Development of an in-vitro model system to investigate the mechanism of muscle protein catabolism induced by proteolysis-inducing factor


The mechanism of muscle protein catabolism induced by proteolysis-inducing factor, produced by cachexia-inducing murine and human tumours has been studied in vitro using C2C12 myoblasts and myotubes. In both myoblasts and myotubes protein degradation was enhanced by proteolysis-inducing factor after 24 h incubation. In myoblasts this followed a bell-shaped dose-response curve with maximal effects at a proteolysis-inducing factor concentration between 2 and 4 nM, while in myotubes increased protein degradation was seen at all concentrations of proteolysis-inducing factor up to 10 nM, again with a maximum of 4 nM proteolysis-inducing factor. Protein degradation induced by proteolysis-inducing factor was completely attenuated in the presence of cycloheximide (1 μM), suggesting a requirement for new protein synthesis. In both myoblasts and myotubes protein degradation was accompanied by an increased expression of the α-type subunits of the 20S proteasome as well as functional activity of the proteasome, as determined by the 'chymotrypsin-like' enzyme activity. There was also an increased expression of the 19S regulatory complex as well as the ubiquitin-conjugating enzyme (E214k), and in myotubes a decrease in myosin expression was seen with increasing concentrations of proteolysis-inducing factor. These results show that proteolysis-inducing factor co-ordinately upregulates both ubiquitin conjugation and proteasome activity in both myoblasts and myotubes and may play an important role in the muscle wasting seen in cancer cachexia. © 2002 Cancer Research UK.

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Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences > Chronic and Communicable Conditions
Life & Health Sciences
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Uncontrolled Keywords: cachexia,myotubes,proteolysis-inducing factor (PIF),ubiquitin-proteasome proteolysis,Cancer Research,Oncology
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
http://www.natu ... s/6600236a.html (Publisher URL)
PURE Output Type: Article
Published Date: 2002-05-20
Authors: Gomes-Marcondes, Maria C.C.
Smith, Helen J.
Cooper, J.C.
Tisdale, Michael J.

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