Retinoic acid prevents experimental Cushing syndrome

Páez-Pereda, Marcelo; Kovalovsky, Damián; Hopfner, Úrsula; Theodoropoulou, Marily; Pagotto, Uberto; Uhl, Eberhard; Losa, Marco; Stalla, Johanna; Grübler, Yvonne; Missale, Cristina; Arzt, Eduardo; Stalla, Günter

doi:10.1172/jci200111098

Cited by 30 publications

(36 citation statements)

References 41 publications

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“…In conclusion, following the demonstration of restricted expression of SF-1 in gonadotropes [38, 39], NURR1/NUR77 and COUP-TFI in corticotropes [24], we are showing here that COUP-TFII and EAR-2 constitute two other orphan receptors expressed in the pituitary gland. Their specific expression in lactotropes and up-regulation during pregnancy suggest an important, but yet unknown role in the control of the lactogenic function.…”

Section: Discussionsupporting

confidence: 71%

“…SF-1 is necessary for the differentiation and activity of the gonadotropes [37,38,39], and NURR1/NUR77 are essential factors involved in both positive and glucocorticoid receptor-dependent negative regulations of the POMC gene in the corticotropes [26, 40]. COUP-TFI is found in normal human corticotropes and absent from ACTH-secreting tumors indicating its possible role as an antiproliferative corticotropic factor [24]. In the present study, we have demonstrated that COUP-TFII and EAR-2 expression is predominant in the lactotropes and upregulated during pregnancy, suggesting that they act as regulators of PRL expression.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the role of COUP-TFs in the anterior pituitary gland is still relatively unknown. The expression of COUP-TFI was found in the corticotropes of normal human pituitary gland where it might control retinoic acid-induced cell proliferation [24]. It has also been shown that nuclear receptors NR5A1 (SF-1) [25] and NR4A1 (NUR77) [26] are respectively necessary for the differentiation of the gonadotropes and proopiomelanocortin gene expression in the corticotropes.…”

Section: Introductionmentioning

confidence: 99%

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Cloning, Expression and Regulation of Chicken Ovalbumin Upstream Promoter Transcription Factors (COUP-TFII and EAR-2) in the Rat Anterior Pituitary Gland

Raccurt¹,

Smallwood²,

Mertani³

et al. 2005

Neuroendocrinology

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Chicken ovalbumin upstream promoter transcription factors (COUP-TF)-II (NR2F2) and EAR-2 (NR2F6) are structurally related orphan members of the nuclear receptors superfamily. There are growing evidences that these factors play important roles during processes of differentiation and proliferation of several tissues. To better understand their role in the differentiated adult rat pituitary gland, we cloned COUP-TFII and EAR-2 cDNAs from an anterior pituitary cDNA library. Subsequently, we raised and characterized specific antibodies to the N-terminal domain of both nuclear receptors. We next examined their cellular and subcellular distribution in the pituitary gland and determined their regulation during pregnancy. COUP-TFII and EAR-2 pituitary genes display, respectively, 90 and 100% homologies with their human and mouse homologues. Cellular expression of both nuclear receptors was mainly detected in the lactotropes of male and female rats, with a prominent distribution in the nuclear compartment for EAR-2, and interestingly both proteins were significantly upregulated in pituitaries of pregnant vs. cycling female rats. Thus, our results have characterized cloning of rat pituitary COUP-TFII and EAR-2 genes, demonstrated that they are both specifically expressed in lactotropes, and strongly suggested that they may play an important role in modulating prolactin (PRL) gene expression during pregnancy.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cloning, Expression and Regulation of Chicken Ovalbumin Upstream Promoter Transcription Factors (COUP-TFII and EAR-2) in the Rat Anterior Pituitary Gland

Raccurt¹,

Smallwood²,

Mertani³

et al. 2005

Neuroendocrinology

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“…Corticotropinoma pathogenesis is marked by alterations in factors regulating cell cycle progression, pro-opiomelanocortin (POMC) transcription and ACTH synthesis [4,5,6,7,8,9] that constitute putative drug targets [reviewed in [10]]. Indeed, targeting POMC transcription and corticotropinoma cell viability with retinoic acid was able to reverse Cushing’s disease in experimental animal models [11,12]. In addition, corticotropinoma cells were shown to express dopamine D 2 (D2DR) [13] and somatostatin receptors (SSTR1, 2, 3 and 5) [14,15,16], making them candidates for treatment with dopamine agonists, such as cabergoline and somatostatin analogs, e.g.…”

Section: Introductionmentioning

confidence: 99%

Effect of SOM230 (Pasireotide) on Corticotropic Cells: Action in Dogs with Cushing’s Disease

et al. 2011

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SOM230 (pasireotide) is a multiligand somatostatin (SRIF) analog able to bind to somatostatin receptor (SSTR) subtypes 1, 2, 3 and 5, and trigger antisecretory and antiproliferative signaling cascades. Canines have become in vivo models to test the pharmacological treatment of corticotropinomas because they frequently develop Cushing’s disease in a spontaneous manner, due to adrenocorticotropic hormone (ACTH)-producing pituitary adenomas. Different levels of expression of SSTR2 and SSTR5 have been shown in both mouse AtT20 cells and canine tumoral corticotropinoma cells. The objective of this study was to evaluate whether SOM230 controls both tumor cell growth and hormone synthesis, therefore controlling the disease. SOM230 was tested in dogs suffering from Cushing’s disease (10 animals were treated continuously during 6 months, and another 10 were treated with 3 cycles consisting of 2 months of treatment followed by a 2-month rest period). A significant decrease in ACTH, urinary cortisol creatinine ratio, adenoma size (magnetic nuclear resonance) and improvement of clinical signs were obtained, without side effects. AtT20 cells treated with SOM230 suppressed pro-opiomelanocortin (POMC) promoter activity through SSTR2, via the G_i α-subunit, and reduced Nur77/Nurr1 transcriptional activity. We conclude that SOM230, in addition to its well-described antisecretory effects, inhibits, as shown in AtT20 cells, ACTH synthesis at the POMC transcriptional level, an effect mediated mainly through SSTR2, and limits tumor growth. The controlled Cushing’s disease in the dogs that received the treatment indicates that SOM230 has a potential therapeutic use in humans suffering from Cushing’s disease.

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“…Also, BMP-4 inhibits not only AtT-20 cell proliferation but also c-myc promoter transcriptional activity, showing its inhibitory action on corticotropic cells [32]. Retinoic acid administration has been shown to completely block corticotropic tumor growth and reverses the endocrine alterations and symptoms of Cushing’s disease [41, 42], but this inhibitory mechanism over cell proliferation is still not clear. Moreover, both BMP-4 and retinoic acid inhibit AtT-20 cell proliferation, but there was no further inhibition in the presence of both factors even at low doses suggesting that they may share an overlapping mechanism [32].…”

Section: Gp130 and Bmps Action In The Pituitary Glandmentioning

confidence: 99%

Pituitary Action of Cytokines: Focus on BMP-4 and gp130 Family

et al. 2007

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The anterior pituitary can develop benign tumors of different sizes, classified as micro- and macroadenomas, frequently associated with high levels of hormone production, leading to different associated syndromes like Cushing’s disease, acromegaly or prolactinomas. Much work has been done in order to understand the signaling pathways and the factors and hormones involved in the pituitary tumorigenic process. In recent years, much evidence has been collected and it is now well documented that cytokines of the gp130 family, such as interleukin-6, that use gp130 as a common signaling protein stimulate not only the proliferation but also the hormone secretion of pituitary cells. Experiments in vivo have shown that the overexpression of the gp130 receptor resulted in pituitary abnormal growth. Moreover, it has been recently described that bone morphogenetic protein-4 (BMP-4), a member of the TGF-β family, has a stimulatory role on lactosomatotropic cells promoting the development of prolactinomas but it has an inhibitory action on the corticotropic lineage. This inhibitory action prevents Cushing’s disease progression. Furthermore, BMP-4 mediates the antiproliferative action of retinoic acid in these cells. The present review highlights the most recent work about gp130 and TGF-β cytokine families and their role in pituitary tumorigenesis.

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Retinoic acid prevents experimental Cushing syndrome

Cited by 30 publications

References 41 publications

Cloning, Expression and Regulation of Chicken Ovalbumin Upstream Promoter Transcription Factors (COUP-TFII and EAR-2) in the Rat Anterior Pituitary Gland

Cloning, Expression and Regulation of Chicken Ovalbumin Upstream Promoter Transcription Factors (COUP-TFII and EAR-2) in the Rat Anterior Pituitary Gland

Effect of SOM230 (Pasireotide) on Corticotropic Cells: Action in Dogs with Cushing’s Disease

Pituitary Action of Cytokines: Focus on BMP-4 and gp130 Family

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