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

Citation
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
Citations number
81
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
274
Issue
22
Year of publication
1999
Pages
15454 - 15465
Database
ISI
SICI code
0021-9258(19990528)274:22<15454:AOT9CB>2.0.ZU;2-G
Abstract
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.