Effects of bradykinin on NIH 3T3 fibroblasts pretreated with lithium. Mimicking events of Ha-ras oncogene expression.
As shown previously, expression of Ha-ras oncogene in NIH 3T3 fibroblasts (+ ras cells) increases cellular concentrations of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 and enhances bradykinin induced Ca2+ entry [1-3]. These cells respond to low concentrations of serum or bradykinin with sustained oscillations of the cell membrane potential due to pulsatile release of calcium from internal stores and subsequent activation of calcium sensitive K+ channels [1]. Furthermore Ha-ras oncogene expression leads to depolymerization of the actin filament network and delayed increase of cell volume [4-6]. Pretreatment of the same cells not expressing the oncogene (-ras cells) with Li+ similarly increases Ins(1,4,5)P3 and Ins(1,3,4,5)P4 [2]. As shown in the present study, -ras cells pretreated with Li+ similar to Ha-ras oncogene expressing cells respond to bradykinin with sustained oscillations of cell membrane potential, depolymerization of the actin filament network and increase of cell volume. The oscillations of the cell membrane potential and the depolymerization of the actin cytoskeleton can be inhibited by the calcium channel blocker lanthanum and the bradykinin induced increase of cell volume is inhibited by HOE 694, pointing to involvement of Na+/H+ exchange. The data indicate a close functional linkage of the calcium oscillations, cytoskeletal rearrangement and activation of the Na+/H+ exchanger. Thus, Li+ pretreatment mimicks crucial cellular events triggered by expression of the Ha-ras oncogene. However, unlike in cells expressing the Ha-ras oncogene, Li+ pretreatment alone does not allow for growth factor-independent proliferation of the cells.
Ritter
M
M
Department of Internal Medicine, University of Innsbruck, Austria. markus.ritter@uibk.ac.at
Dartsch
P
P
Waldegger
S
S
Haller
T
T
Zwierzina
H
H
Lang
H J
HJ
Lang
F
F
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002455:Cell Division; D048429:Cell Size / Q000187:drug effects; D015870:Gene Expression; D011905:Genes, ras; D008094:Lithium / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018631:ras Proteins / Q000378:metabolism*
D008094:Lithium; D018631:ras Proteins; D001920:Bradykinin