Calpain activity is generally elevated during transformation but has oncogene-specific biological functions.
Several oncogene and tumor-suppressor gene products are known substrates for the calpain family of cysteine proteases, and calpain is required for transformation by v-src and tumor invasion. Thus, we have now addressed whether calpain is generally associated with transformation and how calpain contributes to oncogene function. Our results demonstrate that calpain activity is enhanced upon transformation induced by the v-Src, v-Jun, v-Myc, k-Ras, and v-Fos oncoproteins. Furthermore, elevated calpain activity commonly promotes focal adhesion remodelling, disruption of actin cytoskeleton, morphological transformation, and cell migration, although proteolysis of target substrates (such as focal adhesion kinase, talin, and spectrin) is differently specified by individual oncoproteins. Interestingly, v-Fos differs from other common oncoproteins in not requiring calpain activity for actin/adhesion remodelling or migration of v-Fos transformed cells. However, anchorage-independent growth of all transformed cells is sensitive to calpain inhibition. In addition, elevated calpain activity contributes to oncogene-induced apoptosis associated with transformation by v-Myc. Taken together, these studies demonstrate that calpain activity is necessary for full cellular transformation induced by common oncoproteins, but has distinct roles in oncogenic events induced by individual transforming proteins. Thus, targeting calpain activity may represent a useful general strategy for interfering with activated proto-oncogenes in cancer cells.
Carragher
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NO
The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Glasgow G61 1BD, Scotland, UK. n.carragher@beatson.gla.ac.uk
Fonseca
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BD
Frame
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MC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002154:Calpain / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002642:Chick Embryo; D003599:Cytoskeleton / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015151:Immunoblotting; D007150:Immunohistochemistry; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D015513:Oncogene Proteins / Q000378:metabolism*; D009857:Oncogenes / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D015513:Oncogene Proteins; D020928:Mitogen-Activated Protein Kinases; D002154:Calpain