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Modulation of Estrogen Receptor Levels in Mouse Uterus by Protein Kinase C Isoenzymes¹

Department of Histology and Medical Embryology Institute (S.M.), University of Rome La Sapienza, Rome 00161, Italy; Receptor Biology Section, Laboratory of Reproductive and Developmental Toxicology (S.M., T.F.W., K.S.K.), and Hormone Action Group, Laboratory of Signal Transduction (S.F., H.R., W.C.W.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center (W.C.W.), Durham, North Carolina 27710; and the Department of Experimental Medicine, University of L’Aquila (A.T.), Rome, Italy 67100

Address all correspondence and requests for reprints to: Silvia Migliaccio, M.D., Ph.D., Histology and Medical Embryology Department, University of Rome La Sapienza, Via Antonio Scarpa 14, Rome 00161, Italy. E-mail: ateti{at}axrma.uniroma1.it

We have recently shown that protein kinase C (PKC) modifies estrogen receptor (ER) binding and modulates the responsiveness to estrogens in a clonal osteoblast-like cell line stably transfected with the ER. The purpose of the present study was to determine whether the interaction observed between the ER and PKC signaling in these cells occurs in additional estrogen target organs, such as the uterus. When uteri were incubated for 2 h with increasing concentrations of a kinase inhibitor (H7), ER binding was enhanced in a dose-dependent manner. Stimulation of PKC with phorbol ester reduced PKC activity levels, but increased ER binding. Interestingly, the changes in binding appeared to be due primarily to alterations in cytosolic ER levels, as binding in the nuclear fraction was minimally enhanced. When levels of ER messenger RNA were evaluated by Northern blot analysis, no differences were observed among the H7- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated and untreated groups. Western blot analysis, however, demonstrated that levels of ER cytosolic protein in the H7-, TPA-, and staurosporine-treated groups were increased relative to those in the untreated controls. When uteri were incubated with diethylstilbestrol in the presence of either H7 or TPA, no change in cytosolic ER levels was found, suggesting that only unoccupied ERs are responsive to modulation by PKC. Western blotting of the various PKC isoforms indicated that although PKC, -ß_I, -ß_II, -, and - are expressed in the uterus, only PKC and -ß_I are translocated from the soluble to the particulate fraction and then degraded after phorbol ester stimulation. Hence, one or both of these latter PKC isoforms may regulate cytosolic ER levels. Collectively, these data indicate that PKC may play an important role in the modulation of uterine ER levels and that PKC may exert its effect on the ER at some posttranscriptional or posttranslational step. Finally, our results show that an ER-PKC interaction occurs in a whole organ such as the uterus and that this interaction may be important in the regulation of the ER activity in a variety of estrogen-responsive tissues.

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