Transforming Growth Factor β1 Induces Apoptotic Cell Death in Cultured Human Umbilical Vein Endothelial Cells with Down-Regulated Expression of BCL-2

Tsukada, Toshiaki; Eguchi, Katsumi; Migita, Kiyoshi; Kawabe, Yojiro; Kawakami, Atsushi; Matsuoka, Naoki; Takashima, Hiroyuki; Mizokami, Akinari; Nagataki, Shigenobu

doi:10.1006/bbrc.1995.1766

Cited by 98 publications

(53 citation statements)

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“…TGF-␤1 is a potent growth inhibitor of epithelial cells and has been shown to induce apoptosis and down-regulate Bcl-2 expression (40,41). The dramatic elevation of the 44-kDa IGFBP-3 protein within 12 h of TGF-␤1 treatment and the significant effect of TGF-␤1 on apoptosis that was observed about 18 -24 h after treatment suggest that the TGF-␤1-induced elevation of IGFBP-3 protein in the conditioned media is the primary signal that activated apoptosis in this cell line.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor (IGF)-binding Protein-3 Induces Apoptosis and Mediates the Effects of Transforming Growth Factor-β1 on Programmed Cell Death through a p53- and IGF-independent Mechanism

Rajah

Valentinis

Cohen

1997

Journal of Biological Chemistry

685

519

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Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is known to block IGF action and inhibit cell growth. IGFBP-3 is thought to act by sequestering free IGFs or, possibly, act via a novel IGF-independent mechanism. Supporting its role as a primary growth inhibitor, IGFBP-3 production has been shown to be increased by cell growth-inhibitory agents, such as transforming growth factor-␤ (TGF-␤), and the tumor suppressor gene p53. In this paper, we demonstrate, for the first time, a novel function of IGFBP-3 as an apoptosis-inducing agent and show that this action is mediated through an IGF⅐IGF receptor-independent pathway. In the p53 negative prostate cancer cell line, PC-3, the addition of recombinant IGFBP-3 resulted in a dose-dependent induction of apoptosis.125 I-IGFBP-3 bound with high affinity to specific proteins in PC-3 cell lysates and plasma membrane preparations. These membrane-associated molecules may serve as receptors that mediate the direct effect of IGFBP-3 on apoptosis. In addition, in an IGF receptor-negative mouse fibroblast cell line, treatment with recombinant IGFBP-3 as well as transfection of the IGFBP-3 gene induced apoptosis, suggesting that neither IGFs nor IGF receptors are required for this action. Furthermore, treatment with TGF-␤1, a known apoptosis-inducing agent, resulted in the induction of IGFBP-3 expression 6 -12 h before the onset of apoptosis. This effect of TGF-␤1 was prevented by co-treatment with IGFBP-3-neutralizing antibodies or IGFBP-3-specific antisense thiolated oligonucleotides. These findings suggest that IGFBP-3 induces apoptosis through a novel pathway independent of either p53 or the IGF⅐IGF receptor-mediated cell survival pathway and that IGFBP-3 mediates TGF-␤1 induced apoptosis in PC-3 cells.

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Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor (IGF)-binding Protein-3 Induces Apoptosis and Mediates the Effects of Transforming Growth Factor-β1 on Programmed Cell Death through a p53- and IGF-independent Mechanism

Rajah

Valentinis

Cohen

1997

Journal of Biological Chemistry

685

519

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“…21,22 Taken together, our results therefore suggest that CTGF activates caspase 3 and induces apoptosis in HASCs very much as TGF-␤ does in many types of cells. [22][23][24][25][26] At this point, it remains unclear whether apoptosis occurred only in CTGFoverexpressing cells or whether bystander effects also occurred. We used immunocytochemistry for CTGF and the TUNEL method simultaneously, but unfortunately, currently available antibodies are not yet suitable to clarify this aspect.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Connective Tissue Growth Factor Gene Induces Apoptosis in Human Aortic Smooth Muscle Cells

et al. 1999

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Background-Connective tissue growth factor (CTGF) is expressed at very high levels particularly in the shoulder of human atherosclerotic lesions but not in normal blood vessels. Thus, CTGF may be important in the regulation of vascular smooth muscle cell function in atherosclerosis, but its precise role remains elusive. Methods and Results-Full-length CTGF cDNA driven by a cytomegalovirus promoter was transiently transfected into cultured human aortic smooth muscle cells (HASCs). Northern and Western analysis demonstrated that CTGF was overexpressed in these cells 48 hours after transfection. The effects of CTGF overexpression on cell proliferation were evaluated by [ 3 H]thymidine uptake and cell count in quiescent HASCs or those stimulated with platelet-derived growth factor (PDGF). Although mock transfection showed no effect, CTGF overexpression significantly inhibited cell proliferation in cells stimulated by PDGF. Moreover, CTGF overexpression, but not mock transfection, significantly increased apoptosis as assessed by DNA fragmentation associated with histone, TdT-mediated dUTP biotin nick end-labeling, and appearance of hypodiploid cells by flow cytometry. Conclusions-Our results for the first time demonstrate that CTGF can also act as a growth inhibitor in human aortic smooth muscle cells at least in part by inducing apoptosis. This may be important for the formation and composition of lesions and plaque stability in atherosclerosis. (Circulation. 1999;100:2108-2112.)

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“…Cells were harvested 24 h post-transfection for analysis of the expressed proteins by immunoblotting with an anti-T7 epitope monoclonal antibody (Novagen, Madison, WI). For detection of apoptosis by DNA laddering (Tsukada et al, 1995), COS cells (1 ϫ 10 6 ) were transfected with the tagged wild type or mutant Cmh-1 construct and harvested at 36 h post-transfection.…”

Section: /Embl Data Bank With Accession Number(s) U40281mentioning

confidence: 99%

Identification and Characterization of CPP32/Mch2 Homolog 1, a Novel Cysteine Protease Similar to CPP32

Lippke

Sarnecki

et al. 1996

Journal of Biological Chemistry

209

103

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We have identified and characterized a novel cysteine protease named CMH-1 that is a new member of the interleukin 1␤ converting enzyme (ICE) family of proteases with substrate specificity for Asp-X. CMH-1 has the highest similarity to CPP32 (52% amino acid identity) and MCH2 (31% identical). CMH-1 shares conserved amino acid residues that form the core structure of ICE as well as those residues involved in catalysis and in the P1 aspartate binding. Overexpression of CMH-1 in COS cells resulted in the processing of CMH-1 and the induction of apoptosis of transfected cells. Coexpression of CMH-1 with poly(ADP-ribose) polymerase (PARP) also resulted in a specific cleavage of PARP. Purified recombinant CMH-1 cleaved PARP but not interleukin 1␤ precursor in vitro.

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Transforming Growth Factor β1 Induces Apoptotic Cell Death in Cultured Human Umbilical Vein Endothelial Cells with Down-Regulated Expression of BCL-2

Cited by 98 publications

References 0 publications

Insulin-like Growth Factor (IGF)-binding Protein-3 Induces Apoptosis and Mediates the Effects of Transforming Growth Factor-β1 on Programmed Cell Death through a p53- and IGF-independent Mechanism

Insulin-like Growth Factor (IGF)-binding Protein-3 Induces Apoptosis and Mediates the Effects of Transforming Growth Factor-β1 on Programmed Cell Death through a p53- and IGF-independent Mechanism

Overexpression of Connective Tissue Growth Factor Gene Induces Apoptosis in Human Aortic Smooth Muscle Cells

Identification and Characterization of CPP32/Mch2 Homolog 1, a Novel Cysteine Protease Similar to CPP32

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