PubMed · 9791367
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B Garrett. 1998. Re-epithelialisation.. https://doi.org/10.12968/jowc.1998.7.7.358
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Four distinct promoters (1A, 1B, 1C, and 1D) of fibroblast growth factor 1 (FGF1), spaced up to 70 kilobase pairs apart, direct the expression of alternatively spliced transcript variants (FGF1.A, -1. B, -1.C, and -1.D) that encode FGF1. These FGF1 transcripts can be detected in cultured cells as well as in normal and diseased tissues. These transcripts are differentially regulated in a cell-specific manner. To further delineate the biological function of multiple promoter usage by a single gene, we investigated the transcriptional regulation of these promoters by defined signaling pathways associated with cell proliferation and cell survival. Here we show a specific association of two of the FGF1 promoters, 1C and 1D, with signaling cascades of the Ras superfamily of GTPases. A serum-response element, comprised of the Ets and CArG motifs, present in promoter 1D was shown to be the target of distinct signaling cascades; the Ets motif target of Ras, Rac1, and Cdc42 regulation; and the CArG motif target of de novo protein synthesis-independent cascade. Ras and Rac1 also activated the FGF2 promoter. Further, the transcription factor Ets2 synergistically activated FGF1 gene, but not FGF2, in a Ras- and Rac1-dependent signaling pathway. In support of these conclusions high levels of intracellular FGF1 were detected in cells undergoing cytokinesis. Altogether, our results suggest that FGF1 may play a fundamental role in cell division, spreading, and migration, in addition to cell proliferation.
The SH2-containing inositol 5'-phosphatase (SHIP) is tyrosine-phosphorylated in response to cytokines such as interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor. SHIP has been shown to modulate negatively these cytokine signalings; however, a potential role in IL-4 signaling remains uncharacterized. It has been recently shown that IL-4 induces tyrosine phosphorylation of SHIP, implicating the phosphatase in IL-4 processes. Tyrosine kinases, Jak1 and Jak3, involved in IL-4 signaling can associate with SHIP, yet only Jak1 can tyrosine-phosphorylate SHIP when co-expressed. In functional studies, cells overexpressing wild type SHIP are found to be hyperproliferative in response to IL-4 in comparison to parental cells. In contrast, cells expressing catalytically inactive form, SHIP(D672A), show reduced proliferation in response to IL-4. These changes in IL-4-induced proliferation correlate with alterations in phosphatidylinositol 3,4,5-triphosphate levels. However, no differential activation of STAT6, Akt, IRS-2, or p70(S6k), in response to IL-4, was observed in these cells. These data suggest that the catalytic activity of SHIP acts in a novel manner to influence IL-4 signaling. In addition, these data support recent findings that suggest there are uncharacterized signaling pathways downstream of phosphatidylinositol 3,4,5-triphosphate.
The G-protein-coupled peptide YY (PYY)/neuropeptide Y Y1 receptor (Y1R) subtype is highly expressed in the proliferative zone of human colonic crypt epithelial cells but biochemical and biological support for growth effects have been lacking. Using a model gut epithelial cell system, we have stably expressed the human Y1R in IEC-6 cells and show that the Y1R does couple to mitogen-activated protein kinase (MAPK) phosphorylation and cell growth. This pathway uses pertussis-toxin-sensitive G-proteins and betagamma subunits, inhibited by co-transfected alpha-transducin. The Src-family tyrosine kinase inhibitor PP1, as well as specific inhibition of the epidermal growth factor receptor tyrosine kinase (EGFR TK) by PD153035, also blocks PYY stimulation of MAPK. This pathway further requires protein kinase C with EGFR TK inhibition blocking PYY-induced protein kinase Cepsilon (PKCepsilon) translocation to the cell membrane. Finally, we show that PYY stimulates growth in Y1R-expressing gut epithelial cells that is dependent on EGFR TK activity. These results demonstrate a novel pathway involving G(i)/G(o) protein, EGFR and PKC to activate MAPK. Further, they support a role for PYY and the Y1R in regulating growth in human colonic epithelium.