scholarly journals Transforming Growth Factor-β1 Induces Apoptosis through Fas Ligand-independent Activation of the Fas Death Pathway in Human Gastric SNU-620 Carcinoma Cells

2004 ◽  
Vol 15 (2) ◽  
pp. 420-434 ◽  
Author(s):  
Sang Gyun Kim ◽  
Hyun-Soon Jong ◽  
Tae-You Kim ◽  
Jung Weon Lee ◽  
Noe Kyeong Kim ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Transforming Growth Factor ◽  
Death Receptor ◽  
Transforming Growth Factor Β1 ◽  
Mitochondrial Pathway ◽  
Carcinoma Cells ◽  
Caspase 8 ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
Tgf Β1

To date, two major apoptotic pathways, the death receptor and the mitochondrial pathway, have been well documented in mammalian cells. However, the involvement of these two apoptotic pathways, particularly the death receptor pathway, in transforming growth factor-β1 (TGF-β1)-induced apoptosis is not well understood. Herein, we report that apoptosis of human gastric SNU-620 carcinoma cells induced by TGF-β1 is caused by the Fas death pathway in a Fas ligand-independent manner, and that the Fas death pathway activated by TGF-β1 is linked to the mitochondrial apoptotic pathway via Bid mediation. We showed that TGF-β1 induced the expression and activation of Fas and the subsequent caspase-8-mediated Bid cleavage. Interestingly, expression of dominant negative FADD and treatment with caspase-8 inhibitor efficiently prevented TGF-β1-induced apoptosis, whereas the treatment with an activating CH11 or a neutralizing ZB4 anti-Fas antibody, recombinant Fas ligand, or Fas-Fc chimera did not affect activation of Fas and the subsequent induction of apoptosis by TGF-β1. We further demonstrated that TGF-β1 also activates the mitochondrial pathway showing Bid-mediated loss of mitochondrial membrane potential and subsequent cytochrome c release associated with the activations of caspase-9 and the effector caspases. Moreover, all these apoptotic events induced by TGF-β1 were found to be effectively inhibited by Smad3 knockdown and also completely abrogated by Smad7 expression, suggesting the involvement of the Smad3 pathway upstream of the Fas death pathway by TGF-β1.

scholarly journals Smad7 Abrogates Transforming Growth Factor-β1-mediated Growth Inhibition in COLO-357 Cells through Functional Inactivation of the Retinoblastoma Protein

2005 ◽  
Vol 280 (23) ◽  
pp. 21858-21866 ◽  
Author(s):  
Nichole Boyer Arnold ◽  
Murray Korc
Keyword(s):  
Growth Factor ◽  
Growth Inhibition ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Retinoblastoma Protein ◽  
Transforming Growth Factor Β1 ◽  
Type I ◽  
Pancreatic Cancer Cells ◽  
Induced Apoptosis ◽  
Tgf Β1

Smad7 is overexpressed in 50% of human pancreatic cancers. COLO-357 pancreatic cancer cells engineered to overexpress Smad7 are resistant to the actions of transforming growth factor-β1 (TGF-β1) with respect to growth inhibition and cisplatin-induced apoptosis but not with respect to modulation of gene expression. To delineate the mechanisms underlying these divergent consequences of Smad7 overexpression, we studied the effects of Smad7 on TGF-β1-dependent signaling pathways and cell cycle regulating proteins. TGF-β1 induced the phosphorylation of MAPK, p38 MAPK, and AKT2 irrespective of the levels of Smad7, and inhibitors of these pathways did not alter TGF-β1 actions on cell growth. By contrast, Smad7 overexpression interfered with TGF-β1-mediated attenuation of cyclin A and B levels, inhibition of cdc2 dephosphorylation and CDK2 inactivation, up-regulation of p27, and the maintenance of the retinoblastoma protein (RB) in a hypophosphorylated state. Smad7 also suppressed TGF-β1-mediated inhibition of E2F activity but did not alter TGF-β1-mediated phosphorylation of Smad2, the nuclear translocation of Smad2/3/4, or DNA binding of the Smad2/3/4 complex. Although Smad7 did not associate with the type I TGF-β receptor (TβRI), SB-431542, an inhibitor of the kinase activity of this receptor, blocked TGF-β1-mediated effects on Smad-2 phosphorylation. These findings point toward a novel paradigm whereby Smad7 acts to functionally inactivate RB and de-repress E2F without blocking the activation of TβRI and the nuclear translocation of Smad2/3, thereby allowing for TGF-β1 to exert effects in a cancer cell that is resistant to TGF-β1-mediated growth inhibition.

scholarly journals Transforming growth factor β1 attenuates ceramide-induced CPP32/Yama activation and apoptosis in human leukaemic HL-60 cells

1997 ◽  
Vol 327 (3) ◽  
pp. 663-667 ◽  
Author(s):  
Min-Liang KUO ◽  
Chien-Wei CHEN ◽  
Shiou-Hwa JEE ◽  
Shuang-En CHUANG ◽  
Ann-Lii CHENG
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Second Messenger ◽  
Transforming Growth Factor Β1 ◽  
Cellular Functions ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induced Apoptosis ◽  
Tgf Β1

Ceramide, a product of sphingomyelin turnover, is a novel lipid second messenger that mediates important cellular functions including proliferation, differentiation and apoptosis. This study demonstrates that the CPP32/Yama protease was activated during apoptosis induced by the membrane-permeable second messenger C2-ceramide in HL-60 cells. We also found that the addition of a specific tetrapeptide inhibitor of CPP32/Yama, Ac-DEVD-CHO, provided an effective protection against ceramide-induced cell death. These results suggested that CPP32/Yama has a central role in ceramide-mediated apoptosis. Furthermore a wide variety of cytokines were examined for their effect on ceramide-induced apoptosis. Only transforming growth factor β1 (TGF-β1) (1 ng/ml) exerted significant prevention of apoptosis induced by C2-ceramide, or by sphingomyelinase (increases intracellular ceramide). Consistently, TGF-β1 abrogated the cleavage of poly(ADP-ribose) polymerase and the production of the CPP32/Yama active subunit, p17. However, TGF-β1 treatment did not cause growth inhibition or alter the level of cyclin-dependent kinase inhibitor p27. It suggests that the preventive effect of TGF-β1 is not mediated by growth arrest. Interestingly, we found that TGF-β1 prevented the C2-ceramide-caused decrease of Bcl-2 protein. We thus propose that TGF-β1 rescues ceramide-induced cell death, possibly by maintaining the constant level of Bcl-2, thereby abolishing CPP32/Yama protease activation.

scholarly journals Differential Regulation and ATP Requirement for Caspase-8 and Caspase-3 Activation during CD95- and Anticancer Drug–induced Apoptosis

1998 ◽  
Vol 188 (5) ◽  
pp. 979-984 ◽  
Author(s):  
Davide Ferrari ◽  
Ania Stepczynska ◽  
Marek Los ◽  
Sebastian Wesselborg ◽  
Klaus Schulze-Osthoff
Keyword(s):  
Death Receptor ◽  
Mitochondrial Pathway ◽  
Atp Depletion ◽  
Caspase 8 ◽  
Chemotherapeutic Drugs ◽  
Caspase Activation ◽  
Drug Induced ◽  
Regulatory Pathways ◽  
Atp Production ◽  
Induced Apoptosis

Apoptosis is induced by different stimuli, among them triggering of the death receptor CD95, staurosporine, and chemotherapeutic drugs. In all cases, apoptosis is mediated by caspases, although it is unclear how these diverse apoptotic stimuli cause protease activation. Two regulatory pathways have been recently identified, but it remains unknown whether they are functionally independent or linked to each other. One is mediated by recruitment of the proximal regulator caspase-8 to the death receptor complex. The other pathway is controlled by the release of cytochrome c from mitochondria and the subsequent ATP-dependent activation of the death regulator apoptotic protease-activating factor 1 (Apaf-1). Here, we report that both pathways can be dissected by depletion of intracellular ATP. Prevention of ATP production completely inhibited caspase activation and apoptosis in response to chemotherapeutic drugs and staurosporine. Interestingly, caspase-8, whose function appeared to be restricted to death receptors, was also activated by these drugs under normal conditions, but not after ATP depletion. In contrast, inhibition of ATP production did not affect caspase activation after triggering of CD95. These results suggest that chemotherapeutic drug–induced caspase activation is entirely controlled by a receptor-independent mitochondrial pathway, whereas CD95-induced apoptosis can be regulated by a separate pathway not requiring Apaf-1 function.

scholarly journals Transforming growth factor-β1 causes pulmonary microvascular endothelial cell apoptosis via ALK5

2009 ◽  
Vol 296 (5) ◽  
pp. L825-L838 ◽  
Author(s):  
Qing Lu ◽  
Bhuvic Patel ◽  
Elizabeth O. Harrington ◽  
Sharon Rounds
Keyword(s):  
Endothelial Cell ◽  
Growth Factor ◽  
Pulmonary Artery ◽  
Transforming Growth Factor ◽  
Microvascular Endothelial Cell ◽  
Caspase 8 ◽  
Protein Levels ◽  
Pulmonary Microvascular Endothelial Cell ◽  
Induced Apoptosis ◽  
Tgf Β1

We have previously shown that transforming growth factor (TGF)-β1 protected against main pulmonary artery endothelial cell (PAEC) apoptosis induced by serum deprivation and VEGF receptor blockade through a mechanism associated with ALK5-mediated Bcl-2 upregulation. In the current study, we investigated the effect of TGF-β1 on pulmonary microvascular endothelial cell (PMVEC) apoptosis. We found that, in contrast to the results seen in conduit PAEC, TGF-β1 caused apoptosis of PMVEC, an effect that was also dependent on ALK5 activity. We noted that non-SMAD signaling pathways did not play a role in TGF-β1-induced apoptosis. Both SMAD2 and SMAD1/5 were activated upon exposure to TGF-β1. TGF-β1-induced activation of SMAD2, but not SMAD1/5, was abolished by ALK5 inhibition, an effect that associated with prevention of TGF-β1-induced apoptosis. These results suggest that SMAD2 is important in TGF-β1-induced apoptosis of PMVEC. While caspase-12 activity was not altered, caspase-8 was activated by TGF-β1, an effect that correlated with a reduction of cFLIP protein levels. Additionally, TGF-β1 decreased Bcl-2 protein levels and induced cytochrome c cytosolic redistribution. These results suggest that TGF-β1 caused apoptosis of PMVEC likely through both caspase-8-dependent extrinsic pathway and mitochondria-mediated intrinsic pathway. We noted that inhibition of ALK5 attenuated serum deprivation-induced apoptosis, an effect that correlated with increased expression and activation of CREB and its potential target genes, Bcl-2 and cFLIP. These results suggest that CREB may be important in mediating apoptosis resistance of PMVEC upon ALK5 inhibition perhaps through upregulation of Bcl-2 and cFLIP. Finally, we noted that SMAD1/5 were activated upon ALK5 inhibition in the presence of low levels of TGF-β1, an effect associated with enhanced endothelial proliferation. We speculate that imbalance of ALK1 and ALK5 may contribute to the development of pulmonary artery hypertension.

Transforming growth factor–β1 in supernatants from stored red blood cells inhibits neutrophil locomotion

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 1100-1107 ◽  
Author(s):  
Massimo Ghio ◽  
Luciano Ottonello ◽  
Paola Contini ◽  
Massimo Amelotti ◽  
Clemente Mazzei ◽  
...  
Keyword(s):  
Growth Factor ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Fas Ligand ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Increased Risk ◽  
High Dilutions ◽  
Formyl Peptides ◽  
Tgf Β1

Abstract Studies comparing transfusion and nontransfusion patients suggest an increased risk of postoperative infections in transfusion groups. Supernatants of blood components have been shown to affect the function of T lymphocytes and natural killer cells. Here, we found that supernatants from stored red blood cells (RBCs) inhibit human neutrophil migration in response to formyl peptides and stimulate neutrophil locomotion. These effects can be observed with high dilutions of RBC supernatants, such as 1:5 × 106 (vol/vol), able to trigger locomotion as well as desensitization of the cells to alternative chemoattractants. The phenomenon might be mediated by chemoattractants present in the supernatants. As RBC supernatants failed to mobilize intracellular free calcium, the chemoattractants should belong to the group of pure chemoattractants, that is, soluble Fas ligand (sFasL) and transforming growth factor–β1 (TGF-β1), known to act without increasing calcium levels. Recombinant TGF-β1, but not sFasL, was found to reproduce the ability of RBC supernatants to both inhibit neutrophil response to formyl peptides and stimulate neutrophil locomotion. Moreover, TGF-β1–immunodepleted supernatants did not display neutrophil-directed activities. Finally, RBC supernatants from RBCs stored after depletion of leukocytes were incapable of affecting neutrophil function. With neutrophils acting as a first-line antimicrobial defense, the ability, shown here, of high dilutions of RBC supernatants to inhibit neutrophil chemotaxis through TGF-β1 may be a relevant determinant of infections in the postoperative period for transfusion patients. Consistently, the neutrophil chemotactic response to formyl peptide was inhibited by the plasma obtained from 5 transfusion patients.

scholarly journals Requirement for Transforming Growth Factor β1 in Controlling T Cell Apoptosis

2001 ◽  
Vol 194 (4) ◽  
pp. 439-454 ◽  
Author(s):  
WanJun Chen ◽  
Wenwen Jin ◽  
Hongsheng Tian ◽  
Paula Sicurello ◽  
Mark Frank ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Cell Apoptosis ◽  
Transforming Growth Factor ◽  
Death Receptor ◽  
Cell Receptor ◽  
Transforming Growth Factor Β1 ◽  
T Cell Apoptosis ◽  
Tgf Β1

Transforming growth factor (TGF)-β1, a potent immunoregulatory molecule, was found to control the life and death decisions of T lymphocytes. Both thymic and peripheral T cell apoptosis was increased in mice lacking TGF-β1 (TGF-β1−/−) compared with wild-type littermates. Engagement of the T cell receptor enhanced this aberrant T cell apoptosis, as did signaling through either the death receptor Fas or the tumor necrosis factor α receptor in peripheral T cells. Strikingly, TGF-β was localized within the mitochondria of normal T cells, and the absence of TGF-β1 resulted in disruption of mitochondrial membrane potential (Δψm), which marks the point of no return in a cell condemned to die. This TGF-β–dependent regulation of viability appears dissociable from the TGF-β1 membrane receptor–Smad3 signaling pathway, but associated with a mitochondrial antiapoptotic protein Bcl–XL. Thus, TGF-β1 may protect T cells at multiple sites in the death pathway, particularly by maintaining the essential integrity of mitochondria. These findings may have broad implications not only for T cell selection and death in immune responses and in the generation of tolerance, but also for defining the mechanisms of programmed cell death in general.

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