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 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 Inhibits Fas Ligand Expression and Subsequent Activation-induced Cell Death in T Cells via Downregulation of c-Myc

1999 ◽  
Vol 189 (2) ◽  
pp. 231-239 ◽  
Author(s):  
Laurent Genestier ◽  
Shailaja Kasibhatla ◽  
Thomas Brunner ◽  
Douglas R. Green
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Growth Factor ◽  
Fas Ligand ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
T Cell Response ◽  
Activation Induced Cell Death ◽  
Tgf Β1

Activation-induced cell death (AICD) is a process that regulates the size and the duration of the primary immune T cell response. In this report, we investigated the mechanisms involved in the regulation of AICD by transforming growth factor β1 (TGF-β1). We found that TGF-β1 decreased apoptosis of human T cells or T cell hybridomas after activation by anti-CD3. This decrease was associated with inhibition of Fas (Apo-1/CD95) ligand (FasL) expression, whereas Fas signaling was not affected by TGF-β1. In parallel, TGF-β1 inhibited c-Myc expression in T cell hybridomas, and ectopic expression of a chimeric molecule composed of c-Myc and the steroid binding domain of the estrogen receptor (Myc-ER) blocked both the inhibition of FasL and the decrease of AICD induced by TGF-β1, providing that 4-hydroxytamoxifen was present. These results identify one mechanism by which TGF-β1 blocks AICD to allow the clonal expansion of effector T cells and the generation of memory T cells during immune responses.

scholarly journals Ligand-Independent Regulation of Transforming Growth Factor β1 Expression and Cell Cycle Progression by the Aryl Hydrocarbon Receptor

2007 ◽  
Vol 27 (17) ◽  
pp. 6127-6139 ◽  
Author(s):  
Xiaoqing Chang ◽  
Yunxia Fan ◽  
Saikumar Karyala ◽  
Sandy Schwemberger ◽  
Craig R. Tomlinson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Transforming Growth Factor Β1 ◽  
Cyclin Dependent Kinase ◽  
Aryl Hydrocarbon ◽  
Tgf Β1

ABSTRACT The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic effects of its xenobiotic ligands and acts as an environmental checkpoint during the cell cycle. We expressed stably integrated, Tet-Off-regulated AHR variants in fibroblasts from AHR-null mice to further investigate the AHR role in cell cycle regulation. Ahr +/+ fibroblasts proliferated significantly faster than Ahr − / − fibroblasts did, and exposure to a prototypical AHR ligand or deletion of the ligand-binding domain did not change their proliferation rates, indicating that the AHR function in cell cycle was ligand independent. Growth-promoting genes, such as cyclin and cyclin-dependent kinase genes, were significantly down-regulated in Ahr − / − cells, whereas growth-arresting genes, such as the transforming growth factor β1 (TGF-β1) gene, extracellular matrix (ECM)-related genes, and cyclin-dependent kinase inhibitor genes, were up-regulated. Ahr − / − fibroblasts secreted significantly more TGF-β1 into the culture medium than Ahr +/+ fibroblasts did, and Ahr − / − showed increased levels of activated Smad4 and TGF-β1 mRNA. Inhibition of TGF-β1 signaling by overexpression of Smad7 reversed the proliferative and gene expression phenotype of Ahr − / − fibroblasts. Changes in TGF-β1 mRNA accumulation were due to stabilization resulting from decreased activity of TTP, the tristetraprolin RNA-binding protein responsible for mRNA destabilization through AU-rich motifs. These results show that the Ah receptor possesses interconnected intrinsic cellular functions, such as ECM formation, cell cycle control, and TGF-β1 regulation, that are independent of activation by either exogenous or endogenous ligands and that may play a crucial role during tumorigenesis.

scholarly journals Transforming Growth Factor-β1 Abrogates Fas-Induced Growth Suppression and Apoptosis of Murine Bone Marrow Progenitor Cells

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3395-3403 ◽  
Author(s):  
Ingunn Dybedal ◽  
Fengan Guan ◽  
Ole Johan Borge ◽  
Ole Petter Veiby ◽  
Veslemøy Ramsfjell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Growth Suppression ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Induced Apoptosis ◽  
Tgf Β1

Abstract Fas, a member of the tumor necrosis factor (TNF ) receptor superfamily is a critical downregulator of cellular immune responses. Proinflammatory cytokines like interferon-γ (IFN-γ) and TNF-α can induce Fas expression and render hematopoietic progenitor cells susceptible to Fas-induced growth suppression and apoptosis. Transforming growth factor-β1 (TGF-β1 ) is an essential anti-inflammatory cytokine, thought to play a key role in regulating hematopoiesis. In the present studies we investigated whether TGF-β1 might regulate growth suppression and apoptosis of murine hematopoietic progenitor cells signaled through Fas. In the presence of TNF, activation of Fas almost completely blocked clonogenic growth of lineage-depleted (Lin−) bone marrow (BM) progenitor cells in response to granulocyte-macrophage colony-stimulating factor (GM-CSF ), CSF-1, or a combination of multiple cytokines. Whereas TGF-β1 alone had no effect or stimulated growth in response to these cytokines, it abrogated Fas-induced growth suppression. Single-cell studies and delayed addition of TGF-β1 showed that the ability of TGF-β1 to inhibit Fas-induced growth suppression was directly mediated on the progenitor cells and not indirect through potentially contaminating accessory cells. Furthermore, TGF-β1 blocked Fas-induced apoptosis of Lin− BM cells, but did not affect Fas-induced apoptosis of thymocytes. TGF-β1 also downregulated the expression of Fas on Lin− BM cells. Thus, TGF-β1 potently and directly inhibits activation-dependent and Fas-mediated growth suppression and apoptosis of murine BM progenitor cells, an effect that appears to be distinct from its ability to induce progenitor cell-cycle arrest. Consequently, TGF-β1 might act to protect hematopoietic progenitor cells from enhanced Fas expression and function associated with proinflammatory responses.

scholarly journals Transforming Growth Factor β1 Induces Apoptosis through Cleavage of BAD in a Smad3-Dependent Mechanism in FaO Hepatoma Cells

2002 ◽  
Vol 22 (5) ◽  
pp. 1369-1378 ◽  
Author(s):  
Byung-Chul Kim ◽  
Mizuko Mamura ◽  
Kyeong Sook Choi ◽  
Bruno Calabretta ◽  
Seong-Jin Kim
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Hepatoma Cell ◽  
Transforming Growth Factor Β ◽  
Transforming Growth Factor Β1 ◽  
Hepatoma Cell Line ◽  
Steady State Levels ◽  
Induced Apoptosis ◽  
Tgf Β1 ◽  
Dependent Mechanism

ABSTRACT Transforming growth factor β (TGF-β) induces apoptosis in a variety of cells. We have previously shown that TGF-β1 rapidly induces apoptosis in the FaO rat hepatoma cell line. We have now studied the effect of TGF-β1 on the expression of different members of the Bcl-2 family in these cells. We observed no detectable changes in the steady-state levels of Bcl-2, Bcl-XL, and Bax. However, TGF-β1 induced caspase-dependent cleavage of BAD at its N terminus to generate a 15-kDa truncated protein. Overexpression of the 15-kDa truncated BAD protein enhanced TGF-β1-induced apoptosis, whereas a mutant BAD resistant to caspase 3 cleavage blocked TGF-β1-induced apoptosis. Overexpression of Smad3 dramatically enhanced TGF-β1-induced cleavage of BAD and apoptosis, whereas antisense Smad3 blocked TGF-β1-induced apoptosis and BAD cleavage. These results suggest that TGF-β1 induces apoptosis through the cleavage of BAD in a Smad3-dependent mechanism.

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