The Experts below are selected from a list of 1458 Experts worldwide ranked by ideXlab platform
Gero Niess - One of the best experts on this subject based on the ideXlab platform.
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a role for the accessory type iii transforming growth factor β receptor TGFBR3 in lung alveolarisation
European Respiratory Journal, 2016Co-Authors: Agnieszka Pozarska, Gero Niess, Werner Seeger, Rory E. MortyAbstract:Bronchopulmonary dysplasia (BPD) is a common complication of premature birth, characterised by arrested secondary septation. Molecular mechanisms of arrested secondary septation are not known. Members of the transforming growth factor (TGF)-β growth factor superfamily are accredited with key roles in lung development and BPD. We profiled lung expression of the TGF-β signaling machinery in mice in a hyperoxia-based BPD model, and detected a down-regulation TGFBR3 expression. Using laser-capture microdissection, TGFBR3 mRNA expression was reduced in both the lung vascular and parenchymal compartments in response to hyperoxia. Abrogation of TGFBR3 expression using siRNA caused a two-fold increase in proliferation and the migration of pulmonary artery smooth muscle cells. Furthermore, knockdown of TGFBR3 in pulmonary microvascular endothelial cells caused a decrease in endothelial tube formation. We then created a floxed TGFBR3 (TGFBR3fl/fl) mouse line, and used this mouse line, in combination with smooth muscle (SMMHC-CreERT2) and endothelial (Tie2-CreERT2) mouse driver lines where Cre-recombinase can be selectively induced in cells with smooth muscle properties and in endothelial cells, respectively, after tamoxifen injection. Induction of Cre-recombinase in post-natal mouse pups at post-natal day (P)1 and P2 caused a 50% decrease in alveolar number at P7 in SMMHC-CreERT2/TGFBR3fl/fl mice, without any change in septal thickness (assessed by stereological analysis). In contrast, there was no effect noted in lung structure in Tie2-CreERT2/TGFBR3fl/fl mice. These data implicate TGFBR3 in cells with smooth muscle properties, as a key mediator of post-natal lung alveolarisation.
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glucocorticoids recruit TGFBR3 and smad1 to shift transforming growth factor β signaling from the tgfbr1 smad2 3 axis to the acvrl1 smad1 axis in lung fibroblasts
Journal of Biological Chemistry, 2014Co-Authors: Gero Niess, Julian T Schwartze, Simone Becker, Elpidoforos Sakkas, łukasz A WujakAbstract:Abstract Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-β is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-β signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-β signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-β receptor TGFBR3, also called betaglycan. TGFBR3 was demonstrated to be a “switch” that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-β to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung TGFBR3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-β signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions.
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Glucocorticoids recruit TGFBR3 and Smad1 to shift transforming growth factor-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts
Journal of Biological Chemistry, 2013Co-Authors: Julian T Schwartze, Gero Niess, Simone Becker, Elpidoforos Sakkas, łukasz A Wujak, Jakob Usemann, Frank Reichenberger, Susanne Herold, István Vadász, Konstantin MayerAbstract:Abstract Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-β is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-β signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-β signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-β receptor TGFBR3, also called betaglycan. TGFBR3 was demonstrated to be a “switch” that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-β to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung TGFBR3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-β signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions.
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The role of the accessory type III transforming growth factor-β receptors in the regulation of pulmonary vascular development
C64. PULMONARY VASCULAR STRUCTURE FUNCTION AND SIGNALING, 2012Co-Authors: Gero Niess, Matthias Michiels-corsten, Werner Seeger, Rory E. MortyAbstract:Pulmonary artery smooth muscle cell behaviour, including proliferation, apoptosis, and matrix production, is controlled by transforming growth factor (TGF)-β, acting via two type I (Acvrl1 and Tgbfr1) and two type III [endoglin (Eng) and betaglycan (TGFBR3)] TGF-β receptors. Knockdown of TGFBR3 by siRNA in primary human pulmonary artery smooth muscle cells (PASMC) increased PASMC proliferation (3-fold; assessed by BrdU incorporation) in vitro , in a TGF-β-independent manner. However, apoptosis rates of the PASMC were not affected by siRNA knockdown of TGFBR3. The siRNA knockdown of other TGF-β receptors, ACVRL1, TGFBR1, TGFBR2 and ENG, did not impact TGF-β-independent proliferation or apoptosis of PASMC. These data point to a novel, TGF-β-independent role for TGFBR3 in regulating PASMC growth. This idea assumes importance considering that we have also observed perturbed expression of TGFBR3 in the lungs of neonatal mice with hyperoxia (85% O 2 )-induced lung injury, which results in bronchopulmonary dysplasia (BPD). The mRNA levels (assessed by quantitative real-time RT-PCR) for TGFBR3 were downregulated (4.4-fold, p=0.003), while TGFBR3 protein levels were downregulated by 70%. Laser capture microdissection confirmed dysregulated expression of TGFBR3 in the pulmonary vasculature of the developing mouse lung. Taken together, these data suggest a role for TGFBR3 in vascular smooth muscle cell function which could lead to a dysregulation of TGF- β signalling in the pulmonary vasculature, which in turn could contribute to the impaired pulmonary vascular growth and development associated with the lung hypoplasia observed in patients with BPD.
Kaye L Stenvers - One of the best experts on this subject based on the ideXlab platform.
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effects of tgfbeta2 on wild type and TGFBR3 knockout mouse fetal testis
Biology of Reproduction, 2013Co-Authors: Mai A Sarraj, Jock K Findlay, Kaye L Stenvers, Ruth M Escalona, Patrick S WesternAbstract:ABSTRACT TGFBR3 (betaglycan), a TGFbeta superfamily coreceptor, is essential for normal seminiferous cord and Leydig cell development in the fetal mouse testis and has been associated with testicular dysgenesis syndrome in men. However, the mechanisms underlying TGFBR3-regulated testis development are unclear. We tested the hypothesis that loss of TGFBR3 compromises the functions of TGFbeta2 in the differentiating fetal testis. Analysis of expression of transcripts encoding the TGFbeta superfamily members showed a predominance of TGFbeta mRNAs during the critical window of development when testis structure is established (11.5–14.5 days postcoitum [dpc]). When cultured under basal conditions for 2 days, explants of 13.5 dpc wild-type fetal testis/mesonephros complexes exhibited structure and gene expression profiles resembling those observed in vivo between 13.5–15.5 dpc. Similarly, development of TGFBR3 knockout testis explants recapitulated the dysgenesis and decreased somatic cell marker expression pre...
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title effects of tgfbeta2 on wild type and TGFBR3 knockout mouse fetal testis short title tgf beta2 effects on fetal testis summary sentence tgfbeta2 treatment partially rescues cord structure but not leydig cell gene expression in the TGFBR3 knockou
2013Co-Authors: Mai A Sarraj, Jock K Findlay, Ruth M Escalona, Patrick S Western, L Kaye, Kaye L StenversAbstract:TGFBR3 (betaglycan), a TGFbeta superfamily co-receptor, is essential for normal seminiferous cord and Leydig cell development in the fetal mouse testis and has been related to testicular dysgenesis syndrome in men. However, the mechanisms underlying TGFBR3-regulated testis development are unclear. We tested the hypothesis that loss of TGFBR3 compromises the functions of TGFbeta2 in the differentiating fetal testis. Analysis of expression of transcripts encoding the TGFbeta superfamily members showed a predominance of TGFbeta mRNAs during the critical window of development when testis structure is established (11.5-14.5 dpc). When cultured under basal conditions for 2 days, explants of 13.5 dpc wild-type fetal testis/mesonephros complexes exhibited structure and gene expression profiles resembling those observed in vivo between 13.5-15.5 dpc. Similarly, development of TGFBR3 knockout testis explants recapitulated the dysgenesis and decreased somatic cell marker expression previously observed in vivo. TGFbeta2 treatment partially rescued cord development in 11.5-13.5 dpc TGFBR3 knockout explants but did not significantly alter somatic or germ cell gene expression. In contrast, TGFbeta2 treatment of wild-type explants disrupted cord structure and significantly downregulated the somatic and steroidogenic cell markers Amh, Sf1, Star, Cyp11a, Hsd3b1 and Cyp17a1. We conclude that (a) the compromised cord development in TGFBR3 null fetal testis is due, at least in part, to disrupted TGFbeta2 function; (b) the reduction in steroidogenesis observed in the TGFBR3 null testis may be regulated by additional TGFBR3 ligands, rather than TGFbeta2; and (c) both cord maintenance and somatic cell development are highly sensitive to the levels of TGFbeta2.
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differential expression of TGFBR3 betaglycan in mouse ovary and testis during gonadogenesis
Growth Factors Journal, 2007Co-Authors: Mai A Sarraj, Hui Kheng Chua, Alexandria Umbers, Kate L Loveland, Jock K Findlay, Kaye L StenversAbstract:TGFBR3 is an accessory receptor that binds to and modulates the activities of both transforming growth factor-beta (TGFβ) and inhibin, two members of the TGFβ superfamily of growth factors that regulate many aspects of reproductive biology. TGFBR3 is known to be expressed in adult testis and ovary, but little is known about this receptor during gonadogenesis. Herein, we describe TGFBR3 expression in the male and female fetal and neonatal murine gonad. Real-time PCR analysis revealed that TGFBR3 mRNA was expressed at higher levels in the developing testis compared to ovary. TGFBR3 was expressed within the fetal testis interstitium, predominantly by Leydig cells, but expression shifted inside the seminiferous cords at birth. In contrast, TGFBR3 was detected in both the somatic and germ cell lineages in the fetal and neonatal ovary. This differential expression pattern suggests divergent roles for this TGFBR3 in developing testis and ovary.
Julian T Schwartze - One of the best experts on this subject based on the ideXlab platform.
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glucocorticoids recruit TGFBR3 and smad1 to shift transforming growth factor β signaling from the tgfbr1 smad2 3 axis to the acvrl1 smad1 axis in lung fibroblasts
Journal of Biological Chemistry, 2014Co-Authors: Gero Niess, Julian T Schwartze, Simone Becker, Elpidoforos Sakkas, łukasz A WujakAbstract:Abstract Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-β is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-β signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-β signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-β receptor TGFBR3, also called betaglycan. TGFBR3 was demonstrated to be a “switch” that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-β to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung TGFBR3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-β signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions.
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Glucocorticoids recruit TGFBR3 and Smad1 to shift transforming growth factor-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts
Journal of Biological Chemistry, 2013Co-Authors: Julian T Schwartze, Gero Niess, Simone Becker, Elpidoforos Sakkas, łukasz A Wujak, Jakob Usemann, Frank Reichenberger, Susanne Herold, István Vadász, Konstantin MayerAbstract:Abstract Glucocorticoids represent the mainstay therapy for many lung diseases, providing outstanding management of asthma but performing surprisingly poorly in patients with acute respiratory distress syndrome, chronic obstructive pulmonary disease, lung fibrosis, and blunted lung development associated with bronchopulmonary dysplasia in preterm infants. TGF-β is a pathogenic mediator of all four of these diseases, prompting us to explore glucocorticoid/TGF-β signaling cross-talk. Glucocorticoids, including dexamethasone, methylprednisolone, budesonide, and fluticasone, potentiated TGF-β signaling by the Acvrl1/Smad1/5/8 signaling axis and blunted signaling by the Tgfbr1/Smad2/3 axis in NIH/3T3 cells, as well as primary lung fibroblasts, smooth muscle cells, and endothelial cells. Dexamethasone drove expression of the accessory type III TGF-β receptor TGFBR3, also called betaglycan. TGFBR3 was demonstrated to be a “switch” that blunted Tgfbr1/Smad2/3 and potentiated Acvrl1/Smad1 signaling in lung fibroblasts. The Acvrl1/Smad1 axis, which was stimulated by dexamethasone, was active in lung fibroblasts and antagonized Tgfbr1/Smad2/3 signaling. Dexamethasone acted synergistically with TGF-β to drive differentiation of primary lung fibroblasts to myofibroblasts, revealed by acquisition of smooth muscle actin and smooth muscle myosin, which are exclusively Smad1-dependent processes in fibroblasts. Administration of dexamethasone to live mice recapitulated these observations and revealed a lung-specific impact of dexamethasone on lung TGFBR3 expression and phospho-Smad1 levels in vivo. These data point to an interesting and hitherto unknown impact of glucocorticoids on TGF-β signaling in lung fibroblasts and other constituent cell types of the lung that may be relevant to lung physiology, as well as lung pathophysiology, in terms of drug/disease interactions.
Mai A Sarraj - One of the best experts on this subject based on the ideXlab platform.
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effects of tgfbeta2 on wild type and TGFBR3 knockout mouse fetal testis
Biology of Reproduction, 2013Co-Authors: Mai A Sarraj, Jock K Findlay, Kaye L Stenvers, Ruth M Escalona, Patrick S WesternAbstract:ABSTRACT TGFBR3 (betaglycan), a TGFbeta superfamily coreceptor, is essential for normal seminiferous cord and Leydig cell development in the fetal mouse testis and has been associated with testicular dysgenesis syndrome in men. However, the mechanisms underlying TGFBR3-regulated testis development are unclear. We tested the hypothesis that loss of TGFBR3 compromises the functions of TGFbeta2 in the differentiating fetal testis. Analysis of expression of transcripts encoding the TGFbeta superfamily members showed a predominance of TGFbeta mRNAs during the critical window of development when testis structure is established (11.5–14.5 days postcoitum [dpc]). When cultured under basal conditions for 2 days, explants of 13.5 dpc wild-type fetal testis/mesonephros complexes exhibited structure and gene expression profiles resembling those observed in vivo between 13.5–15.5 dpc. Similarly, development of TGFBR3 knockout testis explants recapitulated the dysgenesis and decreased somatic cell marker expression pre...
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title effects of tgfbeta2 on wild type and TGFBR3 knockout mouse fetal testis short title tgf beta2 effects on fetal testis summary sentence tgfbeta2 treatment partially rescues cord structure but not leydig cell gene expression in the TGFBR3 knockou
2013Co-Authors: Mai A Sarraj, Jock K Findlay, Ruth M Escalona, Patrick S Western, L Kaye, Kaye L StenversAbstract:TGFBR3 (betaglycan), a TGFbeta superfamily co-receptor, is essential for normal seminiferous cord and Leydig cell development in the fetal mouse testis and has been related to testicular dysgenesis syndrome in men. However, the mechanisms underlying TGFBR3-regulated testis development are unclear. We tested the hypothesis that loss of TGFBR3 compromises the functions of TGFbeta2 in the differentiating fetal testis. Analysis of expression of transcripts encoding the TGFbeta superfamily members showed a predominance of TGFbeta mRNAs during the critical window of development when testis structure is established (11.5-14.5 dpc). When cultured under basal conditions for 2 days, explants of 13.5 dpc wild-type fetal testis/mesonephros complexes exhibited structure and gene expression profiles resembling those observed in vivo between 13.5-15.5 dpc. Similarly, development of TGFBR3 knockout testis explants recapitulated the dysgenesis and decreased somatic cell marker expression previously observed in vivo. TGFbeta2 treatment partially rescued cord development in 11.5-13.5 dpc TGFBR3 knockout explants but did not significantly alter somatic or germ cell gene expression. In contrast, TGFbeta2 treatment of wild-type explants disrupted cord structure and significantly downregulated the somatic and steroidogenic cell markers Amh, Sf1, Star, Cyp11a, Hsd3b1 and Cyp17a1. We conclude that (a) the compromised cord development in TGFBR3 null fetal testis is due, at least in part, to disrupted TGFbeta2 function; (b) the reduction in steroidogenesis observed in the TGFBR3 null testis may be regulated by additional TGFBR3 ligands, rather than TGFbeta2; and (c) both cord maintenance and somatic cell development are highly sensitive to the levels of TGFbeta2.
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differential expression of TGFBR3 betaglycan in mouse ovary and testis during gonadogenesis
Growth Factors Journal, 2007Co-Authors: Mai A Sarraj, Hui Kheng Chua, Alexandria Umbers, Kate L Loveland, Jock K Findlay, Kaye L StenversAbstract:TGFBR3 is an accessory receptor that binds to and modulates the activities of both transforming growth factor-beta (TGFβ) and inhibin, two members of the TGFβ superfamily of growth factors that regulate many aspects of reproductive biology. TGFBR3 is known to be expressed in adult testis and ovary, but little is known about this receptor during gonadogenesis. Herein, we describe TGFBR3 expression in the male and female fetal and neonatal murine gonad. Real-time PCR analysis revealed that TGFBR3 mRNA was expressed at higher levels in the developing testis compared to ovary. TGFBR3 was expressed within the fetal testis interstitium, predominantly by Leydig cells, but expression shifted inside the seminiferous cords at birth. In contrast, TGFBR3 was detected in both the somatic and germ cell lineages in the fetal and neonatal ovary. This differential expression pattern suggests divergent roles for this TGFBR3 in developing testis and ovary.
Harold L Moses - One of the best experts on this subject based on the ideXlab platform.
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aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas specific blockade of transforming growth factor beta signaling in cooperation with active kras expression
Genes & Development, 2006Co-Authors: Hideaki Ijichi, Anna Chytil, Agnieszka E Gorska, Mary Aakre, Yoshio Fujitani, Shuko Fujitani, Christopher V E Wright, Harold L MosesAbstract:Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-β (TGF-β) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-β, is deleted or mutated in 55% and the type II TGF-β receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (KrasG12D) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific KrasG12D activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with KrasG12D expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with KrasG12D expression also developed PDAC, which indicated a haploinsufficiency of TGF-β signaling in this genetic context. The clinical and histopathological manifestations of the combined KrasG12D expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-β signaling and activated Ras signaling cooperate to promote PDAC progression.
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inactivation of tgf beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy
Oncogene, 2005Co-Authors: Judith Romerogallo, Elif G Sozmen, Anna Chytil, William E Russell, Robert H Whitehead, Tony W Parks, Matthew S Holdren, Shiva Gautam, Mark A Magnuson, Harold L MosesAbstract:The transforming growth factor β (TGF-β) signaling pathway, which is activated by the TGF-β receptor complex consisting of type I and type II TGF-β receptors (TGFBR1 and TGFBR2), regulates cell growth and death. TGF-β and components of its signaling pathway, particularly TGFBR2, have been implicated as tumor suppressor genes and important antimitogenic factors in the gastrointestinal tract and liver. An in vivo approach to study these effects has been hindered by the embryonic lethality of Tgfbr2−/− mice and poor viability of the Tgfb1−/− mice. Consequently, we have developed a hepatocyte-specific Tgfbr2 knockout mouse, the Alb-cre Tgfbr2flx/flx mouse, to study the physiologically relevant effects of TGF-β signaling on epithelial cell proliferation in vivo. After 70% hepatectomy, we observed increased proliferation and an increased liver mass : body weight ratio in the Alb-cre Tgfbr2flx/flx mice compared to Tgfbr2flx/flx mice. We also observed decreased expression and increased phosphorylation of p130 in the livers from the Alb-cre Tgfbr2flx/flx mice as well as increased expression of cyclin E, which is transcriptionally regulated, in part, by p130:E2F4. Consistent with these results, in a hepatocyte cell line derived from the Tgfbr2flx/flx mice, we found that TGF-β increases the nuclear localization of E2F4, and presumably the transcriptional repression of the p130:E2F4 complex. Thus, we have demonstrated that TGF-β signaling in vivo regulates the mitogenic response in the regenerating liver, affecting the liver mass : body weight ratio after partial hepatectomy, and that these mitogenic responses are accompanied by alterations in p130 expression and phosphorylation, implicating p130 as one of the proteins regulated in vivo by TGF-β during liver regeneration.
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effect of conditional knockout of the type ii tgf beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle t antigen induced tumor formation and metastasis
Cancer Research, 2005Co-Authors: Elizabeth Forrester, Anna Chytil, Agnieszka E Gorska, Mary Aakre, Brian Bierie, Alireza Sharifafshar, William J Muller, Harold L MosesAbstract:Transforming growth factor–β (TGF-β) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-β signaling in mammary tumorigenesis is complex, as TGF-β has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-β signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-β receptor, Tgfbr2 , was conditionally deleted in the mammary epithelium (Tgfbr2 MGKO ). Loss of Tgfbr2 in the mammary epithelium results in lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. Tgfbr2 MGKO mice were mated to the mouse mammary tumor virus-polyomavirus middle T antigen (PyVmT) transgenic mouse model of metastatic breast cancer. Loss of Tgfbr2 in the context of PyVmT expression results in a shortened median tumor latency and an increased formation of pulmonary metastases. Thus, our studies support a tumor-suppressive role for epithelial TGF-β signaling in mammary gland tumorigenesis and show that pulmonary metastases can occur and are even enhanced in the absence of TGF-β signaling in the carcinoma cells.