Identification of Chromosomal Regions Involved in decapentaplegic Function in Drosophila

Genetics ◽  
1998 ◽  
Vol 149 (1) ◽  
pp. 203-215 ◽  
Author(s):  
Russell E Nicholls ◽  
William M Gelbart
Keyword(s):  
Growth Factor ◽  
Pattern Formation ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Genetic Interactions ◽  
Genetic Approach ◽  
Wing Vein ◽  
Vein Formation ◽  
Embryonic Lethal ◽  
Β Function

AbstractSignaling molecules of the transforming growth factor β (TGF-β) family contribute to numerous developmental processes in a variety of organisms. However, our understanding of the mechanisms which regulate the activity of and mediate the response to TGF-β family members remains incomplete. The product of the Drosophila decapentaplegic (dpp) locus is a well-characterized member of this family. We have taken a genetic approach to identify factors required for TGF-β function in Drosophila by testing for genetic interactions between mutant alleles of dpp and a collection of chromosomal deficiencies. Our survey identified two deficiencies that act as maternal enhancers of recessive embryonic lethal alleles of dpp. The enhanced individuals die with weakly ventralized phenotypes. These phenotypes are consistent with a mechanism whereby the deficiencies deplete two maternally provided factors required for dpp's role in embryonic dorsal-ventral pattern formation. One of these deficiencies also appears to delete a factor required for dpp function in wing vein formation. These deficiencies remove material from the 54F-55A and 66B-66C polytene chromosomal regions, respectively. As neither of these regions has been previously implicated in dpp function, we propose that each of the deficiencies removes a novel factor or factors required for dpp function.

scholarly journals Interactions between Growth Factors and Integrins: Latent Forms of Transforming Growth Factor-β Are Ligands for the Integrin αvβ1

1998 ◽  
Vol 9 (9) ◽  
pp. 2627-2638 ◽  
Author(s):  
John S. Munger ◽  
John G. Harpel ◽  
Filippo G. Giancotti ◽  
Daniel B. Rifkin
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
A549 Cells ◽  
Transforming Growth Factor Β ◽  
Mutant Form ◽  
Rgd Sequence ◽  
Β Receptor ◽  
Coated Surfaces ◽  
Β Function ◽  
Tgf Β1

The multipotential cytokine transforming growth factor-β (TGF-β) is secreted in a latent form. Latency results from the noncovalent association of TGF-β with its processed propeptide dimer, called the latency-associated peptide (LAP); the complex of the two proteins is termed the small latent complex. Disulfide bonding between LAP and latent TGF-β–binding protein (LTBP) produces the most common form of latent TGF-β, the large latent complex. The extracellular matrix (ECM) modulates the activity of TGF-β. LTBP and the LAP propeptides of TGF-β (isoforms 1 and 3), like many ECM proteins, contain the common integrin-binding sequence RGD. To increase our understanding of latent TGF-β function in the ECM, we determined whether latent TGF-β1 interacts with integrins. A549 cells adhered and spread on plastic coated with LAP, small latent complex, and large latent complex but not on LTBP-coated plastic. Adhesion was blocked by an RGD peptide, and cells were unable to attach to a mutant form of recombinant LAP lacking the RGD sequence. Adhesion was also blocked by mAbs to integrin subunits αv and β1. We purified LAP-binding integrins from extracts of A549 cells using LAP bound to Sepharose. αvβ1 eluted with EDTA. After purification in the presence of Mn2+, a small amount of αvβ5 was also detected. A549 cells migrated equally on fibronectin- and LAP-coated surfaces; migration on LAP was αvβ1 dependent. These results establish αvβ1 as a LAP-β1 receptor. Interactions between latent TGF-β and αvβ1 may localize latent TGF-β to the surface of specific cells and may allow the TGF-β1 gene product to initiate signals by both TGF-β receptor and integrin pathways.

Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2380-2388 ◽  
Author(s):  
Brendan J. Jenkins ◽  
Andrew W. Roberts ◽  
Claire J. Greenhill ◽  
Meri Najdovska ◽  
Therese Lundgren-May ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Interleukin 6 ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Lymphoid Organs ◽  
Genetic Approach ◽  
Α Subunit

Abstract We have previously demonstrated that STAT3 hyperactivation via the interleukin 6 (IL-6) cytokine family receptor gp130 in gp130Y757F/Y757F mice leads to numerous hematopoietic and lymphoid pathologies, including neutrophilia, thrombocytosis, splenomegaly, and lymphadenopathy. Because IL-6 and IL-11 both signal via a gp130 homodimer, we report here a genetic approach to dissect their individual roles in these pathologies. Neutrophilia and thrombocytosis were absent in gp130Y757F/Y757F mice lacking either IL-6 (gp130Y757F/Y757F: IL-6−/−) or the IL-11 receptor α subunit (gp130Y757F/Y757F: IL-11Rα1−/−), and this was associated with a normalized bone marrow compartment. The elevated myelopoiesis and megakaryopoiesis in bone marrow of gp130Y757F/Y757F mice was attributable to an increase by either IL-6 or IL-11 in the STAT3-driven impairment of transforming growth factor β (TGF-β) signaling, which is a suppressor of these lineages. In contrast, the absence of IL-6, but not IL-11 signaling, prevented the splenomegaly, abnormal lymphopoiesis, and STAT3 hyperactivation in lymphoid organs of gp130Y757F/Y757F mice. Furthermore, hyperactivation of STAT3 in lymphoid organs was associated with increased expression of IL-6Rα, and IL-6Rα expression was reduced in gp130Y757F/Y757F: Stat3+/− mice displaying normal levels of STAT3 activity. Collectively, these data genetically define distinct roles of IL-6 and IL-11 in driving pathologic hematopoietic and lymphoid responses mediated by STAT3 hyperactivation.

scholarly journals Cx43 Mediates TGF-β Signaling through Competitive Smads Binding to Microtubules

2007 ◽  
Vol 18 (6) ◽  
pp. 2264-2273 ◽  
Author(s):  
Ping Dai ◽  
Takuo Nakagami ◽  
Hideo Tanaka ◽  
Toshiaki Hitomi ◽  
Tetsuro Takamatsu
Keyword(s):  
Growth Factor ◽  
Knockout Mice ◽  
Opposite Effect ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Positive Regulation ◽  
Functional Link ◽  
Intracellular Regulation ◽  
Β Function

Transforming growth factor-β (TGF-β) superfamily members play an important role in growth, differentiation, adhesion, apoptosis, and development in many species from insects and worms to vertebrates. Recently, TGF-β signaling has been demonstrated to be negatively regulated by microtubules (MTs), which anchor endogenous Smad2/3 to cytosol and also directly interact with connexin43 (Cx43), and the activity of TGF-β is mediated by Cx43. However, the mechanism underlying the intracellular regulation of TGF-β activity by Cx43 remains unknown. Here, we found that the functional link between TGF-β activation and Cx43 is mediated by interactions among Smad2/3, MTs, and Cx43. We confirmed that Cx43 competes with Smad2/3 for binding to MTs, which Cx43 specifically induces release of Smad2/3 from MTs and increases phospho-Smad2 and which, as a result, Smad2/3 and Smad4 are accumulated in the nucleus, leading to activation of the transcription of target genes. Consistently, knockdown of the endogenous Cx43 activity with double-strand RNA (dsRNA) in HL1 cardiomyocytes and Cx43 knockout mice cardiomyocytes consistently show the opposite effect. Our findings demonstrate a novel mechanism for Cx43 positive regulation of TGF-β function.

scholarly journals Transforming Growth Factor-β Function Blocking Prevents Myocardial Fibrosis and Diastolic Dysfunction in Pressure-Overloaded Rats

Circulation ◽  
2002 ◽  
Vol 106 (1) ◽  
pp. 130-135 ◽  
Author(s):  
Fumitaka Kuwahara ◽  
Hisashi Kai ◽  
Keisuke Tokuda ◽  
Mamiko Kai ◽  
Akira Takeshita ◽  
...  
Keyword(s):  
Growth Factor ◽  
Diastolic Dysfunction ◽  
Myocardial Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Β Function

scholarly journals The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs

2006 ◽  
Vol 13 (2) ◽  
pp. 379-400 ◽  
Author(s):  
Markus C Fleisch ◽  
Christopher A Maxwell ◽  
Mary-Helen Barcellos-Hoff
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Therapeutic Interventions ◽  
Mesenchymal Transition ◽  
Endocrine Organs ◽  
Β Function

Transforming growth factor β (TGF-β) is a ubiquitous cytokine that plays a critical role in numerous pathways regulating cellular and tissue homeostasis. TGF-β is regulated by hormones and is a primary mediator of hormone response in uterus, prostate and mammary glands. This review will address the role of TGF-β in regulating hormone-dependent proliferation and morphogenesis. The subversion of TGF-β regulation during the processes of carcinogenesis, with particular emphasis on its effects on genetic stability and epithelial to mesenchymal transition, will also be examined. An understanding of the multiple and complex mechanisms of TGF-β regulation of epithelial function, and the ultimate loss of TGF-β function during carcinogenesis, will be critical in the design of novel therapeutic interventions for endocrine-related cancers.

Perianale Fisteln bei CED: vom Mausmodell zur Klinik

2018 ◽  
Vol 75 (5) ◽  
pp. 287-294
Author(s):  
Michael Scharl
Keyword(s):  
Growth Factor ◽  
Morbus Crohn ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 13

Zusammenfassung. Fisteln stellen nach wie vor eine der wichtigsten Komplikationen bei Patienten mit Morbus Crohn dar. Bei mindestens einem Drittel aller Morbus Crohn Patienten treten im Laufe der Erkrankung Fisteln auf. Eine dauerhafte Heilung der Fistel wird jedoch, auch unter Ausschöpfung sämtlicher medikamentöser und chirurgischer Therapieoptionen, nur in rund einem Drittel dieser Patienten erreicht. Der genaue molekulare Mechanismus der Fistelentstehung ist bis heute nicht ganz klar. Aus histopathologischer Sichtweise stellen Fisteln eine röhrenartige Struktur dar, welche von flachen epithelartigen Zellen ausgekleidet ist. Als ursächlicher Entstehungsmechanismus wird dabei die sogenannte epitheliale-zu-mesenchymale Transition (EMT) angesehen und es kann eine starke Expression der Entzündungsmediatoren Tumor Nekrose Faktor, Interleukin-13 und Transforming Growth Factor β in den Fistelarealen nachgewiesen werden. Zusätzlich zu den bereits etablierten, medikamentösen Therapieoptionen, also Antibiotika, Immunmodulatoren und anti-TNF Antikörper, stellt insbesondere der Einsatz der mesenchymalen Stammzelltherapie einen erfolgversprechenden Therapieansatz für die Zukunft dar.

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