12-O-tetradecanoylphorbol-13-acetate-induced Apoptosis Is Mediated by Tumor Necrosis Factor α in Human Monocytic U937 Cells

Takada, Yasunari; Hachiya, Misao; Osawa, Yoshiaki; Hasegawa, Yoshinori; Andō, Kōichi; Kobayashi, Yoshiro; Akashi, Makoto

doi:10.1074/jbc.274.40.28286

Cited by 30 publications

(36 citation statements)

References 74 publications

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“…Interestingly, TPA-mediated apoptosis has recently been linked to endogenous production of TNF and activation of an auto-or paracrine TNF/TNF-receptor loop, whereas chemotherapy-induced apoptosis can at least in part be a consequence of a Fas/FasL interaction. 21,22 Moreover, we did not observe a protective effect of caspase-8 inhibition prior to TPA treatment.…”

Section: Discussionmentioning

confidence: 72%

Activation of protein kinase C relays distinct signaling pathways in the same cell type: differentiation and caspase-mediated apoptosis

2000

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Activation of PKC with 5 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 72 h in human U937 myeloid leukemia cells is associated with induction of adherence, followed by monocytic differentiation and G 0 /G 1 cell cycle arrest. In this study, we demonstrate that in addition to these effects about 25% of U937 cells accumulated in an apoptotic subG 1 phase after TPA treatment. The appearance of these apoptotic suspension cells was detectable throughout the time course of the culture and was independent of TPA concentrations between 0.5 and 500 nM. Experiments with cells synchronized by centrifugal elutriation revealed dominant susceptibility of G 1 -phase cells to TPA-mediated apoptosis. While adherent cells expressed differentiation markers including the integrin CD11c, this effect was less pronounced in the TPA-treated suspension fraction. Moreover, previous work has demonstrated cell cycle arrest in differentiating U937 cells. Accordingly, PKC activation by TPA treatment was associated with a significant expression of the cdk/cyclin inhibitor p21 WAF/CIP/sdi-1 in the adherent population and subsequent G 0 /G 1 cell cycle arrest. In contrast, suspension cells failed to induce significant levels of p21 WAF/CIP/sdi-1 after TPA stimulation. Immunoblotting experiments demonstrated no difference in the expression of the pro-apoptotic factors Bax, Bad, and Bak in either control U937 and TPA-treated adherent or suspension cells, respectively. However, anti-apoptotic factors including Bcl-2, Bcl-x L , and Mcl-1 were significantly induced in the adherent population whereas no induction was detectable in the suspension cells. In this context, incubation with the caspase-3/caspase-7 specific tetrapeptide inhibitor DEVD prior to TPA treatment prevented an accumulation of cells in subG 1 , respectively, demonstrating an involvement of these caspases. Taken together, these data suggest that PKC activation can relay distinct signaling pathways such as induction of adherence coupled with monocytic differentiation and growth arrest, or induction of caspase-mediated apoptosis coupled with the failure to adhere and to differentiate. Cell Death and Differentiation (2000) 7, 795 ± 803.

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Section: Discussionmentioning

confidence: 72%

Activation of protein kinase C relays distinct signaling pathways in the same cell type: differentiation and caspase-mediated apoptosis

2000

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“…As the agents which regulate activities of PKC, such as PMA or H-7, caused alteration of the levels of phosphorylated-Bcl10, Bcl10 could be directly phosphorylated by PKC. A variety of reports have suggested that PKC can act as a potentiator of apoptosis induced by stimuli such as TNF (Laouar et al, 1999;Takada et al, 1999). It is possible that Bcl10 might be a novel target molecule involved in the signaling of PKC-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Interchangeable binding of Bcl10 to TRAF2 and cIAPs regulates apoptosis signaling

et al. 2001

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Bcl10 was identi®ed as a candidate gene responsible for low grade B cell lymphomas of mucosa-associated lymphoid tissue. Overexpression of Bcl10 in cultured cells was reported to promote apoptosis, however, the mechanism of regulation of apoptosis mediated by Bcl10 has not been demonstrated. In the present study, we analysed the apoptosis signaling pathway mediated by Bcl10, focusing on phosphorylation of Bcl10 and the dynamic interaction with its binding partners during apoptosis. Previously, we have demonstrated that Bcl10 potentially interacts with the other apoptosis regulator, TNF receptor associated factor-2 (TRAF2) and inhibitor of apoptosis proteins (cIAPs). The present results showed that the complex formation of these molecules was regulated by phosphorylation of Bcl10, that is, phosphorylation of Bcl10 resulted in binding of Bcl10 to cIAPs and the dissociation of it from TRAF2. Moreover, hyperphosphorylation of Bcl10 enhanced apoptosis, suggesting that changes in the binding partners of Bcl10 were correlated to the promotion of apoptosis as mediated by Bcl10. Indeed, the mutant which was deleted from the binding site of Bcl10 for cIAPs, could not induce apoptosis. These ®ndings indicate that Bcl10 is a mediator of apoptosis signaling, by switching over binding to cIAPs from TRAF2 through the events of Bcl10 phosphorylation. Oncogene (2001) 20, 4317 ± 4323.

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“…31,33,50 Likewise, PKCd-induced cell death in HeLa cells and HPVtransformed keratinocytes is presumably p53-independent. 21 In the LNCaP prostate epithelial cell line however, TPA-induced apoptosis was preceded by induction of the cdk inhibitor, p21, and dephosphorylation of the retinoblastoma protein (Rb).…”

Section: Discussionmentioning

confidence: 99%

Activation of PKC is sufficient to induce an apoptotic program in salivary gland acinar cells

et al. 2000

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Accumulating evidence suggests that specific isoforms of PKC may function to promote apoptosis. We show here that activation of the conventional and novel isoforms of PKC with 12-O-tetradecanoyl phorbol-13-ester (TPA) induces apoptosis in salivary acinar cells as indicated by DNA fragmentation and activation of caspase-3. TPA-induced DNA fragmentation, caspase-3 activation, and morphologic indicators of apoptosis, can be enhanced by pretreatment of cells with the calpain inhibitor, calpeptin, prior to the addition of TPA. Analysis of PKC isoform expression by immunoblot shows that TPAinduced downregulation of PKCa and PKCd is delayed in cells pre-treated with calpeptin, and that this correlates with an increase of these isoforms in the membrane fraction of cells. TPA-induced apoptosis is accompanied by biphasic activation of the c-jun-N-terminal kinase (JNK) pathway and inactivation of the extracellular regulated kinase (ERK) pathway. Expression of constitutively activated PKCa or PKCd, but not kinase negative mutants of these isoforms, or constitutively activated PKCe, induces apoptosis in salivary acinar cells, suggesting a role for these isoforms in TPAinduced apoptosis. These studies demonstrate that activation of PKC is sufficient for initiation of an apoptotic program in salivary acinar cells.

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12-O-tetradecanoylphorbol-13-acetate-induced Apoptosis Is Mediated by Tumor Necrosis Factor α in Human Monocytic U937 Cells

Cited by 30 publications

References 74 publications

Activation of protein kinase C relays distinct signaling pathways in the same cell type: differentiation and caspase-mediated apoptosis

Activation of protein kinase C relays distinct signaling pathways in the same cell type: differentiation and caspase-mediated apoptosis

Interchangeable binding of Bcl10 to TRAF2 and cIAPs regulates apoptosis signaling

Activation of PKC is sufficient to induce an apoptotic program in salivary gland acinar cells

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