ESTROGEN REGULATES THE STAGE-SPECIFIC EXPRESSION OF KIDNEY ANDROGEN-REGULATED PROTEIN IN RAT UTERUS DURING REPRODUCTIVE-CYCLE AND PREGNANCY

The female sex steroid, estrogen, acting through its nuclear receptor profoundly influences growth and differentiation programs in the mamma lian uterus by regulating the expression of specific cellular genes. T he identity and profile of expression of the estrogen-regulated genes at various stages of the reproductive cycle and pregnancy, however, re main largely unknown. Using a differential gene expression screen meth od, we isolated a gene that is down-regulated in the uterus during pre gnancy. This gene encodes the previously identified androgen-regulated protein known as the kidney androgen-regulated protein (KAP) because of its abundant expression in the kidney. Our results showed a high le vel of KAP messenger RNA (mRNA) in the uteri of nonpregnant rats at al l stages of the estrous cycle. We observed that in the pregnant animal s, the level of KAP mRNA remained high immediately after fertilization (days 1 and 2), but declined sharply with the progression of pregnanc y, falling to almost undetectable levels during midgestation (days 10- 15). Interestingly, the level of KAP mRNA started to rise again toward the end (day 19 onward) of pregnancy and was high during parturition. The temporal pattern of expression of KAP in the uterus closely overl apped with the profile of plasma estrogen during pregnancy. Known anta gonists of estrogen, such as tamoxifen and ICI 182,780, strongly inhib ited uterine KAP gene expression during the estrous cycle and pregnanc y, supporting a regulatory role of estrogen in this process. Consisten t with this observation, administration of estrogen to ovariectomized animals markedly stimulated (similar to 10-fold) the level of KAP mRNA in the uterus. Treatment of these animals with progesterone, on the o ther hand, did not significantly alter KAP gene expression. Immunocyto chemical analyses of uterine sections with an antibody against KAP exh ibited specific staining in both luminal and glandular epithelia and i n myometrium. These uterine locations also possess abundant estrogen r eceptors and are known targets of estrogen action. Our studies, theref ore, revealed that KAP is a useful marker of estrogen action in the ut erus, especially during the reproductive cycle and termination of gest ation.