A role for PKC-δ and PI 3-kinase in TNF-α-mediated  antiapoptotic signaling in the human neutrophil

Kilpatrick, Laurie E.; Lee, Julia Y.; Haines, Kathleen M.; Campbell, Donald E.; Sullivan, Kathleen E.; Korchak, Helen M.

doi:10.1152/ajpcell.00385.2001

Cited by 82 publications

(86 citation statements)

References 59 publications

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“…45,46 Similarly, PKC␦ can have pro-or antiapoptotic functions when activated by the p60 tumor necrosis factor ␣ receptor in human neutrophils depending on whether the cells are in suspension or adherent. 47 Thus, our results and other recent data indicate that the function of PKC␦ can depend on the signaling context of a given receptor. The importance of the present study is that this is the first demonstration that PKC␦ function changes in response to an oncogenic mutation in a receptor.…”

Section: Discussionsupporting

confidence: 78%

“…Indeed, the present work suggests that PKC␦ may be a therapeutic target in mastocytosis or AML associated with mutations in the catalytic domain of Kit. Other recent work has linked PKC␦ expression to B-cell chronic lymphocytic leukemia, 28 multiple myeloma, 29 and inappropriate survival of neutrophils, 47 which occurs in inflammatory diseases. PKC␦ inhibitors offer the possibility of a novel therapy with potentially less toxicity than traditional chemotherapy since PKC412 and ISIS 3521 have been well tolerated.…”

Section: Discussionmentioning

confidence: 99%

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PKCδ plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant

Jelacic

Linnekin

2005

Blood

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IntroductionKit, the receptor for stem cell factor (SCF), is a type III receptor tyrosine kinase of the platelet-derived growth factor (PDGF) subfamily. c-kit maps to the white spotting (W) locus in the mouse, 1,2 while the gene for its ligand SCF maps to the steel (Sl) locus. 3,4 Mutations that reduce function or expression of either the receptor or ligand lead to macrocytic anemia, mast cell deficiency, abnormal pigmentation of skin and hair, infertility, reduced gastrointestinal motility, and impaired hippocampal learning. 5 Gain-offunction mutations in Kit can be oncogenic and are found in various diseases including leukemias, mastocytosis, germ cell tumors, and gastrointestinal stromal tumors (GISTs). 6 One common gain-of-function mutation is the substitution of valine, tyrosine, asparagine, or histidine for aspartic acid 816 in the catalytic domain of human Kit. Mutations of codon 816 have been identified in patients with mastocytosis, 7-10 acute myeloid leukemia (AML), [11][12][13] and germ cell tumors. 14 Mutations of the corresponding codon (D814 in mice, D817 in rats) have been found in a murine mastocytoma cell line P-815 15 and a rat mast cell tumor line RBL-2H3. 16 Expression of D814Y/V Kit in the murine mast cell-like line IC2, as well as several other factor-dependent hematopoietic cell lines, results in factor-independent growth and tumorigenesis. [17][18][19][20] Interestingly, cells expressing a Kit catalytic domain mutant are resistant to STI571/imatinib (Gleevec), an inhibitor of wild-type (WT) Kit. [21][22][23] Thus, drugs targeting this mutant receptor or its downstream effectors could be useful therapeutic agents in the treatment of diseases associated with this mutation.The protein kinase C (PKC) family of serine-threonine protein kinases encompasses at least 12 members, 24 which can be separated into 3 classes: conventional, novel, and atypical. The conventional PKCs include the ␣, ␤, and ␥ isoforms. Activation of these PKCs requires both calcium ions and a lipid, such as diacylglycerol (DAG) or phosphatidylserine, or a phorbol ester. The novel PKCs, including ␦, ⑀, , and isoforms, are calcium-independent and require only a lipid or a phorbol ester for kinase activity. Unlike the conventional isoforms, the novel isoforms can be activated by the products of phosphatidylinositol 3-kinase (PI3K), PtdIns-3,4-P 2 , or PtdIns-3,4,5-P 3, as well as DAG or phosphatidylserine. 25 The atypical PKCs, including the and isoforms, require neither calcium nor a lipid or phorbol ester for kinase activity.PKC isoforms are reported to phosphorylate wild-type (WT) Kit on serine residues after stimulation with SCF. Previous work has shown that this reduces autophosphorylation activity and subsequent interaction with a variety of signaling components. 26,27 Importantly, these studies were performed in porcine aortic endothelial cells, which predominantly express the conventional PKC isoforms ␣ and ␤. The role of novel PKC isoforms in signaling through WT Kit has not been addressed. Further, little is known a...

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

PKCδ plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant

Jelacic

Linnekin

2005

Blood

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“…TNFa receptors also activate survival mechanisms in human neutrophils and thus inhibit neutrophil spontaneous death. This is mediated by elevation of PI3 kinase activity [114], NF-kB-dependent IL-8 release, expression of prosurvival factors Al and Bcl-xL [115][116][117][118], and PI3 kinase-independent activation of PKC-d and ERK 1/2 [119].…”

Section: Tnfamentioning

confidence: 99%

Constitutive neutrophil apoptosis: Mechanisms and regulation

2007

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Neutrophil constitutive death is a critical cellular process for modulating neutrophil number and function, and it plays an essential role in neutrophil homeostasis and the resolution of inflammation. Neutrophils die due to programmed cell death or apoptosis. In this article, we review recent studies on the mechanism of neutrophil apoptosis. The involvement of caspase, calpain, reactive oxygen species, cellular survival/death signaling pathways, mitochondria, and BCL-2 family member proteins are discussed. The fate of neutrophils can be influenced within the inflammatory microenvironment. We summarize the current understanding regarding the modulation of neutrophil apoptotic death by various extracellular stimuli such as proinflammatory cytokines, cell adhesion, phagocytosis, red blood cells, and platelets. The involvement of neutrophil apoptosis in infectious and inflammatory diseases is also addressed. Am. J. Hematol. 83:288-295, 2008. V

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“…By contrast, several lines of studies showed a pivotal role for PKCy in antiapoptotic function in response to cytokines, including tumor necrosis factor-a (TNF-a; refs. [20][21][22]. Expression with a PKCy kinase-dead mutant or with a small interfering RNA (siRNA) targeting PKCy increased the apoptotic effect of TNF-related apoptosis-inducing ligand, whereas overexpression of PKCy decreased it (22).…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase Cδ Activates RelA/p65 and Nuclear Factor-κB Signaling in Response to Tumor Necrosis Factor-α

Liu

Yamaguchi

et al. 2009

Cancer Research

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Nuclear factor-KB (NF-KB) is tightly modulated by IKB kinases and IKBA in the cytoplasm. On stimulation, NF-KB translocates into the nucleus to initiate transcription; however, regulation of its transcriptional activity remains obscure. Here, we show that protein kinase C (PKC) D controls the main subunit of NF-KB, RelA/p65. On exposure to tumor necrosis factor-A (TNF-A), the expression of RelA/ p65 target genes such as IKBA, RelB, and p100/p52 is upregulated in a PKCD-dependent manner. The results also show that PKCD is targeted to the nucleus and forms a complex with RelA/p65 following TNF-A exposure. Importantly, kinase activity of PKCD is required for RelA/p65 transactivation. In concert with these results, PKCD activates RelA/p65 for its occupancy to target-gene promoters, including IKBA and p100/p52. Moreover, functional analyses show that inhibition of PKCD is associated with substantial attenuation of NF-KB activity in response to TNF-A. These findings provide evidence that PKCD orchestrates RelA/p65 transactivation, a requisite for NF-KB signaling pathway in the nucleus.

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A role for PKC-δ and PI 3-kinase in TNF-α-mediated antiapoptotic signaling in the human neutrophil

Cited by 82 publications

References 59 publications

PKCδ plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant

PKCδ plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant

Constitutive neutrophil apoptosis: Mechanisms and regulation

Protein Kinase Cδ Activates RelA/p65 and Nuclear Factor-κB Signaling in Response to Tumor Necrosis Factor-α

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