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

LIAM J. MURPHY, LEIGH C. MURPHY and HENRY G. FRIESEN

Department of Physiology, University of Manitoba Winnipeg, R3E OW3 Manitoba, Canada

Abstract

The mechanisms involved in the proliferative response of the uterus to estrogen are poorly understood. The cmyc 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 17β-estradiol (E₂), 5 µg/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 vehicletreated 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 Nmyc 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 E_2. In contrast the c-myc response is considerably delayed and may be mediated via autocrine, paracrine, or circulating estrogen-dependent growth factors. (Endocrinology 120: 1882–1888,1987)

Footnotes

^* This work was presented in part at the Annual Meeting of the Association of American Physicians, Washington, D. C. 1986. The research was supported by MRC Canada, National Cancer Institute of Canada, and USPHS HD-07843-13.

Recipient of a C. J. Martin Traveling Fellowship from the NHMRC of Australia. To whom correspondence and request for reprints should be addressed.

Received June 25, 1986.

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