Abstract
Epidermal growth factor (EGF) increases prolactin gene expression in GH4 cells, but the promoter element(s) required for this response has not been clearly defined. We identified a bipartite element −96/−87, −76/−67 in the rat proximal promoter that is essential for EGF signaling using deletion and linker-scanning mutants of the prolactin promoter. This element was active in either normal or inverted orientation when transferred to a heterologous promoter (mammary-tumor virus). We had previously identified this element as the cAMP/insulin response element of the prolactin promoter. However, the effects of EGF are additive with the responses to insulin or cAMP implying that EGF activated prolactin gene transcription by a mechanism different from insulin or cAMP. The EGF response element of the prolactin promoter is a recognition sequence for the Ets-related family of transcription factors and Ets-related factors have been shown to bind this element. Expression of the DNA-binding domain of c-Ets-1, which acts as a dominant negative inhibitor of Ets-related transcription factors, reduces EGF-increased prolactin–CAT expression 65% in GH4 cells. Thus, both EGF and insulin may signal through Ets-related transcription factors to activate prolactin gene transcription at the same response element in the prolactin proximal promoter.
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