The signaling pathways used by interleukin-3 (IL-3) and by active phorbol ester (12-0-tetradecanoyl phorbol-13-acetate, TPA) to stimulate mitogenesis in the growth factor dependent myeloid cell line FDC-P1 were studied by 'reporter' analysis of nuclear proto-oncogene expression. These studies revealed that IL-3 strongly stimulated c-myc expression by a transcriptlonal mechanism but IL-3 poorly stimulated c-jun expression, a measure of protein kinase C dependent signals. On the other hand, the protein kinase C agonist, TPA, strongly activated c-jun expression but poorly promoted expression (transcription) of c-myc in FDC-P1. These findings appeared to correlate with the poor mitogenic capacity of TPA for FDC-P1. However, stable transfection of FDC-P1 with a c-myc expression vector driven by a human methallothionein HA promoter containing the TPA responsive element (TRE), led to a cell clone, FDMT myc.A1, in which TPA mediated selective transcription of the transfected TRE driven c-myc vector and down-regulated expression of the endogenous c-myc gene. IL-3 selectively failed to stimulate expression of the TRE driven c-myc vector in FDMT myc.A1. Augmented TPA dependent vector derived c-myc expression was accompanied by enhanced mitogenesis of the cell line FDMT myc.A1 compared with FDC-P1. In addition, TPA mediated expression of the transfected c-myc gene in FDMT myc.A1 was accompanied by augmented transcription of c-jun and c-fos in response to TPA. These studies show the importance of a non-protein kinase C dependent pathway for IL-3 mediated c-myc transcription. However, these studies reveal that protein kinase C mediated pathways can be promitogenic, especially when complemented by unregulated c-myc expression (in this case driven by an alternative, TRE containing promoter).
|Original language||English (US)|
|Number of pages||11|
|State||Published - Dec 1991|
ASJC Scopus subject areas
- Cancer Research