Estrogen Receptor (ER)-α, but Not ER-β, Mediates Regulation of the Insulin-like Growth Factor I Gene by Antiestrogens

Fournier, Brigitte; Gutzwiller, Sabine; Dittmar, Tanja; Matthias, Gabriele; Steenbergh, P. H.; Matthias, Patrick

doi:10.1074/jbc.m105418200

Cited by 49 publications

(24 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Experimental data have indeed shown that TAM suppresses liver IGF-I gene expression (19) and that IGF-I promoter on the hepatocyte cell line Hep3B is transcriptionally regulated by RAL after transfection with estrogen alpha-receptor (20).…”

Section: Discussionmentioning

confidence: 99%

Raloxifene lowers IGF-I levels in acromegalic women

Attanasio

Barausse

Cozzi

2003

European Journal of Endocrinology

View full text Add to dashboard Cite

Background: IGF-I suppression in acromegaly obtained by tamoxifen, a selective estrogen receptor modulator (SERM), prompted us to evaluate the effects of the administration of a newer SERM, raloxifene (RAL), devoid of estrogenic activity at uterine level, on GH/IGF-I levels in patients with this disease. Patients: Thirteen post-menopausal acromegalic women (aged 55-84 years) with active acromegaly entered a prospective open pilot study of RAL treatment at 60 mg/day. Nine of the patients, who were resistant to somatostatin analog and dopamine agonist treatment, were not undertaking therapy; the other four, who were partially sensitive to medical treatment, maintained treatment at the maximally effective dosages throughout the study. Results: IGF-I levels fell significantly from 444 (median, interquartile 393-590) mg/l to 300 (216 -608) mg/l ðP ¼ 0:0192Þ after 1 month of RAL administration and this fall remained stable up to the final evaluation at 5^1 months from the start of RAL treatment (260 (187-410) mg/l). An IGF-I decrease greater than 30% of basal values was observed in 10 patients (mainly in patients with IGF-I levels lower than 600 mg/l) and normal values were reached in seven (54%). GH levels did not change (basal 6 (4.1 -8) mg/l, final 5.5 (3.2-7.4) mg/l). The clinical picture improved in patients sensitive to RAL. RAL withdrawal was followed by the return of IGF-I levels to pretreatment values within 8 weeks in all patients. Conclusions: RAL decreases IGF-I levels in most acromegalic women with mild or intermediate disease (i.e. with values lower than 600 mg/l) and normalizes it in many. A prospective randomized study in patients resistant or partially sensitive to other medical treatments is warranted.

show abstract

Section: Discussionmentioning

confidence: 99%

Raloxifene lowers IGF-I levels in acromegalic women

Attanasio

Barausse

Cozzi

2003

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Furthermore, the release of IGF-I into luminal fluid was abolished by ICI 182,780 treatment, demonstrating an ER-mediated regulation of IGF-I production and secretion. Although ICI 182,780 usually results in an attenuated cellular response of E 2 via antagonism at both ER subtypes (21), extensive work has been performed suggesting that estrogen-mediated regulation of IGF-I is mainly through ER␣ and not through ER␤ in culture cell lines in vitro (13,62) and in rat uterus in vivo (27). Thus our findings indicate that the functional significance of ER␣ is closely related to IGF-I regulation in mouse fallopian tube tissues and fluid in vivo.…”

Section: Discussionmentioning

confidence: 99%

Dynamic regulation of estrogen receptor-α isoform expression in the mouse fallopian tube: mechanistic insight into estrogen-dependent production and secretion of insulin-like growth factors

Shao

Egecioglu²,

Weijdegård³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Estrogen receptors (ERs) are members of the nuclear receptor superfamily and are involved in regulation of fallopian tube functions (i.e., enhancement of protein secretion, formation of tubal fluid, and regulation of gamete transport). However, the ER subtype-mediated mechanisms underlying these processes have not been completely clarified. Recently, we identified ER␤ expression and localization in rat fallopian tubes, suggesting a potential biological function of ER␤ related to calcium-dependent ciliated beating. Here we provide for the first time insight into the less studied ER␣ isoforms, which mediate estrogen-dependent production and secretion of IGFs in vivo. First, Western blot studies revealed that three ER␣ isoforms were expressed in mouse fallopian tubes. Subsequent immunohistochemical analysis showed that ER␣ was detected in all cell types, whereas ER␤ was mainly localized in ciliated epithelial cells. Second, ER␣ isoform levels were dramatically downregulated in mouse fallopian tubes by treatment with E2 or PPT, an ER␣ agonist, in a time-dependent manner. Third, the presence of ICI 182,780, an ER antagonist, blocked the E2-or PPT-induced downregulation of tubal ER␣ isoform expression in mice. However, alteration of ER␣ immunoreactivity following ICI 182,780 treatment was only detected in epithelial cells of the ampullary region. Fourth, changes in ER␣ isoform expression were found to be coupled to multiple E2 effects on tubal growth, protein synthesis, and secretion in mouse fallopian tube tissues and fluid. In particular, E 2 exhibited positive regulation of IGF-I and IGF-II protein levels. Finally, using growth hormone receptor (GHR) gene-disrupted mice, we showed that regulation by E 2 of IGF production was independent of GHinduced GHR signaling in mouse fallopian tubes in vivo. These data, together with previous studies from our laboratory, suggest that the long-term effects of estrogen agonist promote IGF synthesis and secretion in mouse tubal epithelial cells and fallopian tube fluid via stimulation of ER␣.estrogen receptor-␣ isoforms; tubal epithelial cells A CRITICAL FUNCTION of the mammalian fallopian tube (24) is to provide an optimal microenvironment for the necessary transport and maturation of gametes and the establishment of pregnancy. It excretes the intraluminal tubal fluid, containing a number of growth factors (1,4,29,30,34). Compelling evidence suggests that estrogen may be involved in the regulation of biological processes in the fallopian tube. Studies have shown that ovarian-derived estradiol (E 2 ), the principal bioactive estrogen, is involved in the regulation of tubal protein secretion in human fallopian tubes in vivo (34) and in vitro (63). Insulin-like growth factors (IGFs) have been identified in human and rodent fallopian tube fluid (4). Accumulating data suggest that IGF-I may support embryonic development and survival (1). Moreover, E 2 has been shown to increase endogenous IGF-I mRNA levels in rat fallopian tube and uterus (5, 46), and estrogen-responsive elements are...

show abstract

“…Animals with null mutations in genes for either ER or ER show distinct skeletal abnormalities (Korach et al 1996, Lindberg et al 2001, Windahl et al 2001. Furthermore, distinct signal pathways can be activated by ER and ER (Jones et al 1999, Shapiro et al 2000, Fournier et al 2001. In terms of responses in differentiating osteoblastic cells, a recent report documents distinct regulation by ER or ER in stably transfected immortalized fetal osteoblastic cells resulting in differing regulation of select genes (Waters et al 2001).…”

Section: Figurementioning

confidence: 99%

Osteoblast differentiation influences androgen and estrogen receptor-alpha and -beta expression

Wiren

Evans²,

Xw³

2002

Journal of Endocrinology

View full text Add to dashboard Cite

Significant levels of estrogen and androgens circulate in men and women, and both play an important role in bone metabolism. While it is well established that either estrogen or androgen replacement therapy is effective at ameliorating bone loss associated with hypogonadism, recent evidence nevertheless suggests that estrogen and androgens have distinct molecular actions on the skeleton. In this study, we have employed normal rat calvarial osteoblast cultures to characterize relative expression profiles of estrogen (ER and ER ) and androgen receptors (AR) during osteoblast differentiation. Normal osteoblast cultures can proceed through in vitro differentiation with distinct stages of proliferation, matrix maturation and mineralization in the appropriate differentiation medium containing ascorbic acid. Expression profiles of AR, ER and ER in primary cultures during osteoblast differentiation were characterized both by semi-quantitative relative RT-PCR and by Western analysis. In cultures induced to differentiate by growth in the presence of ascorbic acid, the expression profile for each receptor was unique during the course of differentiation. ER levels were elevated during matrix maturation and then declined during mineralization. ER expression was relatively constant throughout differentiation, exhibiting more constitutive expression. In contrast, AR levels were lowest during proliferation, and then increased throughout differentiation with highest levels in the most mature mineralizing cultures. Since steroid hormone action is generally mediated by specific cognate receptors, these results suggest that androgen actions may target cells during the mineralization stage of osteoblast differentiation, while estrogen action through either receptor isoform is more likely to affect osteoblasts earlier during matrix maturation. Interestingly, sex steroid receptor expression profiles did not exhibit the same patterns of regulation if osteoblast cultures were grown without ascorbic acid in medium that did not support extracellular matrix deposition. Thus, sex steroids may distinctly influence skeletal health by differential modulation of function during osteoblast differentiation.

show abstract

Estrogen Receptor (ER)-α, but Not ER-β, Mediates Regulation of the Insulin-like Growth Factor I Gene by Antiestrogens

Cited by 49 publications

References 37 publications

Raloxifene lowers IGF-I levels in acromegalic women

Raloxifene lowers IGF-I levels in acromegalic women

Dynamic regulation of estrogen receptor-α isoform expression in the mouse fallopian tube: mechanistic insight into estrogen-dependent production and secretion of insulin-like growth factors

Osteoblast differentiation influences androgen and estrogen receptor-alpha and -beta expression

Contact Info

Product

Resources

About