Retinoic acid receptor-α up-regulates proopiomelanocortin gene expression in AtT20 corticotroph cells

Uruno, Akira; Saito-Hakoda, Akiko; Yokoyama, Atsushi; Kogure, Naotaka; Matsuda, Ken; Parvin, Rokshana; Shimizu, Kyoko; Sato, Ikuko; Kudo, Masataka; Yoshikawa, Takeo; Kagechika, Hiroyuki; Iwasaki, Yoshinobu; Ito, Sadayoshi; Sugawara, Akira

doi:10.1507/endocrj.ej14-0115

Cited by 11 publications

(12 citation statements)

References 36 publications

(35 reference statements)

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“…Comparison of these isoforms revealed variability in three residues in their ligand binding pocket which may account for the known RAR type selectivity of certain synthetic retinoids [52]. In support of this concept, the synthetic RARα/β agonist Am80 up-regulated POMC gene transcription by increasing NeuroD1 and Tpit expression [53] (Table 1). These apparent contradictory actions of RAR activation to either stimulate or inhibit POMC transcription could be explained by involvement of an RXR homodimer or permissive heterodimer that mediates these complex and mixed RXR/RAR actions [54,55].…”

Section: Retinoic Acid Receptors (Rarα Rarβ Rarγ)mentioning

confidence: 87%

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Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

Zhang

Heaney

2020

Cells

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The hypothalamic–pituitary–adrenal (HPA) axis plays a critical role in adaptive stress responses and maintaining organism homeostasis. The pituitary corticotroph is the central player in the HPA axis and is regulated by a plethora of hormonal and stress related factors that synergistically interact to activate and temper pro-opiomelanocortin (POMC) transcription, to either increase or decrease adrenocorticotropic hormone (ACTH) production and secretion as needed. Nuclear receptors are a family of highly conserved transcription factors that can also be induced by various physiologic signals, and they mediate their responses via multiple targets to regulate metabolism and homeostasis. In this review, we summarize the modulatory roles of nuclear receptors on pituitary corticotroph cell POMC transcription, describe the unique and complex role these factors play in hypothalamic–pituitary–adrenal axis (HPA) regulation and discuss potential therapeutic targets in disease states.

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Section: Retinoic Acid Receptors (Rarα Rarβ Rarγ)mentioning

confidence: 87%

“…RA exerts its biological activities through complicated mechanisms depending on the amount and ratio of tissue-specific metabolite isomers [53]. The retinoic acid receptor (RARα, RARβ, RARγ) and retinoid X receptor (RXRα,RARβ, RXRγ) are the cogent nuclear receptors of retinoic acids [51].…”

Section: Retinoid X Receptors (Rxrα Rxrβ and Rxrγ)mentioning

confidence: 99%

Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

Zhang

Heaney

2020

Cells

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“…Subcloned chimeric constructs containing the rat Pomc genomic DNA and luciferase cDNA (pGL3-Basic, Promega, Madison, WI) were used for the transient transfection studies: r Pomc -Luc (-703/+58-Luc: harboring the rat Pomc 5’-flanking region from -703 to +58 relative to the transcription start site upstream of the luciferase cDNA in pGL3-Basic), -429/+58-Luc; -379/+58-Luc, and -359/+58-luc, and E-box (NeuroD1 binding element) mutant in r Pomc -Luc (r Pomc -Luc-Ebox Neuro -Mut) were described in our previous papers [28,29]. β-galactosidase control plasmid in pRSV (pRSV-β-gal) and in pCMV (pCMV-β-gal) were purchased from Clontech (Mountain View, CA).…”

Section: Methodsmentioning

confidence: 99%

“…AtT20 cells grown to 70% confluence in regular medium in 24-multiwell plates were incubated either without or with DEX at appropriate concentrations in DMEM supplemented with 1% resin and charcoal-treated (stripped) FBS media [28,29] and cultured for 24 hrs. In the overexpression experiments, each expression vector was transfected for 24 hrs before treatment with DEX.…”

Section: Methodsmentioning

confidence: 99%

Role of NeuroD1 on the negative regulation of Pomc expression by glucocorticoid

et al. 2017

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The mechanism of the negative regulation of proopiomelanocortin gene (Pomc) by glucocorticoids (Gcs) is still unclear in many points. Here, we demonstrated the involvement of neurogenic differentiation factor 1 (NeuroD1) in the Gc-mediated negative regulation of Pomc. Murine pituitary adrenocorticotropic hormone (ACTH) producing corticotroph tumor-derived AtT20 cells were treated with dexamethasone (DEX) (1–100 nM) and cultured for 24 hrs. Thereafter, Pomc mRNA expression was studied by quantitative real-time PCR and rat Pomc promoter (-703/+58) activity was examined by luciferase assay. Both Pomc mRNA expression and Pomc promoter activity were inhibited by DEX in a dose-dependent manner. Deletion and point mutant analyses of Pomc promoter suggested that the DEX-mediated transcriptional repression was mediated via E-box that exists at -376/-371 in the promoter. Since NeuroD1 is known to bind to and activate E-box of the Pomc promoter, we next examined the effect of DEX on NeuroD1 expression. Interestingly, DEX dose-dependently inhibited NeuroD1 mRNA expression, mouse NeuroD1 promoter (-2.2-kb) activity, and NeuroD1 protein expression in AtT20 cells. In addition, we confirmed the inhibitory effect of DEX on the interaction of NeuroD1 and E-box on Pomc promoter by chromatin immunoprecipitation (ChIP) assay. Finally, overexpression of mouse NeuroD1 could rescue the DEX-mediated inhibition of Pomc mRNA expression and Pomc promoter activity. Taken together, it is suggested that the suppression of NeuroD1 expression and the inhibition of NeuroD1/E-box interaction may play an important role in the Gc-mediated negative regulation of Pomc.

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“…In a separate laboratory study by Uruno et al, the role of the retinoic acid receptor was examined in greater detail. 53 Surprisingly, the authors found that the retinoic acid receptor interacts closely with NeuroD1 and Tpit expression and resulted in increased POMC mRNA expression, ACTH secretion, and POMC promoter activity. These findings are contradictory to those in earlier studies.…”

Section: Molecular Biology and Future Targeted Therapy For CDmentioning

confidence: 98%

Cushing's disease: current medical therapies and molecular insights guiding future therapies

Lau

Rutledge²,

Aghi³

2015

FOC

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OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD. METHODS A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase “(name of agent) and Cushing's” was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review. RESULTS A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%–100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth. CONCLUSIONS Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.

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Retinoic acid receptor-α up-regulates proopiomelanocortin gene expression in AtT20 corticotroph cells

Cited by 11 publications

References 36 publications

Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

Nuclear Receptors as Regulators of Pituitary Corticotroph Pro-Opiomelanocortin Transcription

Role of NeuroD1 on the negative regulation of Pomc expression by glucocorticoid

Cushing's disease: current medical therapies and molecular insights guiding future therapies

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