AN ETS SITE IN THE WHEY ACIDIC PROTEIN GENE PROMOTER MEDIATES TRANSCRIPTIONAL ACTIVATION IN THE MAMMARY-GLAND OF PREGNANT MICE BUT IS DISPENSABLE DURING LACTATION

The whey acidic protein (WAR) gene is specifically expressed in mammar y tissue, and its transcription is,induced several thousand-fold durin g pregnancy and remains high throughout lactation. A purine-rich seque nce (PRS) located around -110 of the WAP gene promoter is conserved be tween mice, rats, and rabbits, suggesting that it features a regulator y element. This PRS contains an invariant GGAA/T core motif characteri stic of the binding site for Ets transcription factors. Electromobilit y shift assays demonstrate that Ets1 binds specifically to the PRS. Ex periments in transgenic mice further demonstrate that this PRS/Ets sit e plays a critical role in the activation of WAP transgenes during pre gnancy, but that its presence is not required for high expression thro ughout lactation. Transgenes with an intact PRS/Ets site are expressed at high levels at day 13 of pregnancy, with little further increase d uring late pregnancy and lactation. In contrast, WAP transgenes with a mutation in the PRS/Ets site, which abrogates the binding of Ets1, ar e not expressed at midpregnancy, but their transcriptional activity is not affected during lactation. These results demonstrate that Ets-sig naling pathways can function as stage-specific transcriptional activat ors of milk protein genes in the developing mammary gland. In addition , this work extends earlier findings that gene activation during pregn ancy and lactation is mediated, in part, by different mechanisms.