A.M. Kaye, N. Reiss and M.D. Walker,      Department of Hormone Research, The Weizmann Institute of Science, Rehovot, Israel

ABSTRACT

The postnatal development of responsiveness to estrogen in the rat uterus can be divided into three stages. In the first stage (lasting for a period of approximately 10 days after birth) a single dose of estrogen, administered to Wistar-derived rats, results in the stimulation of the synthesis of a limited number of uterine proteins. Those which are presently known are the ‘estrogen induced protein’ (IP) first described by Notides and Gorski, ornithine decarboxylase, the first and rate-limiting enzyme in the pathway of polyamine biosynthesis, and estrogen and progesterone receptors. During the second stage of responsiveness, seen at approximately two weeks after birth, both RNA and protein synthesis are stimulated by estrogen, while there is no effect on DNA synthesis. By three weeks after birth, all growth parameters, including DNA synthesis, are increased by estrogen treatment.We have concentrated our investigation on the early and late stages of responsiveness. IP has been characterized and identified as a constitutive component of uterus as well as of pituitary, hypothalamus and cerebral cortex. It has been purified from rat brain where it occurs in both males and females; antisera against it have been made in rabbits and a radioimmunoassay for IP is under development.The stimulation of DNA synthesis by estrogen, as measured by incorporation of tritiated thymidine, was found to be paralleled by an increase in the activity of DNA polymerase α, the putative replicative polymerase, with no increase in DNA polymerase β, possibly a repair enzyme.Throughout the entire period of postnatal development, the presence and, recently, the replenishment, of estrogen receptors have been demonstrated. We therefore use the working hypothesis that the acquisition of responsiveness to estrogen is a result of differentiation of specific chromosomal ‘acceptor sites’ for the estrogenreceptor complex.

Keywords

Estrogen

induced protein

DNA polymerase α

ornithine decarboxylase

receptors

uterus

brain

INTRODUCTION

A steroid hormone such as estrogen, which stimulates the growth and division of uterine cells, displays a wide variety of those actions which culminate in cell division. From both a basic viewpoint-elucidation of the mechanism of regulation of macromolecular synthesis-and an applied approach leading to the safer use of estrogens in contraception and therapy, it is crucial to know whether independent activation of any of estrogen’s actions is experimentally demonstrable. Such a functional dissection of estrogen’s action should provide powerful tools essential for the study of its molecular biology.

Fortunately, for investigation of this problem, the uterus of the rat shows a progressive and differential sensitivity to stimulation by estrogen during the period from birth to puberty. Price and Ortiz (1944) found that when a series of 6 daily injections of estradiol-benzoate (totalling 10 μg) was given to non-inbred rats aged 0 to 50 days, the wet weight increase and estrogen-associated histologic changes in uterus became more pronounced with age up to 26 days after birth. Thereafter the magnitude of these responses declined. A single injection of 0.5 μg estradiol–17β to Sprague-Dawley rats, ovariectomized at 21 days, showed an increase in their uterine weight response until puberty, followed by a decline in responsiveness in older animals (Liu, 1960).

More interestingly, the responsiveness to estrogen can be shown to be acquired in distinct developmental stages when individual components of the overall estrogen response are analyzed (Kaye and colleagues, 1972, 1974, 1975; Katzenellenbogen and Greger, 1974; Sömjen and colleagues, 1973a, b, 1974; Walker and colleagues, 1976, 1978; Peleg and colleagues, 1977, 1979; Peleg and Kaye, 1978). In perinatal life, although estrogen receptors are present in uterine cytoplasm and are capable of being transferred into the nucleus, there is a period of approximately two weeks after birth during which there is a stimulation of synthesis of a limited number of proteins following a single estrogen injection. Bulk protein and RNA synthesis can be stimulated by estrogen only after, the second week of life. DNA synthesis is accelerated by estrogen only in uteri of rats that are 20 days of age or older.

The emphasis in this review will be placed on the initial stage of the acquisition of estrogen responsiveness epitomized by the ‘estrogen induced protein’ first described by Notides and Gorski (1966) and on the culminating stage of stimulation of DNA synthesis.

THE PERINATAL STAGE OF RESPONSIVENESS: STIMULATION OF A SMALL GROUP OF PROTEINS