Bryostatin-1 attenuates TNF-induced epithelial barrier dysfunction: role of novel PKC isozymes

Yoo, James J.; Nichols, Anthony C.; Song, Jae Chul; Mammen, Joshua M.V.; Calvo, Isabel Olmos; Worrell, Roger T.; Cuppoletti, John; Matlin, Karl S.; Matthews, Jeffrey B.

doi:10.1152/ajpgi.00214.2002

Cited by 26 publications

(19 citation statements)

References 48 publications

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“…Therefore, due to maintenance of PKCδ activation, bryostatin-1 could be translated into therapies for other disorders benefiting from consistent PKCδ activation. Bryostatin-1 has been shown in one study to enhance solute barrier and prevent the loss of barrier caused by TNF-α in T84 intestinal epithelia, and in another to have no affect on T84 epithelial barrier integrity [59,60]. The fact that studies show bryostatin-1 does not decrease epithelial barrier function and we show no change in endothelial barrier with bryostatin-1 treatment is important.…”

Section: Discussionsupporting

confidence: 40%

Endothelial PKCδ activation attenuates neutrophil transendothelial migration

Carpenter

Alexander

2008

Inflamm. res.

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Section: Discussionsupporting

confidence: 40%

Endothelial PKCδ activation attenuates neutrophil transendothelial migration

Carpenter

Alexander

2008

Inflamm. res.

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“…In a similar fashion, L32 and GAPDH expression remained constant indicating equal loading. Bryostatin stimulates various PKC isoforms in certain cell lines (46,47). Treatment with bryostatin induced cIAP-2 mRNA expression and this induction was completely blocked by GF109203x treatment (Fig.…”

Section: Ciap-2 Regulation In Human Colon Cancersmentioning

confidence: 87%

Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

Wang

Evers

2003

Journal of Biological Chemistry

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Activation of protein kinase C (PKC) prevents apoptosis in certain cells; however, the mechanisms are largely unknown. Inhibitors of apoptosis (IAP) family members, including NAIP, cIAP-1, cIAP-2, XIAP/hILP, survivin, and BRUCE, block apoptosis by binding and potently inhibiting caspases. Activation of NF-B contributes to cIAP-2 induction; however, the cellular mechanisms regulating cIAP-2 expression have not been entirely defined. In this study, we examined the role of the PKC and NF-B pathways in the regulation of cIAP-2 in human colon cancers. We found that cIAP-2 mRNA levels were markedly increased in human colon cancer cells by treatment with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), or bryostatin 1. Inhibitors of the Ca 2؉ -independent, novel PKC isoforms, but not inhibitors of MAPK, PI3-kinase, or PKA, blocked PMA-stimulated cIAP-2 mRNA expression, suggesting a role of PKC in PMA-mediated cIAP-2 induction. Pretreatment with the PKC␦-selective inhibitor rottlerin or transfection with an antisense PKC␦ oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC␦ plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC␦ in cIAP-2 induction. Treatment with the proteasome inhibitor, MG132 or inhibitors of NF-B (e.g. PDTC and gliotoxin), decreased PMA-induced up-regulation of cIAP-2. PMAinduced NF-B activation was blocked by either GF109203x, MG132, PDTC, or gliotoxin. Moreover, overexpression of PKC␦-induced cIAP-2 promoter activity and increased NF-B transactivation, suggesting regulation of cIAP-2 expression by a PKC␦/NF-B pathway. In conclusion, our findings demonstrate a role for a PKC/NF-B-dependent pathway in the regulation of cIAP-2 expression in human colon cancer cells. These data suggest a novel mechanism for the anti-apoptotic function mediated by the PKC␦/NF-B/cIAP-2 pathway in certain cancers.

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“…It is thus not surprising that the effects of PKC signaling in cells are highly complex and seem to vary widely with respect to experimental conditions as well as tissue and cell types. For example, pharmacological studies suggest that PKC-⑀, a member of novel PKC subfamily, mediates cytokine-induced disruption of the intestinal cells (Yoo et al, 2003b). We previously showed that attenuation of the novel PKC isoform, PKC-␦, via molecular interventions protects against oxidantinduced damage to intestinal cells (Banan et al, 2002a).…”

Section: Discussionmentioning

confidence: 99%

θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

Banan¹,

Zhang²,

Shaikh³

et al. 2005

J Pharmacol Exp Ther

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Using monolayers of intestinal Caco-2 cells, we discovered that the isoform of protein kinase C (PKC), a member of the "novel" subfamily of PKC isoforms, is required for monolayer barrier function. However, the mechanisms underlying this novel effect remain largely unknown. Here, we sought to determine whether the mechanism by which PKC-disrupts monolayer permeability and dynamics in intestinal epithelium involves PKC--induced alterations in claudin isotypes. We used cell clones that we recently developed, clones that were transfected with varying levels of plasmid to either stably suppress endogenous PKC-activity (antisense, dominant-negative constructs) or to ectopically express PKC-activity (sense constructs). We then determined barrier function, claudin isotype integrity, PKC-subcellular activity, claudin isotype subcellular pools, and claudin phosphorylation. Antisense transfection to underexpress the PKC-led to monolayer instability as shown by reduced 1) endogenous PKC-activity, 2) claudin isotypes in the membrane and cytoskeletal pools (2claud-1, 2claud-4 assembly), 3) claudin isotype phosphorylation (2 phospho-serine, 2 phospho-threonine), 4) architectural stability of the claudin-1 and claudin-4 rings, and 5) monolayer barrier function. In these antisense clones, PKC-activity was also substantially reduced in the membrane and cytoskeletal cell fractions. In wild-type (WT) cells, PKC-(82 kDa) was both constitutively active and coassociated with claudin-1 (22 kDa) and claudin-4 (25 kDa), forming endogenous PKC-/claudin complexes. In a second series of studies, dominant-negative inhibition of the endogenous PKC-caused similar destabilizing effects on monolayer barrier dynamics, including claudin-1 and -4 hypophosphorylation, disassembly, and architectural instability as well as monolayer disruption. In a third series of studies, sense overexpression of the PKC-caused not only a mostly cytosolic distribution of this isoform (i.e., Ͻ12% in the membrane ϩ cytoskeletal fractions, indicating PKC-inactivity) but also led to disruption of claudin assembly and barrier function of the monolayer. The conclusions of this study are that PKC-activity is required for normal claudin assembly and the integrity of the intestinal epithelial barrier. These effects of PKC-are mediated at the molecular level by changes in phosphorylation, membrane assembly, and/or organization of the subunit components of two barrier function proteins: claudin-1 and claudin-4 isotypes. The ability of PKC-to alter the dynamics of permeability protein claudins is a new function not previously ascribed to the novel subfamily of PKC isoforms.The epithelium of the intestinal mucosa is the largest interface between the body and the external environment. An important characteristic of this interface is its ability to maintain a highly selective permeability barrier that protects the internal milieu from hostile factors in the lumenal environment. Barrier permeability, which in general is maintained by epithelial tight-junctional proteins, pe...

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Bryostatin-1 attenuates TNF-induced epithelial barrier dysfunction: role of novel PKC isozymes

Cited by 26 publications

References 48 publications

Endothelial PKCδ activation attenuates neutrophil transendothelial migration

Endothelial PKCδ activation attenuates neutrophil transendothelial migration

Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

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