scholarly journals Transforming growth factor-alpha and beta-amyloid precursor protein share a secretory mechanism.

1995 ◽  
Vol 128 (3) ◽  
pp. 433-441 ◽  
Author(s):  
J Arribas ◽  
J Massagué
Keyword(s):  
Growth Factor ◽  
Membrane Protein ◽  
Cell Surface ◽  
Cho Cells ◽  
Transforming Growth Factor ◽  
Surface Proteins ◽  
Transforming Growth Factor Alpha ◽  
Wild Type ◽  
Cell Surface Proteins ◽  
Factor Alpha

Cleavage and release of membrane protein ectodomains, a regulated process that affects many cell surface proteins, remains largely uncharacterized. To investigate whether cell surface proteins are cleaved through a shared mechanism or through multiple independent mechanisms, we mutagenized Chinese hamster ovary (CHO) cells and selected clones that were unable to cleave membrane-anchored transforming growth factor alpha (TGF-alpha). The defect in TGF-alpha cleavage in these clones is most apparent upon cell treatment with the protein kinase C (PKC) activator PMA, which stimulates TGF-alpha cleavage in wild-type cells. The mutant clones do not have defects in TFG-alpha expression, transport to the cell surface or turnover. Concomitant with the loss of TGF-alpha cleavage, these clones have lost the ability to cleave many structurally unrelated membrane proteins in response to PMA. These proteins include beta-amyloid precursor protein (beta-APP), whose cleavage into a secreted form avoids conversion into the amyloidogenic peptide A beta, and a group of cell surface proteins whose release into the medium is stimulated by PMA in wild type CHO cells but not in mutants. The mutations prevent cleavage by PKC-dependent as well as PKC-independent mechanisms, and thus affect an essential component that functions downstream of these various signaling mechanisms. We propose that regulated cleavage and secretion of membrane protein ectodomains is mediated by a common system whose components respond to multiple activators and act on susceptible proteins of diverse structure and function.

Transforming growth factor alpha in arterioles: cell surface processing of its precursor by elastases

1990 ◽  
Vol 10 (9) ◽  
pp. 4596-4602
Author(s):  
S G Mueller ◽  
A J Paterson ◽  
J E Kudlow
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor ◽  
Immunoblot Analysis ◽  
Integral Membrane Protein ◽  
Cathepsin G ◽  
Transforming Growth Factor Alpha ◽  
Reading Frame ◽  
Pancreatic Elastase ◽  
Factor Alpha

Analysis of the transforming growth factor alpha (TGF alpha) cDNA predicts that the mature TGF alpha polypeptide is cleaved from the extracellular domain of its precursor, which is an integral membrane protein. Furthermore, the cleavage sites for the release of this mitogen are compatible with the participation of an elastaselike protease. We have immunohistochemically localized TGF alpha to the vascular smooth muscle cells in the arterioles. To investigate whether polymorphonuclear (PMN) leukocytic elastase, a blood-borne protease, could process the cell surface TGF alpha, NR6 cells were transfected with the rat TGF alpha cDNA. The cDNA encoded the entire open reading frame, and its expression was under the control of the mouse metallothionein I promoter. A cloned transfectant, termed 1B2, synthesized the TGF alpha precursor in a zinc-inducible manner, and the precursor was localized to the cell surface. Western blot (immunoblot) analysis indicated that treatment of the zinc-induced 1B2 cells with either PMN leukocytic or pancreatic elastase resulted in the release of the mature TGF alpha polypeptide. The released TGF alpha was bioactive, as it was capable of both competing with epidermal growth factor for binding to its receptor and stimulating [3H]thymidine incorporation in the mitogenic assay. Formaldehyde fixation of the 1B2 cells eliminated basal release of TGF alpha but allowed normal processing by both PMN leukocytic and pancreatic elastase to occur. However, human cathepsin G, bovine pancreatic alpha 1-chymotrypsin, collagenase, trypsin, subtilisin, and plasmin failed to release any detectable fragments of the TGF alpha precursor from the fixed cells. The location of TGF alpha in the arterioles and ability of PMN leukocytic elastase to process the membrane-bound TGF alpha precursor suggests a novel role for this elastase at the wound site.

scholarly journals Transforming growth factor alpha in arterioles: cell surface processing of its precursor by elastases.

1990 ◽  
Vol 10 (9) ◽  
pp. 4596-4602 ◽  
Author(s):  
S G Mueller ◽  
A J Paterson ◽  
J E Kudlow
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor ◽  
Immunoblot Analysis ◽  
Integral Membrane Protein ◽  
Cathepsin G ◽  
Transforming Growth Factor Alpha ◽  
Reading Frame ◽  
Pancreatic Elastase ◽  
Factor Alpha

Analysis of the transforming growth factor alpha (TGF alpha) cDNA predicts that the mature TGF alpha polypeptide is cleaved from the extracellular domain of its precursor, which is an integral membrane protein. Furthermore, the cleavage sites for the release of this mitogen are compatible with the participation of an elastaselike protease. We have immunohistochemically localized TGF alpha to the vascular smooth muscle cells in the arterioles. To investigate whether polymorphonuclear (PMN) leukocytic elastase, a blood-borne protease, could process the cell surface TGF alpha, NR6 cells were transfected with the rat TGF alpha cDNA. The cDNA encoded the entire open reading frame, and its expression was under the control of the mouse metallothionein I promoter. A cloned transfectant, termed 1B2, synthesized the TGF alpha precursor in a zinc-inducible manner, and the precursor was localized to the cell surface. Western blot (immunoblot) analysis indicated that treatment of the zinc-induced 1B2 cells with either PMN leukocytic or pancreatic elastase resulted in the release of the mature TGF alpha polypeptide. The released TGF alpha was bioactive, as it was capable of both competing with epidermal growth factor for binding to its receptor and stimulating [3H]thymidine incorporation in the mitogenic assay. Formaldehyde fixation of the 1B2 cells eliminated basal release of TGF alpha but allowed normal processing by both PMN leukocytic and pancreatic elastase to occur. However, human cathepsin G, bovine pancreatic alpha 1-chymotrypsin, collagenase, trypsin, subtilisin, and plasmin failed to release any detectable fragments of the TGF alpha precursor from the fixed cells. The location of TGF alpha in the arterioles and ability of PMN leukocytic elastase to process the membrane-bound TGF alpha precursor suggests a novel role for this elastase at the wound site.

scholarly journals p53 stimulates transcription from the human transforming growth factor alpha promoter: a potential growth-stimulatory role for p53.

1995 ◽  
Vol 15 (9) ◽  
pp. 4694-4701 ◽  
Author(s):  
T H Shin ◽  
A J Paterson ◽  
J E Kudlow
Keyword(s):  
Growth Factor ◽  
Binding Site ◽  
Proliferative Response ◽  
Transforming Growth Factor ◽  
Tata Box ◽  
Stable Cell Line ◽  
Protective Mechanism ◽  
Transforming Growth Factor Alpha ◽  
Wild Type ◽  
Factor Alpha

Physical and chemical agents can damage the genome. Part of the protective response to this damage is the increased expression of p53. p53, a transcription factor, controls the expression of genes, leading to cell cycle arrest and apoptosis. Another protective mechanism is the proliferative response required to replace the damaged cells. This proliferation is likely to be signaled by growth factors. In this communication, we show that the transforming growth factor alpha (TGF-alpha) gene is a direct target for p53-mediated transcriptional activation. In a stable cell line containing an inducible p53 construct, p53 induction leads to a threefold accumulation of the native TGF-alpha mRNA. IN cotransfection assays using a TGF-alpha promoter reporter construct, we show that expression of wild-type but not mutant p53 increases transcriptional activity of the TGF-alpha promoter by approximately 2.5-fold. In vitro, wild-type p53 binds to a consensus binding site found in the proximal portion of the promoter, and this sequence is necessary for the p53 transcriptional response. Furthermore, this element confers p53 induction to the otherwise nonresponsive adenovirus major late promoter. In addition to these results, we found that the TGF-alpha promoter contains a nonconsensus but functional TATA box-binding protein-binding site approximately 30 bp upstream of the transcription start site. Although p53 can repress transcription from promoters containing a TATA box, the nonconsensus TGF-alpha TATA motif is resistant to this effect. On the basis of these results, we propose that p53 may play a dual role, which includes both the elimination of irreparably genetically damage cells and the proliferative response necessary for their replacement, in the response to physical-chemical damage.

Transforming Growth Factor Alpha Taq I Polymorphisms and Nonsyndromic Cleft Lip and/or Palate Risk

2018 ◽  
Vol 55 (6) ◽  
pp. 814-820 ◽  
Author(s):  
Chen Yan ◽  
He Deng-qi ◽  
Chen Li-ya ◽  
Yang Mang ◽  
Yang Ke-hu
Keyword(s):  
Growth Factor ◽  
Confidence Intervals ◽  
Odds Ratio ◽  
Cleft Lip ◽  
Transforming Growth Factor ◽  
Meta Analysis ◽  
Biomedical Literature ◽  
Transforming Growth Factor Alpha ◽  
Wild Type ◽  
Factor Alpha

Background: A series of epidemiological studies were conducted to investigate the association between transforming growth factor alpha ( TGFA) polymorphism and nonsyndromic cleft lip and/or palate (CL/P) risk, but the findings remain conflicting. The present meta-analysis summarizes the association between the TGFA Taq I polymorphisms and nonsyndromic CL/P risk. Methods: We searched PubMed, EMBASE, Web of Science, and Chinese Biomedical Literature databases from their inception to May 1, 2015. Fixed-effects or random-effects models were used to calculate the pooled odds ratio for two genetic comparisons (heterozygous mutation versus wild type, homozygous mutation versus wild type). All of the statistical tests were conducted by STATA 10.0 (StataCorp, College Station, TX). Results: A total of 26 case-control studies were identified for this meta-analysis. There was evidence of a significant association between the TGFA Taq I polymorphism and nonsyndromic CL/P risk in the overall population. The TGFA polymorphism was associated with nonsyndromic CL/P susceptibility in Asian populations under any of genetic models. However, in subgroup analysis, we did not find a significant association of TGFA gene polymorphisms with a reduced cancer risk in White and other populations and (recessive model, odds ratio = 2.37, 95% confidence intervals = 0.92-6.07; odds ratio = 3.45, 95% confidence intervals = 1.07-11.09, respectively). Conclusion: Our study indicates that the TGFA gene polymorphism might be associated with nonsyndromic CL/P susceptibility. However, these findings still need to be confirmed by single, large, well-designed prospective studies.

scholarly journals Epidermal growth factor and transforming growth factor-alpha: differential intracellular routing and processing of ligand-receptor complexes.

1991 ◽  
Vol 2 (8) ◽  
pp. 599-612 ◽  
Author(s):  
R Ebner ◽  
R Derynck
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Surface ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Alpha ◽  
Down Regulation ◽  
Surface Receptors ◽  
Receptor Complexes ◽  
Epidermal Growth ◽  
Factor Alpha

Two structurally related but different polypeptide growth factors, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), exert their activities after interaction with a common cell-surface EGF/TGF-alpha-receptor. Comparative studies of the effects of both ligands have established that TGF-alpha is more potent than EGF in a variety of biological systems. This observation is not explained by differences in affinities of the ligands for the receptor, because the affinity-constants of both factors are very similar. We have compared the intracellular processing of ligand-receptor complexes using either EGF or TGF-alpha in two different cell systems. We found that TGF-alpha dissociates from the EGF/TGF-alpha-receptor at much higher pH than EGF, which may reflect the substantial difference in the calculated isoelectric points. After internalization, the intracellular TGF-alpha is more rapidly cleared than EGF, and a substantial portion of the released TGF-alpha represents undegraded TGF-alpha in contrast to the mostly degraded EGF. In addition, TGF-alpha did not induce a complete down-regulation of cell surface receptors, as observed with EGF, which is at least in part responsible for a much sooner recovery of the ligand-binding ability after down-regulation, in the case of TGF-alpha. These differences in processing of the ligand-receptor complexes may explain why TGF-alpha exerts quantitatively higher activities than EGF.

MOLECULAR CONTROL OF ARTICULAR CARTILAGE DEGENERATION BY TRANSFORMING GROWTH FACTOR ALPHA

2008 ◽  
Vol 31 (4) ◽  
pp. 2
Author(s):  
Tom Appleton ◽  
Shirine Usmani ◽  
John Mort ◽  
Frank Beier
Keyword(s):  
Gene Expression ◽  
Articular Cartilage ◽  
Growth Factor ◽  
P38 Mapk ◽  
Transforming Growth Factor ◽  
Cartilage Degeneration ◽  
Signalling Pathways ◽  
Transforming Growth Factor Alpha ◽  
Factor Alpha ◽  
Articular Cartilage Degeneration

Background: Articular cartilage degeneration is a hallmark of osteoarthritis (OA). We previously identified increased expression of transforming growth factor alpha (TGF?) and chemokine (C-C motif) ligand 2 (CCL2) in articular cartilage from a rat modelof OA (1,2). We subsequently reported that TGF? signalling modified chondrocyte cytoskeletal organization, increased catabolic and decreased anabolic gene expression and suppressed Sox9. Due to other roles in chondrocytes, we hypothesized that the effects ofTGF? on chondrocytes are mediated by Rho/ROCK and MEK/ERK signaling pathways. Methods: Primary cultures of chondrocytes and articularosteochondral explants were treated with pharmacological inhibitors of MEK1/2(U0126), ROCK (Y27632), Rho (C3), p38 MAPK (SB202190) and PI3K (LY294002) to elucidate pathway involvement. Results: Using G-LISA we determined that stimulation of primary chondrocytes with TGF? activates RhoA. Reciprocally, inhibition of RhoA/ROCK but not other signalling pathways prevents modification of the actin cytoskeleton in responseto TGF?. Inhibition of MEK/ERKsignaling rescued suppression of anabolic gene expression by TGF? including SOX9 mRNA and protein levels. Inhibition of MEK/ERK, Rho/ROCK, p38 MAPK and PI3K signalling pathways differentially controlled the induction of MMP13 and TNF? gene expression. TGF? also induced expression of CCL2 specifically through MEK/ERK activation. In turn, CCL2 treatment induced the expression of MMP3 and TNF?. Finally, we assessed cartilage degradation by immunohistochemical detection of type II collagen cleavage fragments generated by MMPs. Blockade of RhoA/ROCK and MEK/ERK signalling pathways reduced the generation of type IIcollagen cleavage fragments in response to TGF? stimulation. Conclusions: Rho/ROCK signalling mediates TGF?-induced changes inchondrocyte morphology, while MEK/ERK signalling mediates the suppression ofSox9 and its target genes, and CCL2 expression. CCL2, in turn, induces the expression of MMP3 and TNF?, two potent catabolic factors known to be involved in OA. These pathways may represent strategic targets for interventional approaches to treating cartilage degeneration in osteoarthritis. References: 1. Appleton CTG et al. Arthritis Rheum 2007;56:1854-68. 2. Appleton CTG et al. Arthritis Rheum 2007; 56:3693-705.

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