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Istituto di Patologia Generate e Oncologia, Prima Facoltà di Medicina e Chirurgia, Università di Napoli Napoli 1-80138, Italy
Address requests for reprints to: Dr. Alessandro Weisz, Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Unité 184 de Biologie Moléculaire et de Génie Génétique de I'INSERM, Institute de Chimie Biologique, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg, Cédéx, France.
Abstract
Estrogen stimulates DNA synthesis and cell proliferation in the luminal and glandular epithelia of rodent uterus. We tested the hypothesis that the mitogenic effect of estrogen occurs via activation of the expression of cellular proto-oncogenes by measuring the rate of transcription of 20 proto-oncogenes (abl, bas, erb-A, erb-B, ets, fms, fos, fps/fes, mos, myb, myc, N-myc, raf, Ha-ras, Ki-ras, N-ras, rel, sis, src, and B-lym) in the uterus of ovariectomized rats before and after injection of estrogen, c-onc transcriptional activity was monitored both by an in vitro transcription assay on isolated nuclei (run-on) and by analysis of mature mRNA. c-fos and c-myc protooncogenes were found to respond to estrogen with increased expression: c-fos within 30 min, with a first, sharp peak at 2 h and c-myc within 1.5 h, with a first, broad peak at 4–6 h. DNA synthesis start to increase in the uterus 13 h after estrogen injection and show a first peak at 24 h. In the liver and muscle of the same animals there is neither elevation of c-fos and c-myc expression nor increase of DNA synthesis. The kinetics of the induction by estrogen of c-fos gene expression in the uterus parallels the rate of formation of active nuclear estrogen-receptor complex. Furthermore, the ability of estrogen to induce c-fos mRNA was not abolished by the protein synthesis inhibitor cycloheximide. These data suggest that the initial steps in the mechanism of mitogenesis by estrogen involve activation of c-fos and c-myc gene expression and that transcriptional activation of c-fos is a primary response to estrogen in rat uterus.
FOOTNOTES
Research supported by grants from the Italian National Research Council, Special Project Oncology, Contact 86.00328.44., and Associazione Italiana per la Ricerca sul Cancro.
Preliminary results of this work have been presented at the UCLA Symposia on Molecular & Cellular Biology (Park City, UT) Jan. 17–Feb. 5,1987 and at the 3rd International Congress on Hormones and Cancer, Hamburg (FRG): September 6–11, 1987.
Received for publication February 22, 1988. Accepted for publication May 19, 1988.
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