Eva Zahradníčková

Lipoxygenase inhibitors enhance tumor suppressive effects of Jun proteins on v-myb-transformed monoblasts BM2

Inhibitors of arachidonic acid (AA) conversion were described as suppressors of proliferation and inducers of differentiation of various leukemic cells. Certain AA metabolites have been shown to cooperate with Jun proteins that are important factors controlling cell proliferation, differentiation and apoptosis. Using lipoxygenase (LOX) inhibitors of various specifity we studied possible participation of lipoxygenase pathway in regulation of proliferation and apoptosis of v-myb-transformed chicken monoblasts BM2 and its functional interaction with Jun proteins. We found that nordihydroguaiaretic acid (NDGA) and esculetin (Esc) negatively regulate proliferation of BM2 cells causing accumulation in either G0/G1-phase (nordihydroguaiaretic acid) or S-phase (esculetin) of the cell cycle. BM2 cells can be also induced to undergo growth arrest and partial differentiation by ectopic expression of Jun proteins. We demonstrated that lipoxygenase inhibitors further enforce tumor suppressive capabilities of Jun proteins by inducing either more efficient cell cycle block and/or apoptosis in BM2 cells. This suggests that there is a cross-talk between the lipoxygenase- and Jun-directed pathways in regulation of differentiation and proliferation of monoblastic cells. Thus pharmacologic agents that specifically block lipoxygenase-catalyzed activity and enforce the effects of differentiation-inducers may be important components in anti-tumor therapies.

c-Fos but not v-Fos protein induces programmed cell death of v-myb-transformed monoblasts

Abstractc-Fos and v-Fos belong to a group of proteins forming the transcription factor AP-1 that is important for regulation of proliferation, differentiation and programmed cell death in multiple cell types. In this study, we examined the role of c-Fos and v-Fos proteins in v-myb-transformed BM2 monoblasts. We show that while the v-Fos protein prolongs the G0G1 phase of the BM2 cell cycle, c-Fos leaves the cell cycle unaffected and, rather, induces programmed cell death. The apoptosis-promoting activity of the c-Fos protein is markedly enhanced in cells cultivated under serum-free conditions. c-Fos-induced apoptosis of BM2 cells occurred in the presence of Bcl-2 and was not dependent on the transcription activation function of the c-Fos protein. No differentiation-promoting activity of the Fos proteins was observed. The effects of Fos proteins on BM2 cells differ from those induced by Jun proteins, suggesting differential roles of individual components of the AP-1 transcription factor in regulation of essential cellular processes.