TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase

Jang, Chuan-Wei; Chen, Chun-Hau; Chen, Chun‐Chieh; Chen, Jiayun; Su, Yi-Hsien; Chen, Ruey‐Hwa

doi:10.1038/ncb731

Cited by 360 publications

(297 citation statements)

References 47 publications

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“…In other HCC cell lines, TGF-b1 induced apoptosis of Hep3B but not of HepG2 cells (Jang et al, 2002;Zhang et al, 2004). We have observed that PDCD4 expression was upregulated in Hep3B but rarely in HepG2 cells by TGF-b1 treatment (unpublished data).…”

Section: Discussionmentioning

confidence: 68%

“…In our present data, PDCD4-antisense expression was less effective for the recovery of cell growth inhibited by TGF-b1 than for that by Smad7 (compare Figures 6b and 8b) despite PDCD4 expression was almost depressed by the antisense construct. A different signaling pathway also might be present in the TGF-b1-induced apoptosis of Huh7 cells as shown in Hep3B (Jang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma

et al. 2006

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The programmed cell death 4 (PDCD4) gene was originally identified as a tumor-related gene in humans and acts as a tumor-suppressor in mouse epidermal carcinoma cells. However, its function and regulatory mechanisms of expression in human cancer remain to be elucidated. We therefore investigated the expression of PDCD4 in human hepatocellular carcinoma (HCC) and the role of PDCD4 in human HCC cells. Downregulation of PDCD4 protein was observed in all HCC tissues tested compared with corresponding noncancerous liver, as revealed by Western blotting or immunohistochemical staining. Human HCC cell line, Huh7, transfected with PDCD4 cDNA showed nuclear fragmentation and DNA laddering characteristic of apoptotic cells associated with mitochondrial changes and caspase activation. Transforming growth factor-b1 (TGF-b1) treatment of Huh7 cells resulted in increased PDCD4 expression and occurrence of apoptosis, also concomitant with mitochondrial events and caspase activation. Transfection of Smad7, a known antagonist to TGF-b1 signaling, protected cells from TGF-b1-mediated apoptosis and suppressed TGF-b1-induced PDCD4 expression. Moreover, antisense PDCD4 transfectants were resistant to apoptosis induced by TGF-b1. In conclusion, these data suggest that PDCD4 is a proapoptotic molecule involved in TGF-b1-induced apoptosis in human HCC cells, and a possible tumor suppressor in hepatocarcinogenesis.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma

et al. 2006

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“…Recently, death associating protein (DAP) kinase, which induces apoptosis in certain cell types, was found to be transcriptionally induced by the TGF-b/Smad pathway. Inhibition of DAP kinase activity protected the cells from TGF-b-induced apoptosis (Jang et al, 2002).…”

Section: Regulation Of Apoptosis By Smadsmentioning

confidence: 99%

Regulation of cell proliferation by Smad proteins

Dijke

Goumans

Itoh

2002

Journal Cellular Physiology

399

278

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Transforming growth factor-b (TGF-b) family members which include TGF-bs, activins, and bone morphogenetic proteins (BMPs) regulate a broad spectrum of biological responses on a large variety of cell types. TGF-b family members initiate their cellular responses by binding to distinct receptors with intrinsic serine/ threonine kinase activity and activation of speci®c downstream intracellular effectors termed Smad proteins. Smads relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes. Smad activation, subcellular distribution, and stability have been found to be intricately regulated and a broad array of transcription factors have been identi®ed as Smad partners. Important activities of TGF-b are its potent anti-mitogenic and pro-apoptotic effects that, at least in part, are mediated via Smad proteins. Escape from TGF-b/ Smad-induced growth inhibition and apoptosis is frequently observed in tumors. Certain Smads have been found to be mutated in speci®c types of cancer and gene ablation of particular Smads in mice has revealed increased rate of tumorigenesis. In late stage tumors, TGF-b has been shown to function as a tumor promoter. TGFb can stimulate the de-differentiation of epithelial cells to malignant invasive and metastatic ®broblastic cells. Interestingly, TGF-b may mediate these effects directly on tumor cells via subverted Smad-dependent and/or Smad-independent pathways.

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“…4 In contrast, TGF-b-induced type-I cell death is mediated by DAPk in a p53-independent manner. 5 Another mode of programmed cell death in which DAPk is involved in some cellular settings is autophagic type-II cell death, characterized by the formation of double-membrane vesicles that consume cell contents. 6 Overexpression of DAPk leads, in some cells, to the appearance of autophagic vesicles and cell death that does not involve activation of caspases.…”

mentioning

confidence: 99%

DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress

Eisenberg‐Lerner

Kimchi

2007

Cell Death Differ

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The stress-activated kinase JNK mediates key cellular responses to oxidative stress. Here we show that DAP kinase (DAPk), a cell death promoting Ser/Thr protein kinase, plays a main role in oxidative stress-induced JNK signaling. We identify protein kinase D (PKD) as a novel substrate of DAPk and demonstrate that DAPk physically interacts with PKD in response to oxidative stress. We further show that DAPk activates PKD in cells and that induction of JNK phosphorylation by ectopically expressed DAPk can be attenuated by knocking down PKD expression or by inhibiting its catalytic activity. Moreover, knockdown of DAPk expression caused a marked reduction in JNK activation under oxidative stress, indicating that DAPk is indispensable for the activation of JNK signaling under these conditions. Finally, DAPk is shown to be required for cell death under oxidative stress in a process that displays the characteristics of caspase-independent necrotic cell death. Taken together, these findings establish a major role for DAPk and its specific interaction with PKD in regulating the JNK signaling network under oxidative stress.

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TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase

Cited by 360 publications

References 47 publications

Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma

Involvement of programmed cell death 4 in transforming growth factor-β1-induced apoptosis in human hepatocellular carcinoma

Regulation of cell proliferation by Smad proteins

DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress

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