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

Kim, Byung-Chul; Mamura, Mizuko; Choi, Kyeong Sook; Calabretta, Bruno; Kim, Seong‐Jin

doi:10.1128/mcb.22.5.1369-1378.2002

Cited by 98 publications

(63 citation statements)

References 44 publications

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“…Studies have also shown that overexpression of wild-type Smad3 induces apoptosis in human lung epithelial cells (58) and that overexpression of dominantnegative forms of Smad3 inhibit TGF␤ induced apoptotic cell death in Hep3B cells (63). More recently, TGF␤-induced cell death in rat FAO cells was shown to be potently enhanced by overexpression of Smad3 and blocked by antisense Smad3 RNA expression (33). In this same report, it was shown that TGF␤ induced the cleavage of the BH3-only protein BAD through an as yet to be determined Smad3-dependent mechanism (33).…”

Section: Discussionmentioning

confidence: 92%

“…TGF␤ Induces Bim Protein Expression-Previous reports have implicated members of the Bcl-2 family of proteins in mediating the apoptotic effects of TGF␤ (27,33). We therefore examined whether TGF␤-mediated apoptosis in the Smad3-overexpressing clones might be associated with changes in the expression profile of Bcl-2 family members.…”

Section: Increased Smad3 Expression Sensitizes Cells To Tgf␤-inducedmentioning

confidence: 99%

“…More recently, it was shown in the FaO rat hepatoma cell line that TGF␤ does not effect the expression levels of many members of the Bcl-2 family but did induce the caspase-dependent cleavage of BAD, a pro-apoptotic Bcl-2 family member (33). Overexpression of Smad3 in these cells was shown to promote the caspase 3-mediated cleavage of BAD and apoptosis, whereas antisense Smad3 cDNA blocked TGF␤-mediated apoptosis and BAD cleavage (33).…”

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confidence: 99%

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Smad3 Potentiates Transforming Growth Factor β (TGFβ)-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes

Wildey

Patil

Howe

2003

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 92%

Section: Increased Smad3 Expression Sensitizes Cells To Tgf␤-inducedmentioning

confidence: 99%

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confidence: 99%

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Smad3 Potentiates Transforming Growth Factor β (TGFβ)-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes

Wildey

Patil

Howe

2003

Journal of Biological Chemistry

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“…Furthermore, TGFβ-induced apoptosis occurs through ROS generation, the mitochondrial permeability transition (MPT), and caspase activation [5]. Moreover, Smad3-dependent cleavage of the mitochondrial, pro-apoptotic protein, BAD, results in TGFβ-induced apoptosis in FaO hepatoma cells and suggests a distinct role for Smad3 [2]. Thus, these findings suggest that the TGFβ apoptotic pathway includes ROS generation, Smad3 activation, mitochondria involvement, and caspase cleavage.…”

Section: Introductionmentioning

confidence: 78%

“…After partial hepatectomy, TGFβ has an integral role in terminating liver regeneration secondary to its hepatocyte anti-proliferative effects. In vitro and in vivo studies have also shown that TGFβ controls hepatocyte growth directly by inducing apoptosis [2][3][4]. Furthermore, TGFβ-induced apoptosis occurs through ROS generation, the mitochondrial permeability transition (MPT), and caspase activation [5].…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor beta mediates hepatocyte apoptosis through Smad3 generation of reactive oxygen species

et al. 2007

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TGFβ induces hepatocyte apoptosis via reactive oxygen species (ROS) generation, the mitochondrial permeability transition (MPT), and caspase activation. The role of the Smad pathway in these events is unknown. In this study primary hepatocytes were isolated from Smad3 wild-type (+/+) and knockout (−/−) mice, and were treated with TGFβ (5 ng/ml) and/or trolox (2 mM). ROS generation, MPT, TGFβ-dependent transcription, and apoptosis were assessed in the presence or absence of Smad3 wild-type (WT) and dominant-negative (DN) plasmids. With TGFβ treatment, Smad3 (−/−) hepatocytes did not generate ROS activity, exhibit MPT, activate caspases, or undergo apoptosis when compared to Smad 3 (+/+) hepatocytes. Similarly, transfection of Smad3 (+/+) hepatocytes with DN-Smad3 inhibited TGFβ-mediated transcription, ROS generation, MPT, and apoptosis. However, Smad3 (−/−) cells transfected with WT-Smad3 and treated with TGFβ demonstrated increased transcriptional activity, the MPT, and TGFβ-induced apoptosis. TGFβ-mediated ROS generation occurred through an NADPH-like oxidase pathway since diphenyleneiodonium chloride inhibited ROS induction. In conclusion, TGFβ-induced hepatocyte apoptosis occurs through Smad3 dependent activation of ROS with subsequent activation of the MPT and caspases.

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The aberrant methylation of TSP1 suppresses TGF‐β1 activation in colorectal cancer

Rojas¹,

Meherem²,

Kim³

et al. 2008

Intl Journal of Cancer

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Colorectal cancer arises from the progressive accumulation of mutations and epigenetic alterations in colon epithelial cells. Such alterations often deregulate signaling pathways that affect the formation of colon cancer, such as the Wnt, RAS-MAPK and TGF-b pathways. The tumor promoting effects of mutations in genes, such as APC, have been demonstrated in cancer cell lines and in mouse models of intestinal cancer; however, the biological effects of most epigenetic events identified in colorectal cancer remain unknown. Consequently, we assessed whether the aberrant methylation of TSP1, the gene for thrombospondin 1, a regulator of TGF-b ligand activation, is an epigenetic mechanism for inhibiting the TGF-b signaling pathway. We found methylated TSP1 occurs in colon cancer cell lines (33%), colon adenomas (14%) and colon adenocarcinomas (21%). In primary colorectal cancers, loss of TSP1 expression correlated with impaired TGF-b signaling as indicated by decreased Smad2 phosphorylation and nuclear localization. Furthermore, methylation-induced silencing of TSP1 expression reduced the concentration of secreted active TGF-b1 and attenuated TGF-b signaling. Reversal of TSP1 methylation resulted in increased TSP1 mediated activation of the latent LAP:TGF-b complex and subsequent TGF-b receptor activation. Our results demonstrate that the aberrant methylation of TSP1 has biological consequences and provide evidence that the aberrant methylation of TSP1 is a novel epigenetic mechanism for suppressing TGF-b signaling in colorectal cancer. ' 2008 Wiley-Liss, Inc.Key words: thrombospondin; transforming growth factor b; methylation; colorectal cancer; epigenetics Colorectal cancer is the third most common cancer in the United States. In 2008, 154,000 new cases of colorectal cancer will be diagnosed and more than 52,000 people are predicted to die from the disease. 1 Colon cancer arises from the accumulation of DNA alterations in colon epithelial cells, which mediate the initiation and progression of this cancer. Mutations in genes such as KRAS, TP53 and members of the transforming growth factor (TGF-b) signaling pathway play a pathogenic role in the polypcarcinoma sequence. [2][3][4] TGF-b is a pluripotent cytokine that has a multitude of effects on epithelial cells including the inhibition of proliferation, the induction of apoptosis and the stimulation of differentiation. Inactivating mutations in central members of the TGF-b signaling pathway, TGFBR2 and SMAD4, have been identified in approximately half of colon cancers. [5][6][7][8] The biological effects of TGF-b in the colon and the identification of inactivating mutations in TGFBR2 and SMAD4 in colon cancers have demonstrated that the TGF-b signaling pathway can act as a colon cancer tumor suppressor pathway.The TGF-b signaling pathway consists of the TGF-b ligand; the heteromeric TGF-b receptor composed of the type I and type II TGF-b receptors (TGFBR1 and TGFBR2); and the post-receptor signaling proteins, including SMAD2, 3, and 4. TGF-b1 is the most commonly expre...

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

Cited by 98 publications

References 44 publications

Smad3 Potentiates Transforming Growth Factor β (TGFβ)-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes

Smad3 Potentiates Transforming Growth Factor β (TGFβ)-induced Apoptosis and Expression of the BH3-only Protein Bim in WEHI 231 B Lymphocytes

Transforming growth factor beta mediates hepatocyte apoptosis through Smad3 generation of reactive oxygen species

The aberrant methylation of TSP1 suppresses TGF‐β1 activation in colorectal cancer

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