Co-administration of estradiol and EGF or IGF-I increases ER target gene expression to an extent greater than either agent alone, and in some instances, this response appears to be synergistic. Interestingly, the ability of IGF-I and estrogen-dependent activation pathways to synergize does not require the AF-1 domain, suggesting that growth factor signaling pathways may target different regions of ER depending on the presence or absence of ligand, potentially as a result of the different receptor conformations induced by ligand. buy ortho tri-cyclen online
Treatment of primary rat uterine cells with IGF-I increases the overall extent of ER phosphorylation. Similarly, ER phosphorylation in COS-1 and SK-Br-3 breast cancer cells is stimulated by EGF and IGF-I to an extent similar to that by estrogen. EGF is unable to stimulate the phosphorylation of an alanine118 mutant of full-length or carboxyl-terminal-deleted ER, and this is consistent with the A/В domain’s being critical for ER activation by EGF. The transcriptional activity of an alanine118 ER mutant examined in COS-1, HeLa, or SK-Br-3 cells is not increased by EGF or by expression of a dominant active Ras mutant. Interestingly, when a glutamic acid is substituted for serine118, the receptor retains its ability to respond to EGF signaling pathways, suggesting that a negative charge at position 118 may contribute to growth factor activation of ER transcriptional activity.