IDENTIFICATION OF A SPECIFIC PATTERN OF IMMEDIATE-EARLY GENE ACTIVATION-INDUCED BY ESTROGEN DURING MITOGENIC STIMULATION OF RAT UTERINE CELLS

Estrogen hormones are potent mitogens for certain target tissues, wher e they stimulate cell growth by inducing recruitment of quiescent cell s in cycle and by fostering cell cycle progression. To define the mole cular bases of the mitogenic action of these steroid hormones, the pat tern of ''immediate-early'' gene expression was monitored during the e arly phases of estrogen stimulation of rat uterine cells in vivo. Nucl ear run-on transcription and/or Northern blot RNA analysis indicate th at c-jun, junB, jun-D, c-fos, TIS 1 (also called NGFI-B or nur/77) and TIS 8 (zif-268, krox24, egr-1, or NGFI-A) genes are all transiently a ctivated in the uterus (up to 20-fold) within 30-120 min after treatme nt of adult ovariectomized rats with a mitogenic dose of 17b-estradiol . Conversely, JE gene mRNA accumulates progressively in estrogen-stimu lated uterine cells, whereas TIS 11 and 21 genes are only slightly res ponsive to the hormone (less than twofold induction) and fos B, fra-1, fra-2, krox20 (egr-2), TIS 7 and 10, KC, and c-rel mRNAs are undetect able in rat uterus either before or after estrogen treatment. Stimulat ion in the presence of cycloheximide shows that only c-jun, jun-D, c-f os, and JE gene activations are primary responses to the hormone in ra t uterine cells. These findings establish the direct mitogenic role of estrogen and identify for the first time a specific genetic program a ctivated by these steroid hormones during stimulation of target cell p roliferation. Furthermore, since most of the activated genes encode fo r transcription factors, these results enable us to envision how the m itogenic signal transmitted by the hormone can be elaborated and ampli fied within target cells by the products of estrogen-responsive genes, leading to a cascade of growth-dependent gene regulation, cell cycle progression, and, ultimately, cell division.