transcription 5 (STAT5) in human prostate cancers is linked with high-grade tumors and more aggressive disease [XREF_BIBR]; therefore, targeting autocrine and/or paracrine prolactin mediated activation of STAT5 may represent a novel therapeutic target for patients with prostate cancer."
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"XREF_BIBR, XREF_BIBR Restoring PRL receptor expression in TNBC cell lines decreases their invasive capacity while blocking JAK2 and STAT5 in luminal breast cancer cell lines increases their invasiveness, suggesting that PRL activation of STAT5 restricts the metastatic potential of breast tumors."
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"This is because mammary-selective promoters such as MMTV or WAP have the progesterone receptor and STAT5-binding sites (Chalepakis et al. 1988; Préfontaine et al. 1999) and are induced during pregnancy and lactation when high progesterone and prolactin levels activate progesterone receptor and STAT5."
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"These include lactogenic hormone response elements, such as GAS motifs bound by the prolactin-activated transcription factor STAT5, glucocorticoid response elements (GREs) and sites recognized by NFIB, another key TF to the 10,000-fold stimulation of casein gene expression during pregnancy and lactation xref , xref , xref , xref ."
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"Short term incubation (< 60 min) of prolactin responsive Nb2 lymphoma cells at high density selectively blocked prolactin stimulation of p42 and p44 mitogen activated protein kinases and transcription factors Stat1 and Stat3 but not prolactin activation of Stat5 or the tyrosine kinase Jak2."
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"As expected, acini formed under PRL and EGF co-treatment were deprived of β-casein expression in agreement with our previous data showing a negative crosstalk between PRL and EGF by which EGF blocks PRL-induced STAT5 activation of the β-casein gene promoter, whereas PRL blocks EGF-induced MEC growth [63] (Fig. S1)."
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"Stat5 chromatin immunoprecipitation demonstrated physical interaction with a BCL6 gene regulatory region, and BCL6 transcript repression required histone deacetylase activity based on sensitivity to trichostatin A. Functionally, BCL6 overexpression disrupted prolactin induction of Stat5 reporter genes."
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"Given the important role for estrogens in maternal behavior and the recent finding that PRL treatment enhances STAT5 activity in ERalpha neurons in the female mouse brain, the relationships between alterations in neural sensitivity to PRL and the apparent shift in estrogen receptor activity may play an important role in regulating enhancements of maternal care, i.e. the retention of maternal behavior, long after the cessation of lactation."
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"Short term incubation (<60 min) of prolactin-responsive Nb2 lymphoma cells at high density selectively blocked prolactin stimulation of p42/p44 mitogen-activated protein kinases and transcription factors Stat1 and Stat3 but not prolactin activation of Stat5 or the tyrosine kinase Jak2."
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"In addition, Prl is known to modulate various downstream signaling pathways which include the Janus kinase/signal transducer and activator of transcription (JAK2/STAT5), MAPK extracellular regulated kinase 1/2 (ERK1/2), and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) [60,61]."
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"Taken together, those data suggested that the PRLR/STAT5 signaling activated by PRL might be involved in maintaining and regulating the functions of the scented glands in the muskrats.The present study demonstrated that PRL, PRLR and STAT5 were expressed in the scented glands of the muskrats and there was higher concentration of PRL in the scented glandular tissues during the breeding season."
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"Not only has this work elegantly and conclusively shown that the PI3K and Akt pathway induces autocrine prolactin production which is required for the initiation of lactation, but it has the additional merit of the use of genetically altered mouse models to study the activation of STAT5 by prolactin in vivo in the correct cellular environment so we can be confident that the data are biologically relevant."
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"IGF-I stimulates DNA binding activity of one of the key transcription regulators of casein genes: STAT5 (signal transducer and activator of transcription 5), which belongs to the Janus kinase—signal transducer and activator of transcription pathway (JAK2/STAT5 pathway) stimulated by prolactin [60]."
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"To understand the intrinsic effect of 17beta-estradiol (E2) and ICI on expression of the STAT5 isoforms and how these outcomes affect the interplay with PRL activated STAT5 isoforms in mammary epithelia of differing phenotypes, we compared the well characterized, differentiated HC11 mouse cell line [XREF_BIBR] and ERalpha + mouse mammary tumor cell (TC) lines generated from PRL induced adenocarcinomas [XREF_BIBR]."
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"In mammary glands, PRL activated Stat5 in a majority of luminal epithelial cells but not myoepithelial cells, stromal fibroblasts, or adipocytes, whereas GH activated Stat5 in a significant fraction of myoepithelial cells, fibroblasts, and adipocytes but only in a minority of luminal cells."
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"Although PRL is a known activator of STAT5 in the mammary gland, these data showing ErbB3 dependent induction of STAT5 expression, taken with previous data demonstrating ErbB4 mediated phosphorylation and activation of STAT5, suggest that NRGs produced locally in the mammary microenvironment enable PRL mediated STAT5A activation, while at the same time promoting PI3K and Akt signaling, which together amplify, sustain, and differentiate this unique cell population on which newborn mammals depend."
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"Despite RANKL/NF-κB/ Cyclin D1 axis playing an important role in MECs proliferation and alveolargenesis, it has been reported that enhanced RANKL/Rank signaling affects lactogenic differentiation in MECs by inhibiting the PRL-induced activation of Stat5 and expression of Elf5 required for lactation, and that RANKL inhibition at mid-pregnancy resulted in increased Elf5 expression and activation of Stat5, leading to a premature secretory differentiation [ xref , xref ]."
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"It remains to be seen whether the increased beta-cell replication observed in pregnancy is also achieved through this mechanism, but evidence suggests that in pregnancy, prolactin not only increases STAT5 signalling, it also reduces the levels of the tumour suppressor gene menin, which is a known inhibitor of Cdk2 activity [XREF_BIBR]."
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"Prolactin activates pSTAT5 in the supraoptic nucleus of virgin and lactating rats A–D, representative images of pSTAT5 (nuclear staining) and oxytocin immunostaining (cytoplasmic staining) in the supraoptic nucleus of virgin and lactating rats after three injections of bromocriptine over 28–4 h before the experiment."
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"Although the PRL-induced activation of Jak2 and Stat5 is able to regulate the levels of active Akt1 and nuclear accumulation of Cyclin D1 in normal cells ( xref ; xref ; xref ), we have demonstrated recently that the expression of constitutively active ErbB2 was sufficient to elevate the expression of these downstream mediators independently of Jak2."
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"Our data indicate that in the mammary gland CIS and SOCS3 are involved in regulating STAT5 signaling at three different instances : 1) SOCS3 serves as a mediator of the inhibitory EGF effect on PRL induced STAT5 activation; 2) CIS and SOCS3 play a role as negative feedback inhibitors of PRL action; 3) Inhibition of CIS and SOCS3 expression by glucocorticoids contributes to the positive effect of glucocorticoids on PRL induced STAT5 activation."
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"Second, beta1 integrins are actively required for Prl signaling both in culture and in vivo because function perturbing anti-beta1 integrin antibodies block MEC differentiation, a dominant negative (DN) beta1 integrin transgene compromises Stat5 activation and milk production, and Prl can not activate Stat5 in beta1 integrin-null MECs."
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"In a separate assay to quantify the percentage of cells in which Prl induced Stat5 translocation to the nucleus, monolayer cultured cells were differentiated by adding diluted BM matrix to the culture medium (i.e., 2D culture with BM overlay) before stimulation with Prl for 15 min."
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"The present study of prolactin (PRL) receptor mediated recruitment of signal transducers and activators of transcription (STATs) demonstrates that PRL activates STAT3, in addition to STAT1 and STAT5 as previously reported, and that STAT1, STAT3 and STAT5 are mediators of PRL effects in cells whether of lymphoid, myeloid or mammary epithelial origin."
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"Prolactin activates pSTAT5 in the paraventricular nucleus of virgin and lactating rats A–D, representative images of pSTAT5 (nuclear staining) and oxytocin immunostaining (cytoplasmic staining) in the paraventricular nucleus of virgin and lactating rats after three injections of bromocriptine over 28–4 h before the experiment."
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"In mammary glands, PRL activated Stat5 in a majority of luminal epithelial cells but not myoepithelial cells, stromal fibroblasts, or adipocytes, whereas GH activated Stat5 in a significant fraction of myoepithelial cells, fibroblasts, and adipocytes but only in a minority of luminal cells."
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"PRL stimulates the Jak and Stat pathway (Jak2 and Stat5) in the mammary gland, which is responsible for the induction of milk protein expression in BMEC as well as other mammary epithelial cells due to the presence of Stat5 binding sites on the epithelial cells, and this could be a potential regulatory pathway by which 5-HT acts through 5-HT 2A."
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"STAT5 pathway activation by PRL in these experiments is evident in regulation of multiple STAT5 target genes, including the immune system modulating genes and pathways: IL-2, IL-3 and Bcl-2 signaling, Il2ra , Tnfsf10 , Foxp3, Slfn2, C3ar1, Osm, Socs1 , etc. ( xref ; xref ; xref ) (Supplementary Excel files/material)."
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"In recent studies, we have demonstrated in breast cancer ERalpha + and HER2 + cells, up-regulation of PRLR transcription and expression induced by endogenous and exogenous PRL in the absence of estrogen via the long form of the prolactin receptor with essential participation of ERalpha and JAK2 and STAT5, mitogen activated protein kinase (MAPK) and PI3K pathways [XREF_BIBR]."
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"This study demonstrated that STAT5 can be activated by prolactin in mammary glands. xref Since then, several studies have further described the critical role of STAT5 proteins in adipogenesis, cellular differentiation, immune function, and oncogenesis. xref , xref STAT5 also controls cell survival through the regulation of prosurvival genes such as BCL-XL . xref In addition, STAT5 is activated by numerous cytokines such as IL-15, erythropoietin, growth hormone, and prolactin."
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"We report that (i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, (ii) this model recapitulates prostate tumorogenesis from precancer lesions to invasive carcinoma, and (iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63 positive basal cells, and of stem cell antigen-1-positive cells identified as a stem and progenitor like subpopulation."
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"Second, β1 integrins are actively required for Prl signaling both in culture and in vivo because function-perturbing anti–β1 integrin antibodies block MEC differentiation ( xref ), a dominant-negative (DN) β1 integrin transgene compromises Stat5 activation and milk production ( xref ), and Prl cannot activate Stat5 in β1 integrin–null MECs ( xref )."
sparser
"Not only has this work elegantly and conclusively shown that the PI3K/Akt pathway induces autocrine prolactin production which is required for the initiation of lactation, but it has the additional merit of the use of genetically altered mouse models to study the activation of STAT5 by prolactin in vivo in the correct cellular environment so we can be confident that the data are biologically relevant."
sparser
"Our data indicate that in the mammary gland CIS and SOCS3 are involved in regulating STAT5 signaling at three different instances: 1) SOCS3 serves as a mediator of the inhibitory EGF effect on PRL-induced STAT5 activation; 2) CIS and SOCS3 play a role as negative feedback inhibitors of PRL action; 3) Inhibition of CIS and SOCS3 expression by glucocorticoids contributes to the positive effect of glucocorticoids on PRL-induced STAT5 activation."
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"In addition to its pivotal role for mammary epithelial cell proliferation, specification, and differentiation, we demonstrate that this kinase is indispensable for the prolactin mediated activation of Stat5 and the maintenance of functionally differentiated alveolar cells during lactation."
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