TGF‐β Latency: Biological Significance and Mechanisms of Activation

Gleizes, Pierre‐Emmanuel; Munger, John S.; Nunes, Irene; Harpel, John G.; Mazzieri, Roberta; Noguera, Irene; Rifkin, Daniel B.

doi:10.1002/stem.150190

Cited by 240 publications

(202 citation statements)

References 73 publications

Supporting

Mentioning

193

Contrasting

Unclassified

Order By: Relevance

“…Transforming growth factor-b is generally released from cells in a latent, biologically inactive form (Miyazono et al, 1993). Following release, it is activated by a variety of mechanisms, including exposure to proteolytic enzymes or alkaline pH conditions (Gleizes et al, 1997;Khalil, 1999). The presence of proteases in the pancreas and the alkaline pH of pancreatic juice may result in ideal conditions for activation of latent TGF-b.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TGF-β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer

et al. 2004

View full text Add to dashboard Cite

Pancreatic cancer is often associated with an intense production of interstitial collagens, known as the desmoplastic reaction. To understand more about desmoplasia in pancreatic cancer, the expression of mRNA for type I and III collagens and potent desmoplastic inducing growth factors transforming growth factor-b (TGF-b), connective tissue growth factor (CTGF), acidic and basic fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) A and C and epidermal growth factor (EGF) was analysed by quantitative RT-PCR. Expression of both collagens in 23 frozen primary pancreatic cancer nodules was significantly higher than that in 15 nonneoplastic pancreatic tissues. The expressions of mRNAs for TGF-b, acidic FGF, basic FGF and PDGF C were likewise higher in surgical cancer nodules, while that of CTGF, PDGF A and EGF were not. Among these growth factors, the expression of TGF-b mRNA showed the most significant correlation with that of collagens (Po0.0001). By immunohistochemistry, TGF-b showed faint cytoplasmic staining in cancer cells. In contrast, isolated cells, mainly located on the invasive front surrounding cancerous nests, were prominently and strongly stained. These TGF-b-positive cells contained a segmented nucleus, were negative for anti-macrophage (CD68) and positive for anti-granulocyte antibodies, indicating their granulocytic nature. In conclusion, TGF-b seemed to play a major role among the various growth factors in characteristic overproduction of collagens in pancreatic cancer. Moreover, the predominant cells that express TGF-b were likely to be infiltrated granulocytes (mostly are neutrophils) and not pancreatic cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Overexpression of TGF-β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer

et al. 2004

View full text Add to dashboard Cite

show abstract

“…One possible explanation for this finding is that the processing of TGF-␤1 from its inactive precursor may be limiting (McDowell et al, 2001). Processing of TGF-␤ superfamily members is complex but clearly very important (Gleizes et al, 1997). They are synthesized as zymogen-like pre-proteins whose carboxyl-terminal one third is the actual ligand, whereas the amino-terminal two thirds is a "latency peptide" or "pro-domain."…”

Section: Establishment Of Morphogen Gradients Part I: Evidence For Dmentioning

confidence: 99%

Morphogen gradients, positional information, and Xenopus: Interplay of theory and experiment

Green

2002

Developmental Dynamics

View full text Add to dashboard Cite

The idea of morphogen gradients has long been an important one in developmental biology. Studies with amphibians and with Xenopus in particular have made significant contributions to demonstrating the existence, identity, and mechanisms of action of morphogens. Mesoderm induction and patterning by activin, nodals, bone morphogenetic proteins, and fibroblast growth factors have been analyzed thoroughly and reveal recurrent and combinatorial roles for these protein growth factor morphogens and their antagonists. The dynamics of nodal-type signaling and the intersection of VegT and ␤-catenin intracellular gradients reveal detailed steps in early long-range patterning. Interpretation of gradients requires sophisticated mechanisms for sharpening thresholds, and the activin-Xbra-Gsc system provides an example of this. The understanding of growth factor signal transduction has elucidated growth factor morphogen action and provided tools for dissecting their direct longrange action and distribution. The physical mechanisms of morphogen gradient establishment are the focus of new interest at both the experimental and theoretical level. General themes and emerging trends in morphogen gradient studies are discussed.

show abstract

“…16 TGF-b 1 is produced in a latent complex, which consists of TGF-b 1 noncovalently bound to a latentassociated peptide (LAP). 17 It is the removal of the LAP, which allows TGF-b 1 to be biologically active. This activation step is a major controlling point in the regulation of TGF-b 1 biological activity, but the mechanisms controlling TGF-b 1 activation are only partially understood.…”

mentioning

confidence: 99%

“…This activation step is a major controlling point in the regulation of TGF-b 1 biological activity, but the mechanisms controlling TGF-b 1 activation are only partially understood. Several activation mechanisms have been shown, including proteolytic and enzymatic processes, 17 as well as integrin binding. 18,19 Some earlier work provided evidence that ROS could play a role in activating TGF-b.…”

mentioning

confidence: 99%

Asbestos-derived reactive oxygen species activate TGF-β1

Pociask

Sime

Brody

2004

Laboratory Investigation

132

View full text Add to dashboard Cite

Transforming growth factor-beta 1 (TGF-b 1 ) is a potent peptide that inhibits epithelial and mesenchymal cell proliferation and stimulates the synthesis of extracellular matrix components. This cytokine is produced in a biologically latent complex bound to a latent-associated peptide (LAP), and it is the disassociation of this complex that regulates TGF-b activity. A number of mechanisms have been shown to activate TGF-b 1 . We show here that reactive oxygen species (ROS), generated by the iron in chrysotile or crocidolite asbestos, mediate the biological activity of TGF-b 1 . Recombinant human latent TGF-b 1 was activated in a cell free system in the presence of asbestos and ascorbic acid. Latent TGF-b 1 was overexpressed in both A549 and mink lung epithelial cell lines through an adenovirus vector containing the full-length construct for porcine TGF-b 1 . This latent TGF-b 1 was activated in a concentration-dependant fashion by introducing asbestos into the cell cultures. This activation was reduced significantly through the use of superoxide dismutase, catalase or deferoxamine. Amino-acid constituents of the LAP were oxidized as demonstrated by the appearance of carbonyls detected by Western analysis. The oxidized LAP could no longer form a complex with TGF-b 1 . Our data support the postulate that ROS derived from asbestos provide a mechanism for activating TGF-b 1 in the alveolar environment by oxidizing amino acids in LAP.

show abstract

TGF‐β Latency: Biological Significance and Mechanisms of Activation

Cited by 240 publications

References 73 publications

Overexpression of TGF-β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer

Overexpression of TGF-β by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer

Morphogen gradients, positional information, and Xenopus: Interplay of theory and experiment

Asbestos-derived reactive oxygen species activate TGF-β1

Contact Info

Product

Resources

About