Activation of the PKC‐isotypes α, β<sub>1</sub>, γ, δ, and ε by phorbol esters of different biological activities

Ryves, W. J.; Evans, A.T.; Olivier, Andrée R.; Parker, Peter J.; Evans, Fred J.

doi:10.1016/0014-5793(91)80989-g

Cited by 183 publications

(115 citation statements)

References 26 publications

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“…In separate experiments, phenylephrine-precontracted PA rings (n ϭ 5) were incubated in the presence of the PKC activator thymeleatoxin (THX, 1 mol/l) for 60 min. THX has been demonstrated to be an effective activator of multiple PKC isozymes (25,26).…”

Section: Animalsmentioning

confidence: 99%

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Tsai¹,

Wang²,

Pitcher³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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. Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C. Am J Physiol Lung Cell Mol Physiol 287: L1215-L1219, 2004. First published August 20, 2004 doi:10.1152/ ajplung.00179.2004.-Pulmonary arteries exhibit a marked vasoconstriction when exposed to hypoxic conditions. Although this may be an adaptive response to match lung ventilation with perfusion, the potential consequences of sustained pulmonary vasoconstriction include pulmonary hypertension and right heart failure. Concomitant production of proinflammatory mediators during hypoxia may exacerbate acute increases in pulmonary vascular resistance. We hypothesized that acute hypoxia causes pulmonary arterial contraction and increases the pulmonary artery tissue expression of proinflammatory cytokines via a protein kinase C (PKC)-mediated mechanism. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings during hypoxia in the presence and absence of the PKC inhibitors calphostin C or chelerythrine. In separate experiments, pulmonary artery rings were treated with the PKC activator thymeleatoxin for 60 min. After hypoxia, with or without PKC inhibition, or PKC activation alone, pulmonary artery rings were subjected to mRNA analysis for TNF-␣ and IL-1␤ via RT-PCR. Our results showed that, in isolated pulmonary arteries, hypoxia caused a biphasic contraction and increased expression of TNF-␣ and IL-1␤ mRNA. Both effects were inhibited by PKC inhibition. PKC activation resulted in pulmonary artery contraction and increased the pulmonary artery expression of TNF-␣ and IL-1␤ mRNA. These findings suggest that hypoxia induces the expression of inflammatory cytokines and causes vasoconstriction via a PKC-dependent mechanism. We conclude that PKC may have a central role in modulating hypoxic pulmonary vasoconstriction, and further elucidation of its involvement may lead to therapeutic application. hypoxia; pulmonary hypertension; inflammation; tumor necrosis factor HYPOXIA FREQUENTLY OCCURS in conjunction with inflammatory conditions such as the acute respiratory distress syndrome or severe pulmonary infection. In the absence of infection, an inflammatory response may occur following acute injuries such as ischemia-reperfusion and hypoxia (4, 17). Although much data exist regarding the systemic release of proinflammatory cytokines following acute injury, little is known about the local tissue production of inflammatory cytokines. It is now known that cardiomyocytes generate an intense inflammatory response following acute ischemia-reperfusion injury (14), and these inflammatory mediators contribute to myocardial dysfunction. Therefore, it is possible that hypoxia may stimulate inflammatory cytokine expression from the pulmonary artery (PA) tissue itself.The signaling pathways involved in generating an acute inflammatory response involve mediators such as protein kinase C (PKC). PKC is a regulatory enzyme activated by numerous effectors, growth factors, hormones, and ne...

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Section: Animalsmentioning

confidence: 99%

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Tsai¹,

Wang²,

Pitcher³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Various phorbol ester and related promoters, proin¯ammatory agents and irritants are able to mimic the e ect of diacylglycerol in vitro and cause activation of PKC (at least the cPKC and nPKC subfamilies; see for example Ryves et al, 1991). However in vivo, the slow metabolism of these pharmacological PKC activators distinguishes the temporal pattern of responses both by maintaining activation of PKC over prolonged periods and by causing increased proteolysis of PKC and hence its downregulation (Young et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Loss of protein kinase C function induces an apoptotic response

1998

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“…Rsk activation can be promoted by multiple signaling pathways in cancer cells, including those triggered by steroids, insulin, EGF, and estrogen (10,(12)(13)(14)(15). Additionally, Rsk activation can be triggered by PKC signaling [via the PKC/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinases (MAPK) pathway], which is activated by phorbol12-myristate13-acetate (PMA) (16,17). Previous studies have found that Rsk2 is overexpressed in 50% of breast cancers and prostate tumors (18,19), and Rsk signaling has been implicated in the regulation of survival, anchorage-independent growth, and transformation of breast cancer cells in culture (20).…”

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confidence: 99%

Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11

Chen

Zhang

Huang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Ataxia telangiectasia mutant (ATM) is an S/T-Q-directed kinase that is critical for the cellular response to double-stranded breaks (DSBs) in DNA. Following DNA damage, ATM is activated and recruited by the MRN protein complex [meiotic recombination 11 (Mre11)/DNA repair protein Rad50/Nijmegen breakage syndrome 1 proteins] to sites of DNA damage where ATM phosphorylates multiple substrates to trigger cell-cycle arrest. In cancer cells, this regulation may be faulty, and cell division may proceed even in the presence of damaged DNA. We show here that the ribosomal s6 kinase (Rsk), often elevated in cancers, can suppress DSB-induced ATM activation in both Xenopus egg extracts and human tumor cell lines. In analyzing each step in ATM activation, we have found that Rsk targets loading of MRN complex components onto DNA at DSB sites. Rsk can phosphorylate the Mre11 protein directly at S676 both in vitro and in intact cells and thereby can inhibit the binding of Mre11 to DNA with DSBs. Accordingly, mutation of S676 to Ala can reverse inhibition of the response to DSBs by Rsk. Collectively, these data point to Mre11 as an important locus of Rsk-mediated checkpoint inhibition acting upstream of ATM activation.

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Activation of the PKC‐isotypes α, β₁, γ, δ, and ε by phorbol esters of different biological activities

Cited by 183 publications

References 26 publications

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Loss of protein kinase C function induces an apoptotic response

Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11

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Activation of the PKC‐isotypes α, β1, γ, δ, and ε by phorbol esters of different biological activities

Cited by 183 publications

References 26 publications

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Hypoxic pulmonary vasoconstriction and pulmonary artery tissue cytokine expression are mediated by protein kinase C

Loss of protein kinase C function induces an apoptotic response

Suppression of DNA-damage checkpoint signaling by Rsk-mediated phosphorylation of Mre11

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Activation of the PKC‐isotypes α, β₁, γ, δ, and ε by phorbol esters of different biological activities