Mevalonate dependency of the early cell cycle mitogenic response to epidermal growth factor and prostaglandin F2 alpha in Swiss mouse 3T3 cells.
Lovastatin (LOV), a hydroxy-methylglutaryl-coenzyme A (HMGCoA) reductase competitive inhibitor, blocks epidermal growth factor (EGF)- or prostaglandin F2 alpha (PGF2 alpha)-induced mitogenesis in confluent resting Swiss 3T3 cells. This inhibition occurs even in the presence of insulin, which potentiates the action of these mitogens in such cells. LOV exerts its effect in a 2-80 microM concentration range, with both mitogens attaining 50% inhibition at 7.5 microM. LOV exerted its effect within 0-8 h following mitogenic induction. Mevanolactone (10-80 microM) in the presence of LOV could reverse LOV inhibition within a similar time period. LOV-induced blockage of PGF2 alpha response is reflected in a decrease in the rate of cell entry into S phase. Neither cholesterol, ubiquinone, nor dolichols of various lengths could revert LOV blockage. In EGF- or PGF2 alpha-stimulated cells, LOV did not inhibit [3H]leucine or [3H]mannose incorporation into proteins, while tunicamycin, an inhibitor of N' glycosylation, prevented this last phenomenon. Thus, it appears that LOV exerts its action neither by inhibiting unspecific protein synthesis nor by impairing the N' glycosylation process. These findings strongly suggest that either EGF or PGF2 alpha stimulations generate early cell cycle signals which induce mevalonate formation, N' glycoprotein synthesis, and proliferation. The causal relationship of these events to various mechanisms controlling the onset of DNA synthesis is also discussed.
Ortiz
M B
MB
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Buenos Aires, Argentina.
Goin
M
M
Gomez de Alzaga
M B
MB
Hammarstrom
S
S
Jimenez de Asua
L
L
D016475:3T3 Cells / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D015237:Dinoprost / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D006031:Glycosylation; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D016196:S Phase
D004815:Epidermal Growth Factor; D008148:Lovastatin; D015237:Dinoprost; D008798:Mevalonic Acid