scholarly journals Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Antonio Layoun ◽  
Alexander A. Goldberg ◽  
Ayesha Baig ◽  
Mikaela Eng ◽  
Ortal Attias ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nuclear Import ◽  
Target Of Rapamycin ◽  
Interferon Β ◽  
Structural Mechanism ◽  
Mechanistic Target Of Rapamycin ◽  
Kinase C ◽  
Nuclear Content ◽  
In Cells

AbstractInactivation of the protein complex ‘mechanistic target of rapamycin complex 1’ (mTORC1) can increase the nuclear content of transcriptional regulators of metabolism and apoptosis. Previous studies established that nuclear import of signal transducer and activator of transcription-1 (STAT1) requires the mTORC1-associated adaptor karyopherin-α1 (KPNA1) when mTORC1 activity is reduced. However, the role of other mTORC1-interacting proteins in the complex, including ‘protein kinase C delta’ (PKCδ), have not been well characterized. In this study, we demonstrate that PKCδ, a STAT1 kinase, contains a functional ‘target of rapamycin signaling’ (TOS) motif that directs its interaction with mTORC1. Depletion of KPNA1 by RNAi prevented the nuclear import of PKCδ in cells exposed to the mTORC1 inhibitor rapamycin or amino acid restriction. Mutation of the TOS motif in PKCδ led to its loss of regulation by mTORC1 or karyopherin-α1, resulting in increased constitutive nuclear content. In cells expressing wild-type PKCδ, STAT1 activity and apoptosis were increased by rapamycin or interferon-β. Those expressing the PKCδ TOS mutant exhibited increased STAT1 activity and apoptosis; further enhancement by rapamycin or interferon-β, however, was lost. Therefore, the TOS motif in PKCδ is a novel structural mechanism by which mTORC1 prevents PKCδ and STAT1 nuclear import, and apoptosis.

scholarly journals p21WAF1 expression by an activator of protein kinase C is regulated mainly at the post-transcriptional level in cells lacking p53: important role of RNA stabilization

1999 ◽  
Vol 337 (3) ◽  
pp. 607-616 ◽  
Author(s):  
Makoto AKASHI ◽  
Yoshiaki OSAWA ◽  
H. Phillip KOEFFLER ◽  
Misao HACHIYA
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Esters ◽  
P53 Protein ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Transcriptional Level ◽  
Kinase C ◽  
In Cells

p21WAF1 inhibits cyclin–cyclin-dependent kinase (Cdk) complexes, causing cell cycle arrest. p21WAF1 contains p53-binding sites in its promoter and expression of p21WAF1 is induced by functional p53. In the present work, we have studied the role of protein kinase C (PKC) in the induction of p21WAF1 and show that induction of p21WAF1 expression can occur by activation of PKC in cells having no p53. Human ovarian carcinoma cells, SKOV-3, lack p53 protein and PMA, a potent activator of PKC, did not induce p53. PMA increased the expression of p21WAF1 mRNA both in these cells and in other cells which do not contain p53 (THP-1 and U937). Treatment of human embryonic fibroblasts, WI38, with PMA also induced the accumulation of p21WAF1 without affecting p53 levels. However, PMA did not increase levels of p21WAF1 mRNA in cells where either the PKC or the mitogen-activated protein kinase pathway was blocked. Furthermore, treatment of cells with various phorbol ester derivatives which activate PKC resulted in the induction of p21WAF1 in SKOV-3 cells. In contrast, phorbol esters which do not activate PKC failed to induce p21WAF1 expression. PMA increased the transcriptional rate of p21WAF1 and activated the transcription of a luciferase reporter gene, controlled by the p21 promoter, in SKOV-3 cells with or without a p53 consensus-binding sequence. By contrast, PMA markedly stabilized p21WAF1 mRNA; the half-life (t1/2) of p21WAF1 in PMA-treated cells was > 8 h compared with < 1 h in untreated cells. These findings provide evidence that the PKC pathway induces expression of p21WAF1 independently of p53. Our present study also suggests that the accumulation of p21WAF1 transcripts by PMA occurs mainly at post-transcriptional level.

scholarly journals Protein kinase C-mediated desensitization of the neurokinin 1 receptor

2001 ◽  
Vol 280 (5) ◽  
pp. C1097-C1106 ◽  
Author(s):  
Olivier Déry ◽  
Kathryn A. Defea ◽  
Nigel W. Bunnett
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phosphorylation Sites ◽  
Wild Type ◽  
Neurokinin 1 Receptor ◽  
Kinase C ◽  
Naturally Occurring ◽  
Neurokinin 1 ◽  
In Cells

An understanding of the mechanisms that regulate signaling by the substance P (SP) or neurokinin 1 receptor (NK1-R) is of interest because of their role in inflammation and pain. By using activators and inhibitors of protein kinase C (PKC) and NK1-R mutations of potential PKC phosphorylation sites, we determined the role of PKC in desensitization of responses to SP. Activation of PKC abolished SP-induced Ca2+ mobilization in cells that express wild-type NK1-R. This did not occur in cells expressing a COOH-terminally truncated NK1-R (NK1-Rδ324), which may correspond to a naturally occurring variant, or a point mutant lacking eight potential PKC phosphorylation sites within the COOH tail (NK1-R Ser-338, Thr-339, Ser-352, Ser-387, Ser-388, Ser-390, Ser-392, Ser-394/Ala, NK1-RKC4). Compared with wild-type NK1-R, the t ½ of SP-induced Ca2+mobilization was seven- and twofold greater in cells expressing NK1-Rδ324 and NK1-RKC4, respectively. In cells expressing wild-type NK1-R, inhibition of PKC caused a 35% increase in the t ½ of SP-induced Ca2+mobilization. Neither inhibition of PKC nor receptor mutation affected desensitization of Ca2+ mobilization to repeated challenge with SP or SP-induced endocytosis of the NK1-R. Thus PKC regulates SP-induced Ca2+ mobilization by full-length NK1-R and does not regulate a naturally occurring truncated variant. PKC does not mediate desensitization to repeated stimulation or endocytosis of the NK1-R.

scholarly journals Conformational sampling of membranes by Akt controls its activation and inactivation

2018 ◽  
Vol 115 (17) ◽  
pp. E3940-E3949 ◽  
Author(s):  
Iva Lučić ◽  
Manoj K. Rathinaswamy ◽  
Linda Truebestein ◽  
David J. Hamelin ◽  
John E. Burke ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Conformational Changes ◽  
Membrane Binding ◽  
Second Messenger ◽  
Target Of Rapamycin ◽  
Conformational Sampling ◽  
Mechanistic Target Of Rapamycin ◽  
Protein Kinase Akt ◽  
In Cells ◽  
Phosphoinositide Dependent Kinase

The protein kinase Akt controls myriad signaling processes in cells, ranging from growth and proliferation to differentiation and metabolism. Akt is activated by a combination of binding to the lipid second messenger PI(3,4,5)P3 and its subsequent phosphorylation by phosphoinositide-dependent kinase 1 and mechanistic target of rapamycin complex 2. The relative contributions of these mechanisms to Akt activity and signaling have hitherto not been understood. Here, we show that phosphorylation and activation by membrane binding are mutually interdependent. Moreover, the converse is also true: Akt is more rapidly dephosphorylated in the absence of PIP3, an autoinhibitory process driven by the interaction of its PH and kinase domains. We present biophysical evidence for the conformational changes in Akt that accompany its activation on membranes, show that Akt is robustly autoinhibited in the absence of PIP3 irrespective of its phosphorylation, and map the autoinhibitory PH−kinase interface. Finally, we present a model for the activation and inactivation of Akt by an ordered series of membrane binding, phosphorylation, dissociation, and dephosphorylation events.

scholarly journals Role of protein kinase C in the adaptive increase in Na-H antiporter in respiratory acidosis.

1993 ◽  
Vol 4 (4) ◽  
pp. 1079-1086
Author(s):  
P Pahlavan ◽  
L J Wang ◽  
E Sack ◽  
J A Arruda
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Brush Border ◽  
Cultured Cells ◽  
Respiratory Acidosis ◽  
Kinase C ◽  
22Na Uptake ◽  
Renal Brush Border ◽  
In Cells

Chronic respiratory acidosis stimulates the Vmax of the renal brush border Na-H antiporter. The activation of protein kinase C (PKC) by phorbol esters stimulates the activity of the renal Na-H antiporter. In this study, the hypothesis that PKC plays a role in the adaptive increase of the renal brush border Na-H antiporter activity to respiratory acidosis was tested. In vivo respiratory acidosis was associated with an increase in in vitro Na-H antiporter activity and also with an increase in brush border membrane PKC activity, without changes in PKC activity in cytosol or basolateral membranes. Na-H antiporter activity, assessed as the amiloride-sensitive component of 22Na uptake, was measured in cultured proximal tubule cells exposed to 10% CO2 for 48 h. Na-H antiporter activity was significantly higher in cells exposed to 10% CO2 than in those exposed to 5% CO2. To evaluate the role of PKC, cultured cells were depleted of PKC by exposure to the active phorbol ester phorbol 12-myristate 13-acetate (PMA; 10(-7) or 10(-6) M) for 48 h before exposure to 10% CO2. In the presence of 10% CO2, Na-H antiporter activity was significantly lower in PKC-depleted cells than in control. In addition, sphingosine, an inhibitor of PKC, also prevented the adaptation of the Na-H antiporter to 10% CO2 as compared with 5% CO2. In cells treated with the inactive analog 4 alpha-PMA, 22Na uptake was not different than that in control. PMA-treated cells also had a decrease in Na-H antiporter activity during exposure to 5% CO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulus-secretion coupling in parathyroid cells deficient in protein kinase C activity

1994 ◽  
Vol 267 (3) ◽  
pp. E429-E438
Author(s):  
F. K. Racke ◽  
E. F. Nemeth
Keyword(s):  
Protein Kinase C ◽  
Parathyroid Hormone ◽  
Protein Kinase ◽  
Kinase C ◽  
Protein Kinase C Activity ◽  
Low Concentrations ◽  
Stimulus Secretion Coupling ◽  
Subsequent Addition ◽  
In Cells

The role of protein kinase C (PKC) in regulating cytosolic Ca2+ concentrations ([Ca2+]i) and parathyroid hormone (PTH) secretion was studied in bovine parathyroid cells rendered deficient in PKC activity by incubation with phorbol 12-myristate 13-acetate (PMA). Pretreatment with PMA caused a time- and concentration-dependent loss of functional PKC activity as assessed by the failure of [Ca2+]i and PTH secretion to respond to the subsequent addition of PKC activators or the inhibitor staurosporine. Pretreatment for 24 h with 1 microM PMA caused a loss of 85% of the total and 98% of the cytosolic PKC activity. Cells so pretreated were considered to be "PKC downregulated." Increasing the concentration of extracellular Ca2+ or Mg2+ caused corresponding increases in [Ca2+]i that were similar in control and in PKC-downregulated cells. PTH secretion regulated by extracellular Ca2+ or Mg2+ was likewise similar in control and PKC-downregulated cells. Stimulus-secretion coupling is thus unimpaired in parathyroid cells deficient in PKC activity. Cytosolic Ca2+ responses remained depressed in cells incubated for 24 h with low concentrations of PMA (30 or 100 nM). However, under these conditions, extracellular Ca2+ still suppressed PTH secretion similarly to control cells. These results reveal a dissociation between cytosolic Ca2+ and PTH secretion and suggest that signals other than cytosolic Ca2+ are involved in the regulation of PTH secretion.

scholarly journals Publisher Correction: Regulation of protein kinase Cδ Nuclear Import and Apoptosis by Mechanistic Target of Rapamycin Complex-1

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Antonio Layoun ◽  
Alexander A. Goldberg ◽  
Ayesha Baig ◽  
Mikaela Eng ◽  
Ortal Attias ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nuclear Import ◽  
Target Of Rapamycin ◽  
Mechanistic Target Of Rapamycin ◽  
Protein Kinase Cδ

Role of protein kinase C in the regulation of steroidogenesis in the mouse Leydig cell

1986 ◽  
Vol 113 (1_Suppl) ◽  
pp. S63-S64
Author(s):  
A. K. MUKHOPADHYAY ◽  
H. G. BOHNET
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Leydig Cell ◽  
Kinase C ◽  
Mouse Leydig Cell

scholarly journals Dysregulation of protein kinase C in adult depression and suicide: evidence from postmortem brain studies

2021 ◽  
Author(s):  
Ghanshyam N Pandey ◽  
Anuradha Sharma ◽  
Hooriyah S Rizavi ◽  
Xinguo Ren
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Expression ◽  
Mrna Expression ◽  
Postmortem Brain ◽  
Cortical Region ◽  
Cytosol Fraction ◽  
Kinase C ◽  
Pkc Isozymes

Abstract Background Several lines of evidence suggest the abnormalities of protein kinase C (PKC) signaling system in mood disorders and suicide based primarily on the studies of PKC and its isozymes in the platelets and postmortem brain of depressed and suicidal subjects. In this study we examined the role of PKC isozymes in depression and suicide. Methods We determined the protein and mRNA expression of various PKC isozymes in the prefrontal cortical region [Brodmann area 9 (BA9)] in 24 normal control (NC) subjects, 24 depressed suicide (DS) subjects and 12 depressed non-suicide (DNS) subjects. The levels of mRNA in the prefrontal cortex (PFC) were determined by qRT-PCR and the protein expression was determined by Western blotting. Results We observed a significant decrease in mRNA expression of PKCα, PKCβI, PKCδ and PKCε and decreased protein expression either in the membrane or the cytosol fraction of PKC isozymes - PKCα, PKCβI, PKCβII and PKCδ in DS and DNS subjects compared with NC subjects. Conclusions The current study provides detailed evidence of specific dysregulation of certain PKC isozymes in the postmortem brain of DS and DNS subjects and further supports earlier evidence for the role of PKC in the platelets and brain of adult and teenage depressed and suicidal population. This comprehensive study may lead to further knowledge of the involvement of PKC in the pathophysiology of depression and suicide.

scholarly journals Role of cadmium in activating nuclear protein kinase C and the enzyme binding to nuclear protein.

1992 ◽  
Vol 267 (28) ◽  
pp. 19824-19828
Author(s):  
C Block ◽  
S Freyermuth ◽  
D Beyersmann ◽  
A.N. Malviya
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Nuclear Protein ◽  
Enzyme Binding ◽  
Kinase C
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