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Daniel I. H. Linzer - One of the best experts on this subject based on the ideXlab platform.
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Printed in U.S.A. Copyright © 1997 by The Endocrine Society Three New Members of the Mouse Prolactin/Growth Hormone Family Are Homologous to Proteins Expressed in the Rat*
2013Co-Authors: Jiandie Lin, Jason Poole, Daniel I. H. LinzerAbstract:THE PRL/GH family includes a number of hormones that are synthesized specifically in the placenta or uterus of many mammals (1–5). Among these hormones are proteins, designated placental lactogens (PLs), that bind to the PRL receptor as well as other proteins that bind neither the PRL receptor nor the GH receptor. Two hormones in this latter group have been discovered in the mouse (6–8), and six have been identified in the rat (9–14). Surprisingly, counterparts of the two mouse hormones, Proliferin (PLF) and Proliferin-related protein (PRP), have not been found in the rat, and homologs of any of the six rat hormones, PRL-like protein (PLP) A, B, C, C-variant, and D and decidual/trophoblast PRL-related protein (d/ tPRP; note that PRP and d/tPRP refer to different proteins), have not been discovered in the mouse. However, if these proteins have important regulatory functions during pregnancy, then it is reasonable to expect that homologs are present in other species. The biological and physiological functions of most of these orphan hormones have not been identified. We have shown that the midpregnant mouse placenta secretes significant angiogenic activity that can be attributed primarily to PLF
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reactivation of Proliferin gene expression is associated with increased angiogenesis in a cell culture model of fibrosarcoma tumor progression
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Daniel J Toft, Olga V. Volpert, Suzanne B Rosenberg, Gabriele Bergers, Daniel I. H. LinzerAbstract:Proliferin (PLF) is an angiogenic placental hormone. We now report that PLF gene expression can also occur in a progressive fibrosarcoma mouse tumor cell model. PLF mRNA and protein are detectable at very low levels in cell lines derived from the mild noninvasive stage of tumor development. Expression is greatly augmented in cell lines from the aggressively invasive stage of development, a stage at which the tumor becomes highly angiogenic, and PLF expression remains high in cell lines from the end stage of fibrosarcoma. Activator protein 1 factors present at high levels in the more invasive stages of the tumor may in part allow for increased PLF expression, as cells from the mild stage in which c-jun and junB are stably expressed secrete levels of PLF comparable to that of the advanced stages. Secreted PLF protein is functionally important in tumor cell angiogenic activity, as demonstrated by the reduction of angiogenic activity in fibrosarcoma cell culture medium by immunodepletion of PLF. These results suggest that an extraembryonic genetic program, which has evolved to support fetal growth, may be reactivated in certain tumors and contribute to tumor growth.
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Inhibition of tumor growth by the antiangiogenic placental hormone, Proliferin-related protein.
Molecular Endocrinology, 2000Co-Authors: Nancy W. Bengtson, Daniel I. H. LinzerAbstract:Proliferin-related protein (PRP) is a potent placental antiangiogenic hormone. To test the antiangiogenic potential of PRP to block tumor growth, we engineered tumor cells to express this hormone. Both SV40-transformed BALB/c mouse 3T3 fibroblasts and rat C6 glioma cells have markedly reduced growth rates as tumors in mice if they express high levels of PRP. In both models, the small tumors that form are largely avascular, whereas control tumors are rich in blood vessels, consistent with PRP limiting tumor growth by preventing neovascularization of the tumors. The antiangiogenic effects of PRP are also detected on human endothelial cells, suggesting that the receptor and signaling pathway of this mouse hormone are conserved between mouse and human and may represent useful targets for the development of antiangiogenic therapeutics. That signaling pathway appears to involve an inhibition of arachidonic acid release, based on the ability of arachidonic acid to overcome the antiangiogenic effects of PRP.
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Proliferin induces endothelial cell chemotaxis through a g protein coupled mitogen activated protein kinase dependent pathway
Endocrinology, 1997Co-Authors: John C Groskopf, Li Jyun Syu, Alan R Saltiel, Daniel I. H. LinzerAbstract:To investigate the mechanism of action of the placental angiogenic hormone Proliferin (PLF), we analyzed the signaling components in endothelial cells that are required for PLF-induced chemotaxis. Pertussis toxin, which inactivates Gi proteins, inhibited PLF-induced chemotaxis of endothelial cells. Gi proteins can lead to activation of the mitogen-activated protein kinase (MAPK) pathway; PLF was found to stimulate MAPK activity, and this induction was blocked by both pertussis toxin and a specific inhibitor of MAPK kinase, PD 098059. Furthermore, a blockade of MAPK activation prevented endothelial cell movement in response to PLF. As PLF functionally interacts with the insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptor, we also examined the effects of pertussis toxin and PD 098059 on another ligand for this receptor, a mutant form of IGF-II; both inhibitors also block the action of this factor on endothelial cells. These data suggest that chemotaxis initiated by PLF and mediated by the IG...
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Proliferin transport and binding in the mouse fetus
Endocrinology, 1997Co-Authors: Dowdy Jackson, Daniel I. H. LinzerAbstract:Proliferin (PLF), a member of the PRL/GH family secreted by the placenta, can be detected in both the maternal and fetal compartments. We now show that PLF immunoreactivity can be detected in association with the yolk sac, consistent with the transport of PLF across this structure into the amniotic fluid. Furthermore, PLF is transported across the extraembryonic membranes in isolated conceptuses that are placed in culture, and specific binding sites for PLF are detected in these embryos. The major binding sites for PLF in the cultured conceptus correspond to sites at which endogenous PLF localizes in the fetus, including developing vertebral and vascular structures. Similar binding patterns were also detected for PLF that was incubated with fetal sections. Competition and comparative binding studies indicate that the insulin-like growth factor II/mannose 6-phosphate receptor is involved in PLF binding to specific cells in the fetus. These results suggest that in addition to the effects of PLF in the place...
Andreas Friedl - One of the best experts on this subject based on the ideXlab platform.
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stat5 and prolactin participate in a positive autocrine feedback loop that promotes angiogenesis
Journal of Biological Chemistry, 2013Co-Authors: Xinhai Yang, Kristy Meyer, Andreas FriedlAbstract:Abstract We have shown previously that the murine prolactin/growth hormone family member Proliferin plays a pivotal role in angiogenesis induced by the FGF2/STAT5 signaling cascade. To delineate the signaling pathway downstream of STAT5 in the human system, where Proliferin does not exist, we expressed constitutively active (CA) or dominant-negative (DN) mutant STAT5A in hCMEC/D3 human brain endothelial cells. We found that conditioned medium from CA-STAT5A- but not from DN-STAT5A-overexpressing endothelial cells (EC) is sufficient to induce EC migration and tube formation but not proliferation, indicating that STAT5A regulates the secretion of autocrine proangiogenic factors. We identified prolactin (PRL) as a candidate autocrine factor. CA-STAT5A expression stimulates PRL production at the RNA and protein level, and STAT5A binds to the PRL promoter region, suggesting direct transcriptional regulation. Medium conditioned by CA-STAT5A-overexpressing EC induces phosphorylation of the PRL receptor and activates MAPK. Knockdown of PRL expression by shRNA or blocking of PRL activity with neutralizing antibodies removed the CA-STAT5A-dependent proangiogenic activity from the conditioned medium of EC. The addition of recombinant PRL restores this activity. STAT5A-induced PRL in the conditioned medium can activate STAT5, STAT1, and to a lesser extent STAT3 in hCMEC/D3 cells, suggesting the existence of a positive feedback loop between STAT5 and PRL that promotes angiogenesis. Furthermore, we find that VEGF, a potent proangiogenic factor, is induced by activation of STAT5A, and VEGF induction depends on PRL expression. These observations demonstrate a STAT5/PRL/VEGF signaling cascade in human brain EC and implicate PRL and VEGF as autocrine regulators of EC migration, invasion, and tube formation.
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angiogenesis induced by signal transducer and activator of transcription 5a stat5a is dependent on autocrine activity of Proliferin
Journal of Biological Chemistry, 2012Co-Authors: Xinhai Yang, Dianhua Qiao, Kristy Meyer, Thomas Pier, Sunduz Keles, Andreas FriedlAbstract:Abstract Multiple secreted factors induce the formation of new blood vessels (angiogenesis). The signal transduction events that orchestrate the numerous cellular activities required for angiogenesis remain incompletely understood. We have shown previously that signal transducer and activator of transcription 5 (STAT5) plays a pivotal role in angiogenesis induced by FGF2 and FGF8b. To delineate the signaling pathway downstream of STAT5, we expressed constitutively active (CA) or dominant-negative (DN) mutant STAT5A in mouse brain endothelial cells (EC). We found that the conditioned medium from CA-STAT5A but not from DN-STAT5A overexpressing EC is sufficient to induce EC invasion and tube formation, indicating that STAT5A regulates the secretion of autocrine proangiogenic factors. Conversely, CA-STAT5A-induced conditioned medium had no effect on EC proliferation. Using a comparative genome-wide transcription array screen, we identified the prolactin family member Proliferin (PLF1 and PLF4) as a candidate autocrine factor. The CA-STAT5A-dependent transcription and secretion of PLF by EC was confirmed by qRT-PCR and Western blotting, respectively. CA-STAT5A binds to the PLF1 promoter region, suggesting a direct transcriptional regulation. Knockdown of PLF expression by sh-RNA or by blocking of PLF activity with neutralizing antibodies removed the CA-STAT5A-dependent proangiogenic activity from the conditioned medium of EC. Similarly, the ability of concentrated conditioned medium from CA-STAT5A transfected EC to induce angiogenesis in matrigel plugs in vivo was abolished when PLF was depleted from the medium. These observations demonstrate a FGF/STAT5/PLF signaling cascade in EC and implicate PLF as autocrine regulator of EC invasion and tube formation.
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angiogenesis induced by signal transducer and activator of transcription 5a stat5a is dependent on autocrine activity of Proliferin
Journal of Biological Chemistry, 2012Co-Authors: Xinhai Yang, Dianhua Qiao, Kristy Meyer, Thomas Pier, Sunduz Keles, Andreas FriedlAbstract:Multiple secreted factors induce the formation of new blood vessels (angiogenesis). The signal transduction events that orchestrate the numerous cellular activities required for angiogenesis remain incompletely understood. We have shown previously that STAT5 plays a pivotal role in angiogenesis induced by FGF2 and FGF8b. To delineate the signaling pathway downstream of STAT5, we expressed constitutively active (CA) or dominant-negative (DN) mutant STAT5A in mouse brain endothelial cells (EC). We found that the conditioned medium from CA-STAT5A but not from dominant-negative STAT5A overexpressing EC is sufficient to induce EC invasion and tube formation, indicating that STAT5A regulates the secretion of autocrine proangiogenic factors. Conversely, CA-STAT5A-induced conditioned medium had no effect on EC proliferation. Using a comparative genome-wide transcription array screen, we identified the prolactin family member Proliferin (PLF1 and PLF4) as a candidate autocrine factor. The CA-STAT5A-dependent transcription and secretion of PLF by EC was confirmed by quantitative RT-PCR and Western blotting, respectively. CA-STAT5A binds to the PLF1 promoter region, suggesting a direct transcriptional regulation. Knockdown of PLF expression by shRNA or by blocking of PLF activity with neutralizing antibodies removed the CA-STAT5A-dependent proangiogenic activity from the conditioned medium of EC. Similarly, the ability of concentrated conditioned medium from CA-STAT5A transfected EC to induce angiogenesis in Matrigel plugs in vivo was abolished when PLF was depleted from the medium. These observations demonstrate a FGF/STAT5/PLF signaling cascade in EC and implicate PLF as autocrine regulator of EC invasion and tube formation.
Carmen Clapp - One of the best experts on this subject based on the ideXlab platform.
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roles of prolactin and related members of the prolactin growth hormone placental lactogen family in angiogenesis
Journal of Endocrinology, 2002Co-Authors: Ana M Corbacho, Martinez G De La Escalera, Carmen ClappAbstract:Prolactin, growth hormone and placental lactogen are members of a family of polypeptide hormones which share structural similarities and biological activities. Numerous functions have been attributed to these hormones, among which stand out their recently discovered effects on angiogenesis, the process by which new blood vessels are formed from the pre-existing microvasculature. Prolactin, growth hormone and placental lactogen, along with two non-classical members of the family, Proliferin and Proliferin-related protein, can act both as circulating hormones and as paracrine/autocrine factors to either stimulate or inhibit various stages of the formation and remodeling of new blood vessels, including endothelial cell proliferation, migration, protease production and apoptosis. Such opposing actions can reside in similar but independent molecules, as is the case of Proliferin and Proliferin-related protein, which stimulate and inhibit angiogenesis respectively. The potential to exert opposing effects on angiogenesis can also reside within the same molecule as the parent protein can promote angiogenesis (i.e. prolactin, growth hormone and placental lactogen), but after proteolytic processing the resulting peptide fragment acquires anti-angiogenic properties (i.e. 16 kDa prolactin, 16 kDa growth hormone and 16 kDa placental lactogen). The unique properties of the peptide fragments versus the full-length molecules, the regulation of the protease responsible for specific protein cleavage, the selective expression of specific receptors and their associated signal transduction pathways are issues that are being investigated to further establish the precise contribution of these hormones to angiogenesis under both physiological and pathological situations. In this review article, we summarize the known and speculative issues underlying the effects of the prolactin, growth hormone and placental lactogen family of proteins on angiogenesis, and address important remaining enigmas in this field of research.
Marit Nilsenhamilton - One of the best experts on this subject based on the ideXlab platform.
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mrp3 a mitogen regulated protein Proliferin gene expressed in wound healing and in hair follicles
Endocrinology, 2001Co-Authors: John T. Fassett, Marit NilsenhamiltonAbstract:During cutaneous wound healing, a marked increase in the local expression of growth factors results in increased migration and proliferation of the cells responsible for tissue repair. The mitogen-regulated protein (MRP)/Proliferin proteins are growth factors and angiogenesis factors. Here it is demonstrated that Mrp3 is induced in wound edge keratinocytes during cutaneous wound healing and also temporally appears in the outer root sheath of the hair follicle during the late anagen phase of the hair cycle. In cultured keratinocytes, Mrp3 is induced by keratinocyte growth factor, but not by epidermal growth factor or by transforming growth factor type α. Transgenic mice, expressing lacZ under the combined control of the cytomegalovirus immediate early enhancer and the Mrp3 flanking sequences, demonstrate wound- and hair cycle-induced transgene expression. These results show that elements within the flanking regulatory sequences of the Mrp3 gene are involved in the activation of Mrp3 in response to these ev...
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mrp4 a new mitogen regulated protein Proliferin gene unique in this gene family for its expression in the adult mouse tail and ear
Endocrinology, 2000Co-Authors: John T. Fassett, Richard T Hamilton, Marit NilsenhamiltonAbstract:Mitogen-regulated proteins (also known as Proliferin; mrp/plf) are nonclassical members of the PRL/GH family. They are expressed at high levels during midgestation when they are thought to induce angiogenesis and uterine growth. There are between four and six mrp/plf genes, and three different complementary DNAs have been cloned. Here we identify a fourth mrp/plf gene (mrp4) that we have cloned and characterized. MRP4 is 91% identical in amino acid sequence with the other MRP/PLF proteins but is missing two glycosylation sites that are present in the other forms. Consistent with the loss of two of three glycosylation sites, the expressed form of MRP4 has a lower apparent molecular weight compared with other MRP/PLFs. In vivo, mrp4 is expressed in the placenta and the adult skin. Expression of mrp4 messenger RNA peaks in the placenta on day 12. In the skin, mrp4 expression is specific to the ears and tails of mice. Our results suggest that, as well as having growth and angiogenic effects during pregnancy, ...
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characterization of the mitogen regulated protein Proliferin receptor
Endocrinology, 1995Co-Authors: J T Nelson, N Rosenzweig, Marit NilsenhamiltonAbstract:Mitogen-regulated protein (MRP/PLF; also called Proliferin) is a member of the PRL-GH family expressed by the placenta in mid-gestation. This report describes an MRP/PLF receptor in uterine membrane preparations from pregnant mice. Peak receptor activity occurred at 11 days of gestation with a dissociation constant of 6 x 10(-10) M and maximal binding capacity of 86 fmole MRP/PLF/mg membrane protein. PRL, PL-I, and mannose-6-phosphate did not compete for binding, and GH competed weakly only at high concentrations. Primary cells cultured from uteri taken at days 8-11 of gestation responded to MRP/PLF with increases in DNA synthesis. Uterine cells from later stages of gestation did not respond to MRP/PLF. This is the first reported evidence of a function mediated by MRP/PLF and suggests a role for this protein in maternal-fetal interactions during reproduction. Thus, it seems that MRP/PLF is a placentally derived growth factor, which stimulates proliferation in the uterus in a developmentally defined period to coordinate uterine growth with fetal development.
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regulation of the expression of mitogen regulated protein mrp Proliferin and cathepsin l in cultured cells and in the murine placenta
Molecular and Cellular Endocrinology, 1991Co-Authors: Marit Nilsenhamilton, Craig L J Parfett, David T Denhardt, Yngju Jang, Michael Delgado, Jaekyoung Shim, Kerry A Bruns, Chiaping Chiang, Yu Fang, Richard T HamiltonAbstract:The genes encoding mitogen-regulated protein (MRP; also called Proliferin; PLF) and procathepsin L (CL; also called major excreted protein; MEP) are expressed to high levels in the mouse placenta. Although they are both regulated by epidermal growth factor (EGF) and fibroblast growth factor (FGF) in 3T3 cells, expression of these genes is differently regulated with growth state. The expression patterns of MRP and CL as a function of murine development are also different. Basal and growth factor-stimulated levels of MRP expression are much higher in growing than in quiescent 3T3 cells, whereas CL levels are similar. These changes in gene expression in cultured quiescent cells parallel the changes in MRP and CL expression observed in the late-gestational quiescent placenta. These results suggest growth factors may regulate the expression of these genes, but other influences also regulate the expression of MRP and CL in vivo.
Ana M Corbacho - One of the best experts on this subject based on the ideXlab platform.
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219 REVIEW Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis
2013Co-Authors: Ana M Corbacho, Martinez G De La EscaleraAbstract:Prolactin, growth hormone and placental lactogen are members of a family of polypeptide hormones which share structural similarities and biological activities. Numerous functions have been attributed to these hormones, among which stand out their recently discovered effects on angiogenesis, the process by which new blood vessels are formed from the pre-existing microvasculature. Prolactin, growth hormone and placental lactogen, along with two non-classical members of the family, Proliferin and Proliferin-related protein, can act both as circulating hormones and as paracrine/autocrine factors to either stimulate or inhibit various stages of the formation and remodeling of new blood vessels, including endothelial cell proliferation, migration, protease production and apoptosis
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roles of prolactin and related members of the prolactin growth hormone placental lactogen family in angiogenesis
Journal of Endocrinology, 2002Co-Authors: Ana M Corbacho, Martinez G De La Escalera, Carmen ClappAbstract:Prolactin, growth hormone and placental lactogen are members of a family of polypeptide hormones which share structural similarities and biological activities. Numerous functions have been attributed to these hormones, among which stand out their recently discovered effects on angiogenesis, the process by which new blood vessels are formed from the pre-existing microvasculature. Prolactin, growth hormone and placental lactogen, along with two non-classical members of the family, Proliferin and Proliferin-related protein, can act both as circulating hormones and as paracrine/autocrine factors to either stimulate or inhibit various stages of the formation and remodeling of new blood vessels, including endothelial cell proliferation, migration, protease production and apoptosis. Such opposing actions can reside in similar but independent molecules, as is the case of Proliferin and Proliferin-related protein, which stimulate and inhibit angiogenesis respectively. The potential to exert opposing effects on angiogenesis can also reside within the same molecule as the parent protein can promote angiogenesis (i.e. prolactin, growth hormone and placental lactogen), but after proteolytic processing the resulting peptide fragment acquires anti-angiogenic properties (i.e. 16 kDa prolactin, 16 kDa growth hormone and 16 kDa placental lactogen). The unique properties of the peptide fragments versus the full-length molecules, the regulation of the protease responsible for specific protein cleavage, the selective expression of specific receptors and their associated signal transduction pathways are issues that are being investigated to further establish the precise contribution of these hormones to angiogenesis under both physiological and pathological situations. In this review article, we summarize the known and speculative issues underlying the effects of the prolactin, growth hormone and placental lactogen family of proteins on angiogenesis, and address important remaining enigmas in this field of research.
