Identification of PKC-isoform-specific biological actions using pharmacological approaches

Way, Kerrie J.; Chou, Eva; King, George L.

doi:10.1016/s0165-6147(00)01468-1

Cited by 392 publications

(381 citation statements)

References 43 publications

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“…However, these same PKC isozymes are also known to be inhibited by one or more of the other PKC inhibitors we found unable to reverse the ability of Wnt-1 or Wnt-3a to inhibit NGF-induced neurite outgrowth (Toullec et al, 1991;Way et al, 2000). Furthermore, taken together, these other PKC inhibitors are effective against more of the known PKC isozymes than is bisindolylmaleimide-I (Way et al, 2000).…”

Section: Discussionmentioning

confidence: 76%

“…A repeat experiment yielded similar results. Using the same protocol described for Figure 4 we have found that none of several other known inhibitors of protein kinase C (Way et al, 2000) reversed the inhibition by Wnt-1 of NGF-induced neurite outgrowth from twnt3-C10 cells (data not shown). The inhibitors used were H7 (10 mM), staurosporine (0.2 mM), Go 6983 (1 mM), Ro31-8220 (5 mM), and rottlerin (5 mM).…”

Section: Effects Of Pkc Inhibitors or A Phorbol Estermentioning

confidence: 80%

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Inhibition by Wnt-1 or Wnt-3a of nerve growth factor-induced differentiation of PC12 cells is reversed by bisindolylmaleimide-I but not by several other PKC inhibitors

Chou

Howard

2002

Oncogene

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Wnt-1 and Wnt-3a exhibit redundancy in neural crest development. We have found that they do not produce the same effects on PC12 cells, which were obtained from the adrenal medulla, a neural crest derivative. However, both Wnt-1 or Wnt-3a inhibit nerve growth factor (NGF)-induced neurite outgrowth. The inhibition is reversed by the protein kinase C (PKC) inhibitor, bisindolylmaleimide-I, but it did not reverse Wnt-1-induced activation of the canonical Wnt pathway. The Wnt-1 inhibitory effect was not reversed by several other PKC inhibitors, by phorbol ester-induced down-regulation of PKC, or by pertussis toxin, which is known to inhibit another Wnt signaling pathway, the Wnt/Ca 2+ pathway. We suggest that bisindolylmaleimide-I acts by affecting either a pathway downstream from Lef-1/Tcf in the canonical pathway or a Wnt signaling pathway other than the canonical pathway. In either case, the bisindolylmaleimide-I sensitivity of this pathway should aid in its identification.

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Section: Discussionmentioning

confidence: 76%

Section: Effects Of Pkc Inhibitors or A Phorbol Estermentioning

confidence: 80%

Inhibition by Wnt-1 or Wnt-3a of nerve growth factor-induced differentiation of PC12 cells is reversed by bisindolylmaleimide-I but not by several other PKC inhibitors

Chou

Howard

2002

Oncogene

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“…Enzyme assays performed on rat brain demonstrated that hypericin is a potent and selective inhibitor of the protein kinase C (PKC) (Takahashi et al 1989), enzyme highly involved in pain modulation (Velazquez et al 2007). PKC is a family of serine/ threonine kinases that are divided into three groups based on calcium and diacylglicerol dependence: conventional (α, βI, βII, γ), novel (δ, ε, η, θ), atypical (ζ, λ/ι) (Way et al 2000). We examined the involvement of PKCε and PKCγ since they appear to be the isoforms with a prominent role in the modulation of pain perception (Velazquez et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

Galeotti¹,

Ghelardini²

2012

Psychopharmacology

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Rationale Hypericum perforatum, popularly called St. John's wort (SJW), is a medicinal plant mainly used as antidepressant with a favorable safety profile than standard antidepressants. Some studies have also documented other SJW bioactivities, including pain modulation. Objectives The aim of this study was to demonstrate the capability of SJW to relieve nitric oxide (NO)-induced nociceptive hypersensitivity and identify the effective component. Methods Nociceptive hypersensitivity induced by administration of the NO donors nitroglycerin (GTN) and sodium nitroprusside (SNP) was assessed by cold and hot plate tests. The cellular pathways and molecular targets involved were investigated by Western blotting. Results GTN and SNP produced a prolonged allodynia and hyperalgesia in mice. A single oral administration of low doses of an SJW dried extract or purified hypericin reversed the NO donor-induced nociceptive behavior whereas hyperforin and flavoinoids were ineffective. Investigating into the cellular pathways involved, an increased CREB and STAT1 phosphorylation, and activation of NF-κB were detected within PAG and thalamus following NO donors' administration. These cellular events were prevented by SJW or hypericin. Since hypericin showed PKC blocking properties, a role of PKC as an upstream modulator of these transcription factors was hypothesized. NO donors increased expression and phosphorylation of protein kinase C (PKC) γ and ε isoforms, molecular events prevented by SJW or hypericin. Conclusions SJW reversed NO-induced nociceptive hypersensitivity through the blockade of a supraspinal signaling pathway involving a PKC-dependent CREB, STAT1 and NF-κB activation due to presence of hypericin. These data indicate SJW/hypericin as a therapeutic perspective for pain treatment.

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“…Although the fact that PMA mimicked the effect of IL-1β indicates that the involved isoform belongs to the novel or classical subfamily, 8 isoforms are still left. The pharmacological PKC inhibitors that we used are not very suitable for distinguishing between the different PKC isoforms, since they both interact at the homologous ATP-binding site, and therefore they do not allow clear distinction between the different isoforms [75]. Lastly, although the involvement of PKC in mRNA stabilization is well established [76], and the pharmacological inhibitors we used have been…”

Section: Discussionmentioning

confidence: 99%

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a β-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-α and IL-1β. We found that IL-1β treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNAstabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1β is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications.

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Identification of PKC-isoform-specific biological actions using pharmacological approaches

Cited by 392 publications

References 43 publications

Inhibition by Wnt-1 or Wnt-3a of nerve growth factor-induced differentiation of PC12 cells is reversed by bisindolylmaleimide-I but not by several other PKC inhibitors

Inhibition by Wnt-1 or Wnt-3a of nerve growth factor-induced differentiation of PC12 cells is reversed by bisindolylmaleimide-I but not by several other PKC inhibitors

Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

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