The aim of this study was to investigate the participation of the 26S proteasome in the regulation of progesterone receptor (PR) concentrations in the rat brain in vivo. Ovariectomized adult female rats were treated with estradiol (10 µg/100 g s.c.), estradiol + progesterone (400 µg/100 g), and vehicle (corn oil/10% ethanol) in the presence or absence of the proteasome inhibitor Z-Ile-Glu (OBu1)-Ala-Leu-H (PSI, 300 µg/100 g). Proteins were extracted from the preoptic area, the hippocampus, and the frontal cortex, and processed for Western blot. Estradiol-induced PR expression in the preoptic area and the hippocampus, whereas progesterone did not modify the effect of estradiol. Neither estradiol nor progesterone modified PR content in the frontal cortex. PSI treatment increased PR content in the preoptic area and the hippocampus. This increase was significant in both regions after 24 h of the treatment with progesterone + PSI in the animals primed with estradiol. In this case, the content of both PR isoforms (PR-A and PR-B) was increased in a similar manner by PSI in the preoptic area (90 and 97%) and in the hippocampus (49 and 50%). PSI did not affect PR content in the frontal cortex. Our results suggest that the 26S proteasome could participate in the turnover of PR in the preoptic area and the hippocampus of the rat in vivo.

Graham JD, Clarke CL: Physiological actions of progesterone in target tissues. Endocr Rev 1997;18:502–519.
Schumacher M, Coirini H, Robert F, Guennoun R, El-Etr M: Genomic and membrane actions of progesterone: Implications for reproductive physiology and behaviour. Behav Brain Res 1999;105:37–52.
Shughrue PJ, Lane MV, Merchenthaler I: Regulation of progesterone receptor messenger ribonucleic acid in the rat medial preoptic nucleus by estrogenic and antiestrogenic compounds: An in situ hybridization study. Endocrinology 1997;138:5476–5484.
MacLusky NJ, McEwen BS: Oestrogen modulates progesterone receptor concentrations in some rat brain regions but not in others. Nature 1978;274:276–278.
Savouret JF, Bailli A, Misrahi M, Rauch C, Redeuilh G, Chauchereau A, Milgrom E: Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene. EMBO J 1991;10:1875–1883.
Kraus WL, Montano MM, Katzenellenbogen BS: Identification of multiple, widely spaced estrogen-responsive regions in the rat progesterone receptor gene. Mol Endocrinol 1994;8:952–969.
Camacho-Arroyo I, Guerra-Araiza C, Cerbón MA: Progesterone receptor isoforms are differentially regulated by sex steroids in the rat forebrain. Neuroreport 1998;9:3993–3996.
Bethea CL, Widmann AA: Differential expression of progestin receptor isoforms in the hypothalamus, pituitary, and endometrium of rhesus macaques. Endocrinology 1998;139:677–687.
Blaustein JD, Turcotte JC: Down-regulation of progestin receptors in guinea pig brain: New findings using an immunocytochemical technique. J Neurobiol 1990;21:675–685.
Camacho-Arroyo I, Pasapera AM, Cerbón MA: Regulation of progesterone receptor gene expression by sex steroid hormones in the hypothalamus and the cerebral cortex of the rabbit. Neurosci Lett 1996;214:25–28.
Turgeon JL, Waring DW: Progesterone regulation of the progesterone receptor in rat gonadotropes. Endocrinology 2000;141:3422–3429.
Syvälä H, Vienonen A, Zhuang YH, Kivineva M, Ylikomi T, Tuohimaa P: Evidence for enhanced ubiquitin-mediated proteolysis of the chicken progesterone receptor by progesterone. Life Sci 1998;63:1505–1512.
Shen T, Horwitz KB, Lange CA: Transcriptional hyperactivity of human progesterone receptors is coupled to their ligand-dependent down-regulation by mitogen-activated protein kinase-dependent phosphorylation of serine 294. Mol Cell Biol 2001;21:6122–6131.
Lange CA, Shen T, Horwitz KB: Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc Natl Acad Sci USA 2000;97:1032–1037.
Okamoto H, Takaoka M, Ohkita M, Itoh M, Nishioka M, Matsumura Y: A proteasome inhibitor lessens the increased aortic endothelin-1 content in deoxycorticosterone acetate-salt hypertensive rats. Eur J Pharmacol 1998;350:R11–R12.
Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates. Sydney, Academic Press, 1986.
Estes PA, Suba EJ, Lawler-Heavner J, Elashry-Stowers D, Wei LL, Sullivan EP, Toft DO, Horowitz KB, Edwars DP: Immunological analysis of progesterone receptors in human breast cancer. I. Purification of transformed receptors and production of monoclonal antibodies. Biochemistry 1987;26:6250–6262.
Rivett AJ, Mason GG, Murray RZ, Reidlinger J: Regulation of proteasome structure and function. Mol Biol Rep 1997;24:99–102.
Nawaz Z, Lonard DM, Dennis AP, Smith CL, O’Malley BW: Proteasome-dependent degradation of the human estrogen receptor. Proc Natl Acad Sci USA 1999;96:1858–1862.
Sheflin L, Keegan B, Zhang W, Spaulding SW: Inhibiting proteasomes in human HepG2 and LNCaP cells increases endogenous androgen receptor levels. Biochem Biophys Res Commun 2000;276:144–150.
Dennis AP, Haq RU, Nawaz Z: Importance of the regulation of nuclear receptor degradation. Front Biosci 2001;6:D954–959.
Ortiz J, Harris HW, Guitart X, Terwilliger RZ, Haycock JW, Nestler EJ: Extracellular signal-regulated protein kinases (ERKs) and ERK kinase (MEK) in brain: Regional distribution and regulation by chronic morphine. J Neurosci 1995;15:1285–1297.
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