Role of protein kinase C and NF-κB in proteolysis-inducing factor-induced proteasome expression in C2C12 myotubes

Smith, Helen; Wyke, Stacey M.; Tisdale, Michael J.

doi:10.1038/sj.bjc.6601767

Cited by 45 publications

(37 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The former causes the release of arachidonic acid from membrane phospholipids, while diacylglycerol, derived from PC-PLC, has been suggested to provide a positive feedback signal to protein kinase C (PKC) . We have shown PKC to be involved in PIF-induced proteasome expression (Smith et al, 2004) and PKC may act as a signal for NF-kB activation through phosphorylation and activation of IKK (Fullman et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…Stable transfections were carried out on cells at 50 -80% confluency using GeneJuice, according to the manufacturer's protocol, and selected by resistance to ampicillin (5 g l À1 ) as described previously (Smith et al, 2004). Transfected myoblasts were stimulated to differentiate by replacing the growth medium with DMEM supplemented with 2% HS, when the cells reached confluence.…”

Section: Myogenic Cell Culture and Transfectionmentioning

confidence: 99%

See 1 more Smart Citation

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

2005

Self Cite

View full text Add to dashboard Cite

Loss of skeletal muscle in cancer cachexia has a negative effect on both morbidity and mortality. The role of nuclear factor-kB (NFkB) in regulating muscle protein degradation and expression of the ubiquitin -proteasome proteolytic pathway in response to a tumour cachectic factor, proteolysis-inducing factor (PIF), has been studied by creating stable, transdominant-negative, muscle cell lines. Murine C 2 C 12 myoblasts were transfected with plasmids with a CMV promoter that had mutations at the serine phosphorylation sites required for degradation of I-kBa, an NF-kB inhibitory protein, and allowed to differentiate into myotubes. Proteolysis-inducing factor induced degradation of I-kBa, nuclear accumulation of NF-kB and an increase in luciferase reporter gene activity in myotubes containing wild-type, but not mutant, I-kBa proteins. Proteolysis-inducing factor also induced total protein degradation and loss of the myofibrillar protein myosin in myotubes containing wild-type, but not mutant, plasmids at the same concentrations as those causing activation of NF-kB. Proteolysis-inducing factor also induced increased expression of the ubiquitinproteasome pathway, as determined by 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the b-subunits of the proteasome, protein expression of 20S a-subunits and the 19S subunits MSS1 and p42, as well as the ubiquitin conjugating enzyme, E2 14k , in cells containing wild-type, but not mutant, I-kBa. The ability of mutant I-kBa to inhibit PIF-induced protein degradation, as well as expression of the ubiquitin -proteasome pathway, confirms that both of these responses depend on initiation of transcription by NF-kB.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Myogenic Cell Culture and Transfectionmentioning

confidence: 99%

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…Other signalling pathways activated by PIF and leading to protein degradation including activation of protein kinase C (PKC) (Fig. 5A) [20], formation of ROS (Fig. 5B) [18], and nuclear accumulation of NF-B (Fig.…”

Section: Resultsmentioning

confidence: 99%

Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate

Russell

Siren²,

Sirén³

et al. 2008

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

D-Myo-inositol 1,2,6-triphosphate (alpha trinositol, AT) has been shown to attenuate muscle atrophy in a murine cachexia model through an increase in protein synthesis and a decrease in degradation. The mechanism of this effect has been investigated in murine myotubes using a range of catabolic stimuli, including proteolysis-inducing factor (PIF), angiotensin II (Ang II), lipopolysaccharide, and tumour necrosis factor- / interferon-. At a concentration of 100M AT was found to attenuate both the induction of protein degradation and depression of protein synthesis in response to all stimuli. The effect on protein degradation was accompanied by attenuation of the increased expression and activity of the ubiquitinproteasome pathway. This suggests that AT inhibits a signalling step common to all four agents. This target has been shown to be activation (autophosphorylation) of the dsRNA-dependent protein kinase (PKR) and the subsequent phosphorylation of eukaryotic initiation factor 2 on the -subunit, together with downstream signalling pathways leading to protein degradation. AT also inhibited activation of caspase-3/-8, which is thought to lead to activation of PKR. The mechanism of this effect may be related to the ability of AT to chelate divalent metal ions, since the attenuation of the increased activity of the ubiquitin-proteasome pathway by PIF and Ang II, as well as the depression of protein synthesis by PIF, were reversed by increasing concentrations of Zn 2+. The ability of AT to attenuate muscle atrophy by a range of stimuli suggests that it may be effective in several conditions.

show abstract

“…Previous studies have shown a role for protein kinase C (PKC) in the induction of proteasome expression by both PIF (43) and Ang II (8). A key step in protein degradation by both PIF and Ang II is the transient formation of reactive oxygen species, possibly through activation of NADPH oxidase by arachidonate and PKC.…”

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle Atrophy, a Link between Depression of Protein Synthesis and Increase in Degradation

Eley

Tisdale

2007

Journal of Biological Chemistry

126

137

View full text Add to dashboard Cite

Both proteolysis-inducing factor (PIF) and angiotensin II have been shown to produce a depression in protein synthesis in murine myotubes concomitant with an increased phosphorylation of eukaryotic initiation factor 2 (eIF2␣). Both PIF and angiotensin II were shown to induce autophosphorylation of the RNA-dependent protein kinase (PKR), and an inhibitor of this enzyme completely attenuated the depression in protein synthesis and prevented the induction of eIF2␣ phosphorylation. The PKR inhibitor also completely attenuated the increase in protein degradation induced by PIF and angiotensin II and prevented the increase in proteasome expression and activity. To confirm these results myotubes were transfected with plasmids that express either wild-type PKR, or a catalytically inactive PKR variant, PKR⌬6. Myotubes expressing PKR⌬6 showed no increase in eIF2␣ phosphorylation in response to PIF or angiotensin II, no depression in protein synthesis, and no increase in protein degradation or increase in proteasome expression. Induction of the ubiquitin-proteasome pathway by PIF and angiotensin II has been linked to activation of the transcription factor nuclear factor-B (NF-B). Inhibition of PKR prevented nuclear migration of NF-B in response to both PIF and angiotensin II, by preventing degradation of the inhibitor protein I-B. Phosphorylation of PKR and eIF2␣ was also significantly increased in the gastrocnemius muscle of weight losing mice bearing the MAC16 tumor, suggesting that a similar process may be operative in cancer cachexia. These results provide a link between the depression of protein synthesis in skeletal muscle and the increase in protein degradation.

show abstract

Role of protein kinase C and NF-κB in proteolysis-inducing factor-induced proteasome expression in C2C12 myotubes

Cited by 45 publications

References 34 publications

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

Attenuation of skeletal muscle atrophy in cancer cachexia by d-myo-inositol 1,2,6-triphosphate

Skeletal Muscle Atrophy, a Link between Depression of Protein Synthesis and Increase in Degradation

Contact Info

Product

Resources

About