TY - JOUR
T1 - Bone morphogenetic protein-2 inhibits MAPK-dependent Elk-1 transactivation and DNA synthesis induced by EGF in mesangial cells
AU - Choudhury, Goutam Ghosh
AU - Jin, Dong Chan
AU - Kim, Yong Soo
AU - Celeste, Anthony
AU - Ghosh-Choudhury, Nandini
AU - Abboud, Hanna E.
N1 - Funding Information:
We thank Sergio Garcia for help with cell culture. This study was supported in part by the Dept. of Veterans Affairs Medical Research Service (G.G.C. and H.E.A.) and National Institutes of diabetes and Digestive and Kidney diseases Grant DK-50190 (to G.G.C.) and DK 43988 (to H.E.A.). N.G.C. is supported by an institutional American Cancer Society grant.
PY - 1999/5/10
Y1 - 1999/5/10
N2 - Bone morphogenetic protein-2 (BMP-2) is a member of the TGFβ superfamily of growth and differentiation factors. We investigated the effect of BMP-2 on epidermal growth factor (EGF)-induced mitogenic signaling in kidney glomerular mesangial cells. BMP-2 dose-dependently inhibits EGF-induced DNA synthesis. Maximum effect was obtained at a concentration of 100 ng/ml. BMP-2 had no inhibitory effect on the EGF receptor (EGFR)-associated tyrosine kinase activity indicating that inhibition of DNA synthesis is due to regulation of post-receptor signaling event(s). EGF stimulates MAPK activity in mesangial cells in a time-dependent manner. Inhibition of MAPK by the MEK inhibitor PD098059 blocks EGF-induced DNA synthesis indicating the requirement of this enzyme activity in EGF-mediated mitogenic signaling. Furthermore, we show that exposure of mesangial cells to BMP-2 blocks EGF-induced MAPK activity which leads to phosphorylattion of Elk-1 transcription factor. Using a GAL-4 DNA binding-domain-Elk-1 transactivation domain fusion protein-based reporter assay, we demonstrate that BMP-2 inhibits EGF-induced Elk-1-mediated transcription. These data provide the first evidence that BMP-2 signaling in mesangial cells initiates a negative regulatory cross-talk with MAPK-based transcription to inhibit EGF-induced DNA synthesis.
AB - Bone morphogenetic protein-2 (BMP-2) is a member of the TGFβ superfamily of growth and differentiation factors. We investigated the effect of BMP-2 on epidermal growth factor (EGF)-induced mitogenic signaling in kidney glomerular mesangial cells. BMP-2 dose-dependently inhibits EGF-induced DNA synthesis. Maximum effect was obtained at a concentration of 100 ng/ml. BMP-2 had no inhibitory effect on the EGF receptor (EGFR)-associated tyrosine kinase activity indicating that inhibition of DNA synthesis is due to regulation of post-receptor signaling event(s). EGF stimulates MAPK activity in mesangial cells in a time-dependent manner. Inhibition of MAPK by the MEK inhibitor PD098059 blocks EGF-induced DNA synthesis indicating the requirement of this enzyme activity in EGF-mediated mitogenic signaling. Furthermore, we show that exposure of mesangial cells to BMP-2 blocks EGF-induced MAPK activity which leads to phosphorylattion of Elk-1 transcription factor. Using a GAL-4 DNA binding-domain-Elk-1 transactivation domain fusion protein-based reporter assay, we demonstrate that BMP-2 inhibits EGF-induced Elk-1-mediated transcription. These data provide the first evidence that BMP-2 signaling in mesangial cells initiates a negative regulatory cross-talk with MAPK-based transcription to inhibit EGF-induced DNA synthesis.
UR - http://www.scopus.com/inward/record.url?scp=0345621668&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0345621668&partnerID=8YFLogxK
U2 - 10.1006/bbrc.1999.0599
DO - 10.1006/bbrc.1999.0599
M3 - Article
C2 - 10329414
AN - SCOPUS:0345621668
SN - 0006-291X
VL - 258
SP - 490
EP - 496
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -