Tumor promoters block tyrosine-specific phosphorylation of the epidermal growth factor receptor.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print Cited Medium: Print ISSN: 0027-8424 (Print) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Carcinogens/*pharmacology ; Epidermal Growth Factor/*metabolism ; Phorbol Esters/*pharmacology ; Phorbols/*pharmacology ; Receptors, Cell Surface/*metabolism; Amino Acids/analysis ; Carcinoma, Squamous Cell ; Cell Line ; ErbB Receptors ; Humans ; Kinetics ; Phosphorylation ; Protein Kinase C ; Protein Kinases/metabolism ; Receptors, Cell Surface/drug effects ; Tyrosine
    • Abstract:
      Tyrosine-specific phosphorylation of the epidermal growth factor (EGF) receptor in hormonally stimulated A431 cells is blocked by three chemically distinct classes of tumor promoters. Tumor-promoting esters of the diterpene phorbol (phorbol 12-myristate 13-acetate, beta-phorbol 12,13-dibutyrate, and beta-phorbol 12,13-didecanoate), indole alkaloids (teleocidin and lyngbyatoxin A), and polyacetates ( aplysiatoxin and debromoaplysiatoxin ) all inhibited EGF-stimulated phosphorylation of the receptor. Non-tumor-promoting analogs (beta-phorbol, alpha-phorbol 12,13-didecanoate, and hydrolyzed teleocidin) had no effect on the levels of receptor phosphorylation. The ED50 values of the inhibitory effect (0.1-3 ng/ml) reflected the relative tumor-promoting abilities of these compounds in vivo. None of the tumor promoters tested significantly decreased the overall specific binding of 125I-labeled EGF to A431 cells. Scatchard analysis, however, revealed two apparent EGF receptors in this cell type. The dose-responses for tumor-promoter inhibition of EGF receptor tyrosine phosphorylation and high-affinity EGF binding were similar, suggesting that the same initial event is responsible for both effects. This demonstrates a correlation between modulation of EGF receptor binding and phosphorylation of tyrosine by tumor promoters. The data suggest a possible role for protein kinase C, the putative cellular receptor for these tumor promoters, in the mechanism of action.
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    • Grant Information:
      5-T32-CA-09255 United States CA NCI NIH HHS; CA32267 United States CA NCI NIH HHS; CA32952 United States CA NCI NIH HHS
    • Accession Number:
      0 (Amino Acids)
      0 (Carcinogens)
      0 (Phorbol Esters)
      0 (Phorbols)
      0 (Receptors, Cell Surface)
      42HK56048U (Tyrosine)
      62229-50-9 (Epidermal Growth Factor)
      EC 2.7.- (Protein Kinases)
      EC 2.7.10.1 (ErbB Receptors)
      EC 2.7.11.13 (Protein Kinase C)
    • Publication Date:
      Date Created: 19840501 Date Completed: 19840716 Latest Revision: 20190501
    • Publication Date:
      20240829
    • Accession Number:
      PMC345215
    • Accession Number:
      10.1073/pnas.81.10.3034
    • Accession Number:
      6328489