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Alan J. Knox - One of the best experts on this subject based on the ideXlab platform.
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endothelin 1 et 1 increases the expression of remodeling genes in vascular smooth muscle through linked calcium and camp pathways role of a phospholipase a2 cpla2 cyclooxygenase 2 cox 2 prostacyclin receptor dependent autocrine loop
Journal of Biological Chemistry, 2010Co-Authors: Karl Deacon, Alan J. KnoxAbstract:Several important genes that are involved in inflammation and tissue remodeling are switched on by virtue of CRE response elements in their promoters. The upstream signaling mechanisms that inflammatory mediators use to activate cAMP response elements (CREs) are poorly understood. Endothelin (ET) is an important vasoactive mediator that plays roles in inflammation, vascular remodeling, angiogenesis, and carcinogenesis by activating 7 transmembrane G protein-coupled receptors (GPCR). Here we characterized the mechanisms ET-1 uses to regulate CRE-dependent remodeling genes in pulmonary vascular smooth muscle cells. These studies revealed activation pathways involving a cyclooxygenase-2 (COX-2)/prostacyclin receptor (IP receptor) autocrine loop and an interlinked calcium-dependent pathway. We found that ET-1 activated several CRE response genes in vascular smooth muscle cells, particularly COX-2, amphiregulin, follistatin, inhibin-β-A, and CYR61. ET-1 also activated two other genes Epiregulin and HB-EGF. Amphiregulin, follistatin, and inhibin-β-A and Epiregulin were activated by an autocrine loop involving cPLA2, arachidonic acid release, COX-2-dependent PGI2 synthesis, and IP receptor-linked elevation of cAMP leading to CRE transcription activation. In contrast COX-2, CYR61, and HB-EGF transcription were regulated in a calcium-dependent, COX-2 independent, manner. Observations with IP receptor antagonists and COX-2 inhibitors were confirmed with IP receptor or COX-2-specific small interfering RNAs. ET-1 increases in intracellular calcium and gene transcription were dependent upon ETa activation and calcium influx through T type voltage-dependent calcium channels. These studies give important insights into the upstream signaling mechanisms used by G protein-coupled receptor-linked mediators such as ET-1, to activate CRE response genes involved in angiogenesis, vascular remodeling, inflammation, and carcinogenesis.
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endothelin 1 et 1 increases the expression of remodeling genes in vascular smooth muscle through linked calcium and camp pathways role of a phospholipase a2 cpla2 cyclooxygenase 2 cox 2 prostacyclin receptor dependent autocrine loop
Journal of Biological Chemistry, 2010Co-Authors: Karl Deacon, Alan J. KnoxAbstract:Several important genes that are involved in inflammation and tissue remodeling are switched on by virtue of CRE response elements in their promoters. The upstream signaling mechanisms that inflammatory mediators use to activate cAMP response elements (CREs) are poorly understood. Endothelin (ET) is an important vasoactive mediator that plays roles in inflammation, vascular remodeling, angiogenesis, and carcinogenesis by activating 7 transmembrane G protein-coupled receptors (GPCR). Here we characterized the mechanisms ET-1 uses to regulate CRE-dependent remodeling genes in pulmonary vascular smooth muscle cells. These studies revealed activation pathways involving a cyclooxygenase-2 (COX-2)/prostacyclin receptor (IP receptor) autocrine loop and an interlinked calcium-dependent pathway. We found that ET-1 activated several CRE response genes in vascular smooth muscle cells, particularly COX-2, amphiregulin, follistatin, inhibin-β-A, and CYR61. ET-1 also activated two other genes Epiregulin and HB-EGF. Amphiregulin, follistatin, and inhibin-β-A and Epiregulin were activated by an autocrine loop involving cPLA2, arachidonic acid release, COX-2-dependent PGI2 synthesis, and IP receptor-linked elevation of cAMP leading to CRE transcription activation. In contrast COX-2, CYR61, and HB-EGF transcription were regulated in a calcium-dependent, COX-2 independent, manner. Observations with IP receptor antagonists and COX-2 inhibitors were confirmed with IP receptor or COX-2-specific small interfering RNAs. ET-1 increases in intracellular calcium and gene transcription were dependent upon ETa activation and calcium influx through T type voltage-dependent calcium channels. These studies give important insights into the upstream signaling mechanisms used by G protein-coupled receptor-linked mediators such as ET-1, to activate CRE response genes involved in angiogenesis, vascular remodeling, inflammation, and carcinogenesis.
Toshi Komurasaki - One of the best experts on this subject based on the ideXlab platform.
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common behavioral influences of the erbb1 ligands transforming growth factor alpha and Epiregulin administered to mouse neonates
Brain & Development, 2008Co-Authors: Noriko Tsuda, Toshi Komurasaki, Makoto Yoshimoto, Makoto Mizuno, Takayuki Yamanaka, Hiroyuki NawaAbstract:Abstract Ligands for epidermal growth factor (EGF) receptor (ErbB1), such as EGF, transforming growth factor alpha (TGFα), and Epiregulin, are enriched in body fluids and blood and regulate development of various peripheral organs. It remains however how such circulating polypeptide growth factors influence brain development and function. Here, we performed peripheral injections of TGFα and Epiregulin to mouse neonates and evaluated immediate physical and neurochemical development and later behavioral consequences. Subcutaneous administration of TGFα and Epiregulin increased phosphorylation of brain ErbB1, suggesting their effects on brain development. Repeated their injections similarly enhanced physical development of eyelid opening and tooth eruption during early postnatal stage and resulted in abnormal behavioral traits in the adult stage. Acoustic startle responses of mice treated with these growth factors as neonates were enhanced and prepulse inhibition was decreased without an apparent correlation between prepulse inhibition level and startle intensity. Locomotor activity and fear-learning performance with tone and context cues were not altered, however. These results suggest that circulating ErbB1 ligands in the periphery of neonates have some common influences on later behavioral traits. Abnormal ErbB1 ligand production at neonatal and potentially prenatal stages might therefore associate with neurodevelopmental disorders such as schizophrenia.
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mesenchymal epithelial interactions involving Epiregulin in tuberous sclerosis complex hamartomas
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Fumiko Takeuchi, Toshi Komurasaki, Jian Wang, Qingyuan Fan, Eric M Billings, Gustavo Pachecorodriguez, Joel Moss, Thomas N DarlingAbstract:Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the existence or location of cells with biallelic mutations (“two-hit” cells) was unclear. We compared TSC skin hamartomas (angiofibromas and periungual fibromas) with normal-appearing skin of the same patient, and we observed more proliferation and mTOR activation in hamartoma epidermis. Two-hit cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal–epithelial interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more Epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of Epiregulin mRNA was confirmed with real-time PCR, and increased amounts of Epiregulin protein were demonstrated with immunoprecipitation. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by two-hit cells in the dermis and that proliferation with mTOR activation of the overlying epidermis is an effect of Epiregulin.
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Effect of Epiregulin on pancreatic beta cell growth and insulin secretion.
Growth Factors, 2005Co-Authors: Emmanuelle Kuntz, Toshi Komurasaki, Christophe Broca, Marie-christine Kaltenbacher, René Gross, Michel Pinget, Christiane DamgéAbstract:The aim of this study was to determine whether Epiregulin, a novel member of EGF-related growth factor family, was able to affect proliferation and secretory function of rat insulinoma INS-1E and RINm5F cell lines. A 24 h treatment with Epiregulin resulted in a stimulation of INS-1E and RINm5F cells proliferation; this effect was completely blocked in the presence of an anti-Epiregulin antibody which did not affect basal DNA synthesis in the absence of added ligand. In acute experiments, Epiregulin was able to potentiate insulin release in the presence of glucose or arginine, in the two cell lines. Finally, in the two cell lines expressing ErbB receptors, we demonstrated that only EGFR/ErbB1 was activated by Epiregulin. Thus, Epiregulin appears as a new growth and insulinotropic factor in pancreatic beta cell lines.
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Epiregulin as a major autocrine paracrine factor released from erk and p38mapk activated vascular smooth muscle cells
Circulation, 2003Co-Authors: Masanori Takahashi, Kenji Yoshida, Toshi Komurasaki, Kenichiro Hayashi, Yasuyuki Ohkawa, Akira Kitabatake, Akira Ogawa, Wataru Nishida, Masahiko Yano, Morito MondenAbstract:Background— The coordinated activation of extracellular signal–regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non–heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs). Methods and Results— We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified Epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The Epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent V...
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topical Epiregulin enhances repair of murine excisional wounds
Wound Repair and Regeneration, 2003Co-Authors: Bradley K Draper, Toshi Komurasaki, Mari K Davidson, Lillian B NanneyAbstract:Epiregulin is a broad specificity epidermal growth factor family member that activates ErbB1 and ErbB4 homodimers and all possible heterodimeric ErbB complexes. Our objective was to determine whether topical Epiregulin enhanced repair of murine excisional wounds. Wounds were treated on days 0–4 with either topical Epiregulin (1 µg/ml), epidermal growth factor (10 µg/ml), or vehicle. At day 5 postinjury, wounds receiving Epiregulin were significantly smaller than those treated with epidermal growth factor or vehicle. Treatment with Epiregulin promoted greater epidermal proliferation and thickening than epidermal growth factor or vehicle due to an expansion of the proliferative compartment of keratinocytes. Dermal thickness was also increased in Epiregulin-treated wounds as compared to those treated with epidermal growth factor or vehicle. In day 5 wounds, matrix metalloproteinase-3 (stromelysin-1) mRNA levels were significantly lower in Epiregulin- or epidermal growth factor-treated wounds than in vehicle-treated controls, suggesting that growth factor-treated wounds were more mature and required less ongoing proteolytic activity than their same-day vehicle-treated counterparts. This is the first report that topical Epiregulin accelerates repair of full-thickness murine excisional wounds as compared to vehicle or epidermal growth factor. Furthermore, Epiregulin is more potent and more effective than epidermal growth factor in promoting proliferation and maturation of the epidermis as well as enhancement of the neodermis. (WOUND REP REG 2003;11:188–197)
Karl Deacon - One of the best experts on this subject based on the ideXlab platform.
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endothelin 1 et 1 increases the expression of remodeling genes in vascular smooth muscle through linked calcium and camp pathways role of a phospholipase a2 cpla2 cyclooxygenase 2 cox 2 prostacyclin receptor dependent autocrine loop
Journal of Biological Chemistry, 2010Co-Authors: Karl Deacon, Alan J. KnoxAbstract:Several important genes that are involved in inflammation and tissue remodeling are switched on by virtue of CRE response elements in their promoters. The upstream signaling mechanisms that inflammatory mediators use to activate cAMP response elements (CREs) are poorly understood. Endothelin (ET) is an important vasoactive mediator that plays roles in inflammation, vascular remodeling, angiogenesis, and carcinogenesis by activating 7 transmembrane G protein-coupled receptors (GPCR). Here we characterized the mechanisms ET-1 uses to regulate CRE-dependent remodeling genes in pulmonary vascular smooth muscle cells. These studies revealed activation pathways involving a cyclooxygenase-2 (COX-2)/prostacyclin receptor (IP receptor) autocrine loop and an interlinked calcium-dependent pathway. We found that ET-1 activated several CRE response genes in vascular smooth muscle cells, particularly COX-2, amphiregulin, follistatin, inhibin-β-A, and CYR61. ET-1 also activated two other genes Epiregulin and HB-EGF. Amphiregulin, follistatin, and inhibin-β-A and Epiregulin were activated by an autocrine loop involving cPLA2, arachidonic acid release, COX-2-dependent PGI2 synthesis, and IP receptor-linked elevation of cAMP leading to CRE transcription activation. In contrast COX-2, CYR61, and HB-EGF transcription were regulated in a calcium-dependent, COX-2 independent, manner. Observations with IP receptor antagonists and COX-2 inhibitors were confirmed with IP receptor or COX-2-specific small interfering RNAs. ET-1 increases in intracellular calcium and gene transcription were dependent upon ETa activation and calcium influx through T type voltage-dependent calcium channels. These studies give important insights into the upstream signaling mechanisms used by G protein-coupled receptor-linked mediators such as ET-1, to activate CRE response genes involved in angiogenesis, vascular remodeling, inflammation, and carcinogenesis.
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endothelin 1 et 1 increases the expression of remodeling genes in vascular smooth muscle through linked calcium and camp pathways role of a phospholipase a2 cpla2 cyclooxygenase 2 cox 2 prostacyclin receptor dependent autocrine loop
Journal of Biological Chemistry, 2010Co-Authors: Karl Deacon, Alan J. KnoxAbstract:Several important genes that are involved in inflammation and tissue remodeling are switched on by virtue of CRE response elements in their promoters. The upstream signaling mechanisms that inflammatory mediators use to activate cAMP response elements (CREs) are poorly understood. Endothelin (ET) is an important vasoactive mediator that plays roles in inflammation, vascular remodeling, angiogenesis, and carcinogenesis by activating 7 transmembrane G protein-coupled receptors (GPCR). Here we characterized the mechanisms ET-1 uses to regulate CRE-dependent remodeling genes in pulmonary vascular smooth muscle cells. These studies revealed activation pathways involving a cyclooxygenase-2 (COX-2)/prostacyclin receptor (IP receptor) autocrine loop and an interlinked calcium-dependent pathway. We found that ET-1 activated several CRE response genes in vascular smooth muscle cells, particularly COX-2, amphiregulin, follistatin, inhibin-β-A, and CYR61. ET-1 also activated two other genes Epiregulin and HB-EGF. Amphiregulin, follistatin, and inhibin-β-A and Epiregulin were activated by an autocrine loop involving cPLA2, arachidonic acid release, COX-2-dependent PGI2 synthesis, and IP receptor-linked elevation of cAMP leading to CRE transcription activation. In contrast COX-2, CYR61, and HB-EGF transcription were regulated in a calcium-dependent, COX-2 independent, manner. Observations with IP receptor antagonists and COX-2 inhibitors were confirmed with IP receptor or COX-2-specific small interfering RNAs. ET-1 increases in intracellular calcium and gene transcription were dependent upon ETa activation and calcium influx through T type voltage-dependent calcium channels. These studies give important insights into the upstream signaling mechanisms used by G protein-coupled receptor-linked mediators such as ET-1, to activate CRE response genes involved in angiogenesis, vascular remodeling, inflammation, and carcinogenesis.
Hitoshi Toyoda - One of the best experts on this subject based on the ideXlab platform.
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mechanism of growth promoting activity of Epiregulin in primary cultures of rat hepatocytes
Growth Factors Journal, 2002Co-Authors: Toshi Komurasaki, Hitoshi Toyoda, Daisuke Uchida, Nobuo NemotoAbstract:In spite of lower receptor affinity, Epiregulin exhibits a stronger stimulation of DNA synthesis than epidermal growth factor (EGF) in rat hepatocytes. To determine the mechanism of stimulation, we examined the activities of Epiregulin on growth stimulation, signal transduction, and mRNA induction of hepatotrophic factors in primary cultures of rat hepatocytes. Epiregulin stimulated hepatocyte proliferation as efficiently as hepatotrophic factors, including heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor-alpha (TGF-alpha). Epiregulin induced a more prolonged activation of EGF receptor (EGFR) and p42/44 mitogen-activated protein kinase (MAPK) than EGF. Furthermore, Epiregulin up-regulated the mRNAs of TGF-alpha and HB-EGF, and in turn, these growth factors enhanced the expression of Epiregulin mRNA. In vivo, increased production of Epiregulin was noted in extracts of the remnant liver obtained 24 h after partial hepatectomy, and EGFR phosphorylation by these extracts was partially inhibited by anti-Epiregulin antibody. Our results showed a more potent hepatocyte proliferative activity for Epiregulin compared with EGF in vitro, which depends on prolonged activation of EGFR and p42/44 MAPK. Our findings suggest that Epiregulin may play significant roles in liver regeneration following partial hepatectomy in cooperation with other growth factors.
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Epiregulin a novel member of the epidermal growth factor family is an autocrine growth factor in normal human keratinocytes
Journal of Biological Chemistry, 2000Co-Authors: Yuji Shirakata, Toshi Komurasaki, Hitoshi Toyoda, Yasushi Hanakawa, Kenshi Yamasaki, Sho Tokumaru, Koji Sayama, Koji HashimotoAbstract:Epiregulin is a new member of the epidermal growth factor (EGF) family purified from conditioned medium of NIH-3T3 clone T7. Some EGF family growth factors play essential roles in human keratinocytes in an autocrine manner. We show here that Epiregulin is another autocrine growth factor for human keratinocytes. Epiregulin stimulated human keratinocyte proliferation under both subconfluent and confluent culture conditions in the absence of exogenous EGF family growth factors. Immunoprecipitation of [35S]methionine-labeled conditioned medium revealed a 5-kDa band corresponding to Epiregulin. Northern blot analysis detected a 4.8-kilobase transcript of Epiregulin, and the addition of Epiregulin up-regulated Epiregulin mRNA synthesis. Furthermore, an anti-Epiregulin blocking antibody reduced DNA synthesis by 25%. Epiregulin up-regulated the mRNA levels of heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, and TGF-α. In turn, the addition of EGF, HB-EGF, amphiregulin, and TGF-α increased Epiregulin mRNA levels. These results demonstrate that Epiregulin acts as an autocrine growth factor in human epidermal keratinocytes and is part of auto- and cross-induction mechanisms involving HB-EGF, amphiregulin, and TGF-α. The mRNA expression profile resulting from induction of differentiation with high calcium and fetal calf serum revealed the differential expression of Epiregulin, HB-EGF, amphiregulin, and TGF-α in keratinocytes. This indicates that these four growth factors have distinct, non-redundant biological functions.
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anti egfr monoclonal antibodies which act as egf tgfα hb egf and btc antagonists block the binding of Epiregulin to egfr expressing tumours
International Journal of Cancer, 1998Co-Authors: Helmout Modjtahedi, Toshi Komurasaki, Hitoshi Toyoda, C J DeanAbstract:Epiregulin is the newest member of the epidermal growth factor (EGF) family of ligands that was isolated from conditioned medium of the murine fibroblast-derived tumour cell line NIH3T3/T7. Here, using a panel of anti-EGFR receptor (EGFR) monoclonal antibodies (MAbs) directed against 4 distinct epitopes on the external domain of the receptor, we have investigated the importance of the EGFR in transmitting the biological action of Epiregulin. We found that MAb ICR9, which enhances the binding of EGF, TGF alpha, HB-EGF and betacellulin to the EGFR, also increases the binding of 125I-Epiregulin to a number of EGFR-expressing tumour cell lines, including EJ, SKBR3, SKOV3, MDA-MB468 and HN5. In addition, anti-EGFR MAbs ICR15, ICR16, ICR61, ICR62 and ICR80, which block the binding of 125I-EGF to the EGFR, inhibit the binding of 125I-Epiregulin to these tumour cell lines. Like EGF, we found that both the Epiregulin-induced growth inhibition of HN5 and MDA-MB468 cells and tyrosine phosphorylation of the 170 kDa EGFR on HN5 cells are reversed in the presence of anti-EGFR MAbs ICR62 and ICR80. Surprisingly and unlike 125I-EGF, radiolabelled Epiregulin bound very poorly to human bladder carcinoma EJ cells and its binding to SKOV3 cells was not inhibited efficiently in the presence of blocking antibodies. We conclude that the EGFR plays an important role in transmitting the biological action of Epiregulin and that these effects could be blocked in the presence of anti-EGFR MAbs. The low level of binding of Epiregulin compared with EGF to EJ cells suggests that the EGFR may not be the primary receptor for Epiregulin.
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Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4.
Oncogene, 1997Co-Authors: Toshi Komurasaki, Hitoshi Toyoda, Daisuke Uchida, Shigeo MorimotoAbstract:Epiregulin is a member of the epidermal growth factor (EGF) family, and has certain characteristics that are different from that of EGF, including mitogenic responses and binding to EGF receptor (EGFR). Epiregulin may also have another cell surface receptor and/or induces different receptor heterodimerizations for intracellular signaling. We investigated the binding ability of Epiregulin to four ErbB family receptors using four human breast carcinoma cell lines that expressed different subsets of receptors. Chemical cross-linking experiments showed that [125I]Epiregulin directly bound to each of EGFR and ErbB-4 but not to ErbB-2 and ErbB-3. Furthermore, although Epiregulin stimulated tyrosine phosphorylation of all four ErbB receptors, the main intracellular signal was mediated by ErbB-4 and/or EGFR. The pattern of activation of ErbB family receptors was different from that of other EGF-related ligands. Our findings indicate that ErbB-4 and EGFR are receptors for Epiregulin, and suggest that EGF-related ligands transduce signals for different biological responses by the hierarchical mechanism.
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distribution of mrna for human Epiregulin a differentially expressed member of the epidermal growth factor family
Biochemical Journal, 1997Co-Authors: Hitoshi Toyoda, Toshi Komurasaki, Daisuke Uchida, Sigeo MorimotoAbstract:We have recently identified Epiregulin as a new growth regulator and a member of the epidermal growth factor (EGF) family. Epiregulin has certain characteristics that are different from those of the classical members of the EGF family, EGF and transforming growth factor α, including mitogenic responses on several normal cells and binding to EGF receptors on epidermoid carcinoma A431 cells. In the present study we cloned and identified the expression of human Epiregulin transcript. The human Epiregulin gene encoded a 163-residue putative transmembrane precursor containing an EGF-like domain in the internal segment, and the structural organization was similar to that of other members of the EGF family that bind to EGF receptors. Northern blot analysis showed the expression of human Epiregulin to be mainly on peripheral blood macrophages and the placenta in normal tissues, and was highest on epithelial tumour cell lines in various types of tumour cell lines. The expression profile was quite different from that of other members of the EGF family in normal and tumour cells. Recombinant expression in mammalian cells also showed that human Epiregulin was secreted as a soluble form of approx. 5 kDa that is biologically active on the basis of the stimulation of DNA synthesis. Our findings suggest that Epiregulin is involved in certain physiological processes such as maintenance or development of normal cell growth, and the progression of carcinomas.
Said Kamel - One of the best experts on this subject based on the ideXlab platform.
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overexpression of a functional calcium sensing receptor dramatically increases osteolytic potential of mda mb 231 cells in a mouse model of bone metastasis through Epiregulin mediated osteoprotegerin downregulation
Oncotarget, 2017Co-Authors: Cedric Boudot, Lucie Henaut, Ursula Thiem, Sandra Geraci, Mariangela Galante, Paulo Saldanha, Zuzana Saidak, Isabelle Six, Philippe Clezardin, Said KamelAbstract:// Cedric Boudot 1, * , Lucie Henaut 1, * , Ursula Thiem 1 , Sandra Geraci 2 , Mariangela Galante 1 , Paulo Saldanha 1 , Zuzana Saidak 1 , Isabelle Six 1 , Philippe Clezardin 2 , Said Kamel 1 and Romuald Mentaverri 1 1 Inserm U1088, Centre Universitaire de Recherche en Sante, Universite de Picardie Jules Verne, Amiens, France 2 Inserm UMR 1033, LYOS, Lyon, France * These authors have contributed equally to this work Correspondence to: Said Kamel, email: said.kamel@u-picardie.fr Keywords: bone metastasis, breast cancer, calcium-sensing receptor, Epiregulin, osteolysis Received: July 15, 2016 Accepted: March 14, 2017 Published: April 10, 2017 ABSTRACT Introduction and Aims: Osteolytic bone metastases are observed in advanced cases of breast cancer. In vitro data suggest that the activity of the calcium-sensing receptor (CaSR) expressed by metastatic cells could potentiate their osteolytic potential. This study aimed to demonstrate in vivo the involvement of the CaSR in breast cancer cells osteolytic potential and to identify potential targets linked to CaSR activity. Methods and Results: MDA-MB-231 stably transfected with plasmids containing either a full-length wild-type CaSR (CaSR-WT), or a functionally inactive dominant negative mutant (CaSR-DN) or an empty vector (EV) were intratibially injected into Balb/c-Nude mice. X-ray analysis performed 19 days after injection showed a dramatic increase of osteolytic lesions in mice injected with CaSR-WT-transfected cells as compared to mice injected with EV- or CaSR-DN-transfected cells. This was associated with decreased BV/TV ratio and increased tumor burden. Epiregulin, an EGF-like ligand, was identified by a DNA microarray as a possible candidate involved in CaSR-mediated osteolysis. Indeed, in vitro , CaSR overexpression increased both Epiregulin expression and secretion as compared to EV- or CaSR-DN-transfected cells. Increased Epiregulin expression was also detected in osteolytic bone lesions from mice injected with CaSR-WT-transfected MDA-MB-231. In vitro , exposure of osteoblastic cells (HOB and SaOS2) to exogenous Epiregulin significantly decreased OPG mRNA expression. Exposure of osteoblastic cells to conditioned media prepared from CaSR-WT-transfected cells also decreased OPG expression. This effect was partially blocked after addition of an anti-Epiregulin antibody. Conclusions: Overexpression of a functional CaSR in metastatic breast cancer cells dramatically amplifies their osteolytic potential through Epiregulin-mediated OPG downregulation.