Regulation of expression of genes for milk proteins.

Our results demonstrate that mRNAs that encode two major milk proteins in the mouse, namely, WAP and beta-casein, are found predominantly in the mammary glands of lactating animals. During the course of mammary development from the virgin to the fully lactating animal the steady-state levels of the two RNAs increase about 10(4)-fold, with the most pronounced increase occurring around midpregnancy. Low levels of WAP and beta-casein RNAs are also found in some nonmammary tissues such as tongue, pancreas, and pituitary gland, but not in others, for example, heart and brain. This variation suggests that the transcriptional machinery in some nonmammary cells is capable of recognizing milk-protein genes. The analysis of transgenic animals that carry a hybrid gene composed of the WAP promoter plus the tPA gene strongly suggests that mammary specificity of gene expression is encoded in the promoter/upstream region of the WAP gene. Induction of the genes for WAP and beta-casein during development of mammary glands requires the synergistic action of insulin, hydrocortisone, and prolactin. The increase in levels of the two mRNAs in mammary tissue from midpregnant animals was about 50-fold upon incubation with all three of these hormones, suggesting that no additional hormones may be required in the intact animal. The characteristics of the hormonal induction of the WAP-tPA hybrid gene in transgenic animals differed from those of the induction of the endogenous milk-protein genes in that the presence of all three hormones was not sufficient to increase the levels of the hybrid RNA. This difference suggests that some elements involved in the hormone-dependent accumulation of WAP RNA are located outside the promoter/upstream region, (Pittius et al. 1988a and 1988b). Similar conclusions have been drawn by Groner and coworkers, who analyzed expression of the WAP promoter in two additional hybrid genes (Andres et al. 1988). In addition to the WAP gene, the beta-casein gene also appears to contain hormone-sensitive regulatory elements within the transcribed region. Hybrid genes containing the rat beta-casein promoter (Lee et al. 1989a and 1989b) are expressed in a mammary-specific fashion in transgenic animals but have lost their ability to be regulated by steroid and peptide hormones, a property of their endogenous counterpart.(ABSTRACT TRUNCATED AT 250 WORDS)