Estrogen Induction of N-myc and c-myc Proto-Oncogene Expression in The Rat Uterus*

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Abstract
The mechanisms involved in the proliferative response of the uterus to estrogen are poorly understood. The c-myc proto-oncogene has recently been shown to be rapidly activated in quiescent cells exposed to various mitogens. We have examined expression of c-myc and a closely related protooncogene, N-myc, in the rat uterus after in vivo administration of 17.beta.-estradiol (E2), 5 .mu.g/100 g body weight, to prepubertal ovariectomized rats. Maximal c-myc messenger RNA (mRNA) accumulation, as determined by densitometric analysis of Northern blots of poly (A)+ uterine RNA was observed 3 h after E2 treatment. Maximal expression of c-myc was 8.6 .+-. 0.8-fold (mean .+-. SEM for 3 separate experiments) compared to basal levels seen in vehicle-treated ovariectomized rats. The maximal level of c-myc mRNA in the E2-stimulated uterus was higher (3- to 6-fold) than that observed in uteri from intact rats in either diestrous or the proestrous-estrous stages of the estrous cycle. There was no significant difference in the level of uterine c-myc mRNA throughout the estrous cycle. Under stringent conditions, the N-myc DNA probe hybridized with a single 3 kilobase (kb) transcript which was virtually undetectable in ovariectomized rat uteri and increased 6-fold within 15 min after E2 treatment. Maximal induction was seen 30-60 min post E2 treatment. At 1 h post E2 the level of N-myc mRNA was 9.3 .+-. 0.4-fold (n = 3) compared to vehicle-treated rats. Under conditions of slightly reduced stringency, N-myc DNA also hybridized with a 2.2 kilobase transcript. Expression of the N-myc related gene also occurred more rapidly after E2 administration than c-myc mRNA. Our in vivo data are analogous to the in vitro observations that mitogen stimulation of quiescent cells results in a rapid accumulation of myc-proto-oncogene mRNAs. In cycling cells in vitro and in the uterus of intact rats throughout the estrous cycle, the level of expression of the myc oncogenes is relatively constant. Since expression of the c-myc and N-myc protooncogenes appears to be restricted to different cell and tissue types our data indicate that there is at least one cell type present in the quiescent uterus that is able to respond rapidly to E2. The rapidity of the N-myc response would argue for a direct effect of E2. In contrast the c-myc response is considerably delayed and may be mediated via autocrine, paracrine, or circulating estrogen-dependent growth factors.