HeLa cell mutants resistant to epidermal growth factor ricin A-chain conjugate.
Epidermal growth factor (EGF) was linked to the toxic A chain of ricin toxin (RTA) to produce an EGF-receptor-specific cytotoxic agent, EGF-RTA. Three EGF-RTA-resistant mutants of the human HeLa cell line were selected. These mutant cell lines are 10-fold to more than 100-fold more resistant to EGF-RTA when compared to HeLa cells. The EGF-RTA-resistant mutants have at least as many EGF receptors as parent cells; the basis for the EGF-RTA-resistant phenotype must be distal to EGF binding. The EGF-RTA-resistant cells are not cross-ressitant to ricin or to diphtheria toxin; their mutant phenotype appears to be EGF specific. The EGF-RTA-resistant mutants are able to internalize and degrade EGF. However, the mutants have altered EGF receptor down-regulation and phorbol 12-tetradecanoate 13-acetate modulation properties. EGF-RTA/ammonium chloride and EGF-RTA/adenovirus co-treatment data suggest that the mutant defect(s) which confers EGF-RTA resistance is either in the endosome or at a step(s) in the intracellular EGF processing pathway between the endosome and the lysosome.
Banker
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Department of Biological Chemistry, UCLA School of Medicine 90024.
Herschman
H R
HR
D000256:Adenoviridae / Q000502:physiology; D000643:Ammonium Chloride / Q000494:pharmacology; D002469:Cell Separation; D004167:Diphtheria Toxin / Q000494:pharmacology; D004351:Drug Resistance; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009154:Mutation; D012276:Ricin / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004167:Diphtheria Toxin; D000643:Ammonium Chloride; D004815:Epidermal Growth Factor; D012276:Ricin; D066246:ErbB Receptors; D013755:Tetradecanoylphorbol Acetate