Epigenetic activation of Gi-2 protein, the product of a putative protooncogene, mediates tumor promotion in vitro.
Promotion of 'initiated' JB6 epidermal cells to the tumor phenotype can be effected by 12-O-tetradecanoylphorbol-13-acetate treatment, by stimulation of epidermal growth factor (EGF) receptor activity with EGF or transforming growth factor alpha and by exposure to the isoquinoline derivative H7. When these cells were incubated with pertussis toxin (PTX), induction of anchorage-independent growth by all four promoting substances was suppressed. The inhibition is specific since cell proliferation is not affected, suggesting that activation of a Gi protein is essential for promotion of the epidermal cells. This interpretation is strongly supported by the observation that the wasp poison mastoparan, which is known to mimic receptor-mediated activation of certain Gi proteins, also promoted anchorage independence. Immunological data and partial amino acid sequence analysis of ADP-ribosyl alpha i isolated from PTX-treated JB6 cells indicate that a Gi-2 protein is a mediator to tumor promotion in this system. The inhibitory action of 4-bromophenacyl bromide may point to a coupling of the Gi protein to phospholipase A2. From our data we infer that promoters induce the tumor phenotype in 'initiated' JB6 epidermal cells by activating epigenetically the same Gi protein that in a number of adrenal and ovarian tumors appears to be persistently activated by mutational events.
Harbers
M
M
Institut für Physiologische Chemie, Universitätskrankenhaus Eppendorf, Hamburg, Germany.
Borowski
P
P
Fanick
W
W
Lengyel
H
H
Buck
F
F
Hinsch
K D
KD
Hilz
H
H
D000310:Adrenal Gland Neoplasms / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics; D037342:Pertussis Toxin; D010641:Phenotype; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013755:Tetradecanoylphorbol Acetate; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D011518:Proto-Oncogene Proteins; D016211:Transforming Growth Factor alpha; D010566:Virulence Factors, Bordetella; D004815:Epidermal Growth Factor; D037342:Pertussis Toxin; D010741:Phospholipases A; D054467:Phospholipases A2; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate