Activation of the 9E3/cCAF chemokine by phorbol esters occurs via multiplesignal transduction pathways that converge to MEK1/ERK2 and activate the Elk1 transcription factor
Qj. Li et al., Activation of the 9E3/cCAF chemokine by phorbol esters occurs via multiplesignal transduction pathways that converge to MEK1/ERK2 and activate the Elk1 transcription factor, J BIOL CHEM, 274(22), 1999, pp. 15454-15465
Using primary fibroblasts in culture, we have investigated the signal trans
duction mechanisms by which phorbol esters, a class of tumor promoters, act
ivate the 9E3 gene and its chemokine product the chicken chemotactic and an
giogenic factor. This gene is highly stimulated by phorbol 12,13-dibutyrate
(PDBu) via three pathways: (i) a small contribution through protein kinase
C (the commonly recognized pathway for these tumor promoters), (ii) a cont
ribution involving tyrosine kinases, and (iii) a larger contribution via pa
thways that can be interrupted by dexamethasone, All three of these pathway
s converge into the mitogen-activated protein kinases, MEK1/ERK2, Using a l
uciferase reporter system, we show that although both the AP-1 and PDRIIkB
(a NF kappa B-like factor in chickens) response elements are capable of act
ivation in these normal cells, regions of the 9E3 promoter containing them
are unresponsive to PDBu stimulation. In contrast, we show for the first ti
me that activation by PDBu occurs through a segment of the promoter contain
ing Elk1 response elements; deletion and mutation of these elements abrogat
es 9E3/ chicken chemotactic and angiogenic factor expression. Electrophoret
ic mobility shift assays and functional studies using PathDetect systems sh
ow that stimulation of the cells by phorbol esters leads to activation of t
he Elk1 transcription factor, which binds to its element in the 9E3 promote
r.