Signal transduction pathways involved in proteolysis-inducing factor induced proteasome expression in murine myotubes

Helen J. Smith, Michael J. Tisdale*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The proteolysis-inducing factor (PIF) is produced by cachexia-inducing tumours and initiates protein catabolism in skeletal muscle. The potential signalling pathways linking the release of arachidonic acid (AA) from membrane phospholipids with increased expression of the ubiquitin-proteasome proteolytic pathway by PIF has been studied using C2C12 murine myotubes as a surrogate model of skeletal muscle. The induction of proteasome activity and protein degradation by PIF was blocked by quinacrine, a nonspecific phospholipase A2 (PLA2) inhibitor and trifluroacetyl AA, an inhibitor of cytosolic PLA2. PIF was shown to increase the expression of calcium-independent cytosolic PLA2, determined by Western blotting, at the same concentrations as those inducing maximal expression of 20S proteasome α-subunits and protein degradation. In addition, both U-73122, which inhibits agonist-induced phospholipase C (PLC) activation and D609, a specific inhibitor of phosphatidylcholine-specific PLC also inhibited PIF-induced proteasome activity. This suggests that both PLA 2 and PLC are involved in the release of AA in response to PIF, and that this is important in the induction of proteasome expression. The two tyrosine kinase inhibitors genistein and tryphostin A23 also attenuated PIF-induced proteasome expression, implicating tyrosine kinase in this process. PIF induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) at the same concentrations as that inducing proteasome expression, and the effect was blocked by PD98059, an inhibitor of MAPK kinase, as was also the induction of proteasome expression, suggesting a role for MAPK activation in PIF-induced proteasome expression. © 2003 Cancer Research UK.

Original languageEnglish
Pages (from-to)1783-1788
Number of pages6
JournalBritish Journal of Cancer
Issue number9
Publication statusPublished - 3 Nov 2003

Bibliographical note

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit obtain permission to re-use content from this article visit RightsLink.

This work has been supported by a grant from the Lustgarten Foundation for Pancreatic Cancer Research.


  • mitogen-activated protein kinase (MAPK)
  • phospholipase A (PLA )
  • phospholipase C (PLC)
  • proteasome expression
  • proteolysis-inducing factor (PIF)
  • tyrosine kinase


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