Cell-Specific Induction of c-fos Expression in the Pituitary Gland by Estrogen*

Allen, Donald L.; Mitchner, Natasha A.; Uveges, Thomas E.; Nephew, Kenneth P.; Khan, Sohaib A.; Ben‐Jonathan, Nira

doi:10.1210/endo.138.5.5101

Cited by 50 publications

(16 citation statements)

References 43 publications

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“…Tissue-specific estrogen responses have also been reported for regulation of the expression of the immediate early gene c-fos. In the rat uterus, estrogen caused a rapid increase followed by a rapid decline in the expression of c-fos, but the increase in c-fos levels in the anterior pituitary was both delayed and sustained (33,40,45,46). Our observations in the present study as well as the reports cited above suggest that the differential effects of estrogen might be due to factors downstream of ER.…”

Section: Er⅐pit-1 Complex Formation Regulated By Estrogensupporting

confidence: 71%

Estrogen-modulated Estrogen Receptor·Pit-1 Protein Complex Formation and Prolactin Gene Activation Require Novel Protein Synthesis

Ying

Lin

2000

Journal of Biological Chemistry

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Both estrogen receptor (ER) and Pit-1 proteins are essential for the estrogen-activated expression of the rat prolactin gene. Our results show that ER⅐Pit-1 protein complex formation is reduced by estrogen in GH3 and PR1 rat pituitary tumor cells. In the latter, this decrease was blocked by cycloheximide, a protein synthesis inhibitor. On the other hand, the direct addition of estrogen to PR1 cell lysates had no effect on the formation of ER⅐Pit-1 complexes. Estrogen-activated prolactin gene expression was also inhibited by cycloheximide, suggesting that some form of protein synthesis is involved in ER⅐Pit-1 complex formation and subsequent prolactin gene activation. In support of this notion, we showed that estrogen-induced regulation of ER⅐Pit-1 complex formation could be transferred from cell lysates prepared from estrogen-treated PR1 cells to control cell lysates. This is not true for GH3 cells; instead, direct administration of estrogen to GH3 cell lysates readily abolished ER⅐Pit-1 protein complex formation in a dosedependent manner, and such estrogen-induced regulation was blocked by the antiestrogen ICI 182,780. These findings thus indicate that 1) interaction between ER and Pit-1 proteins is estrogen-regulated in ways specific to different cell types, and 2) auxiliary protein factor synthesis may be involved in this process.The tissue-specific expression of the rat prolactin (PRL) 1 gene in the anterior pituitary gland is regulated by the synergistic action of two upstream regulatory elements: the distal enhancer and the proximal promoter (1, 2). Complex binding sites for trans-acting factors within these elements control tissue-specific expression and transcription efficiency (3, 4). A pituitary cell-specific transcription factor, Pit-1, a member of the POU domain family of transcription factors, binds to multiple sites in these elements and is required for the tissuespecific expression of rat PRL (5). Gene dysfunction analysis has shown not only that failure to express the PRL gene accounts for genetically dwarfed mice, but also that Pit-1 function is linked to transcriptional activation of the rat PRL gene in the anterior pituitary (6). Pit-1 is also involved in normal pituitary development and the proliferation of specific anterior pituitary cell types such as lactotrophs and somatotrophs (7).The Pit-1 protein by itself, however, is not sufficient for the tissue-specific expression of the rat PRL gene. The promoter activity of the rat PRL gene strongly depends on the synergistic interactions between Pit-1 and other promoter-specific transcription factors, including the thyroid hormone receptor, CAAT/enhancer-binding protein-␣, Ets-1, and c-Jun (8 -10). Moreover, rat PRL gene expression is regulated by the steroid hormone estrogen at the level of transcription (11). Evidence showed that estrogen receptor-␣ (ER-␣), which exhibits affinity for binding sites in the distal enhancer element of the rat PRL gene, synergizes with the Pit-1 protein to permit activation of the distal enhancer in a ligand-depen...

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Section: Er⅐pit-1 Complex Formation Regulated By Estrogensupporting

confidence: 71%

Estrogen-modulated Estrogen Receptor·Pit-1 Protein Complex Formation and Prolactin Gene Activation Require Novel Protein Synthesis

Ying

Lin

2000

Journal of Biological Chemistry

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“…Tissue-specific differences of E2 response are also shown in the immediate early gene, c-fos expression regulation. Uterine c-fos induction by estrogen is rapid followed by a rapid decline (31); however, in anterior pituitary, the induction is delayed and sustained (32). All these reports and our observation in PR1 cells suggest that differential response to E2 might be due to factors downstream of ER.…”

mentioning

confidence: 58%

Differential regulation by estrogens of growth and prolactin synthesis in pituitary cells suggests that only a small pool of estrogen receptors is required for growth

Chun

Gregg

Sarkar³

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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PR1 cells are a prolactin (PRL)-secreting cell line derived from a pituitary lactotroph tumor found in 17␤-estradiol-treated Fischer 344 rats. We examined the effect of estrogen on cell proliferation and PRL synthesis under various culture conditions. Estrogen, at extremely low concentrations, induces cell proliferation in this cell line, whereas antiestrogen inhibits proliferation. Interestingly, the proliferation response is much more sensitive than the PRL response because 0.01 pM estradiol or diethylstilbestrol induces half-maximal growth induction [Ϸ0.1% estrogen receptor (ER) occupancy is required], whereas 0.01 nM concentration is required for half-maximal PRL induction (Ϸ50% ER occupancy is required). The proliferation response is not as sensitive to antiestrogen as the PRL response, because 10 nM concentration of the pure antiestrogen ICI 182,780 could not inhibit 1 nM estradiol-or diethylstilbestrol-induced proliferation. The same concentration of ICI 182,780 decreased PRL secretion to 1% of estradiol-or diethylstilbestrol-induced prolactin secretion suggesting a possible dichotomy of ER control of proliferation and PRL synthesis. The K d of ER binding in these cells is about 3 ؋ 10 ؊11 M. These results with the PR1 cells extend previous studies in other estrogenregulated systems and suggest that only a small pool of ER is required for cell proliferation in contrast with the regulation of expression of specific genes. They also raise questions as to how a dimeric receptor functions when only one ligand site is occupied or when both an estrogen and an antiestrogen occupy one dimer.Estrogen is a physiological regulator of both replication and prolactin (PRL) synthesis in pituitary lactotrophs. Pituitaries of the Fischer 344 (F344) rat strain form tumors in response to 6-10 weeks of estrogen treatment (1-3). The GH3 cell line was derived from the radiation-induced MtT͞W5 transplantable pituitary tumor (4), and the GH4C1 cell line was subcloned from the GH3 cell line (5, 6). These cell lines are somatolactotrophs that secrete both PRL and growth hormone and in some cases proliferate on estrogen treatment (7-9). However, the response of these cell lines has been variable, with some investigators reporting no effect or negative effects of estrogen on proliferation (9-12), whereas others reported estrogen-stimulated proliferation (13, 14).In the above-mentioned research, replication was more sensitive than PRL synthesis to estrogen. GH4C1 pituitary tumor cell growth was 10-fold more sensitive to estrogen than PRL mRNA accumulation (14). GH3 cells showed maximum cell growth at 0.01 nM 17␤-estradiol (E2), whereas only half-maximal PRL production occurred at the same concentration (13). These data, although interesting, did not lead to any additional studies.We have studied the relationship between estrogen-induced cell proliferation and PRL expression by using a newly established pituitary cell line (PR1) from E2-treated F344 female rats (15). The cell growth response in this cell line is 1,000-fold mor...

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“…In addition, estradiol induces c-fos in the medial amygdaloid nucleus [48], the midbrain and the hippocampus, but not the cerebellum [51]. In the pituitary estrogen induces c-fos in a cell-specific manner [52]. Furthermore, estrogens have been shown to induce c-fos in other tissues, such as the rat uterus [53], cultured guinea pig uterine epithelium [54], in the MCF-7 breast cancer cell line [55], and in both bone-resorbing osteoclasts and bone-forming osteoblasts [56, 57].…”

Section: Discussionmentioning

confidence: 99%

Protooncogene c-fos Involvement in the Molecular Mechanism of Rat Brain Sexual Differentiation

Giannakopoulou

Bozas²,

Philippidis³

et al. 2001

Neuroendocrinology

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Brain sexual differentiation is mediated through testosterone, which acts during the perinatal period in the form of both 5α-dihydrotestosterone and estradiol. In order to gain insight into the molecular mechanisms involved, we studied induction of c-fos, an index of functional neuronal activation, in the 2-day-old female rat brain after injection of a masculinizing dose of testosterone. Administration of testosterone resulted in induction of c-fos gene expression in the hypothalamus, as determined by Northern analysis. Following immunocytochemistry, we demonstrated an increase in the number of Fos-positive nuclei in the median and medial preoptic nucleus, the medial preoptic area extending to the lateral preoptic area, and the peri- and paraventricular area. In an effort to see whether testosterone acted as 5α-dihydrotestosterone or as estradiol, we injected either steroid and looked at fos induction. Estradiol mimicked the effect of testosterone, while 5α-dihydrotestosterone was without effect. Furthermore, injection of an estrogen receptor blocker, clomiphene, together with testosterone, abolished the testosterone-induced increase in Fos-positive nuclei, thus confirming the finding that testosterone induces c-fos by acting through estrogen receptors. Electrophoretic mobility shift assays showed that nuclear extracts from 2-day-old female hypothalamus contain a protein, most probably the estrogen receptor, which binds specifically to oligodeoxynucleotides with the sequence of either vitERE, the consensus estrogen-responsive element (ERE) found in the vittelogenin gene, or fosERE, the ERE found in the 3′-untranslated region of the mouse c-fos gene. This suggests that the effect of testosterone-derived estradiol on c-fos expression is a direct one, mediated by binding of estrogen receptors to an ERE in the c-fos gene-regulatory regions.

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Cell-Specific Induction of c-fos Expression in the Pituitary Gland by Estrogen*

Cited by 50 publications

References 43 publications

Estrogen-modulated Estrogen Receptor·Pit-1 Protein Complex Formation and Prolactin Gene Activation Require Novel Protein Synthesis

Estrogen-modulated Estrogen Receptor·Pit-1 Protein Complex Formation and Prolactin Gene Activation Require Novel Protein Synthesis

Differential regulation by estrogens of growth and prolactin synthesis in pituitary cells suggests that only a small pool of estrogen receptors is required for growth

Protooncogene c-fos Involvement in the Molecular Mechanism of Rat Brain Sexual Differentiation

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