Functional PPAR-γ receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas

Heaney, Anthony P.; Fernando, Manory; Yong, William H.; Melmed, Shlomo

doi:10.1038/nm784

Cited by 222 publications

(196 citation statements)

References 38 publications

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“…For example, PPAR␥ has been shown to be abundantly expressed in the adrenal gland (40) and this may explain the ability of MC2-R expression to be maintained in SF-1-haploinsufficient mice in which adrenal MC2-R expression is higher in mutant mice than in their wild type siblings (41,42), suggesting the existence of compensatory mechanisms. PPAR␥ expression has also been demonstrated in the human pituitary gland where thiazolidinedione PPAR␥ agonists are a novel therapeutic target for ACTH-secreting adenomas (43,44). The MC2-R is also expressed in the pituitary gland and has been proposed to FIG.…”

Section: The Mmc2-r Promoter Responds To Rxr␣/ppar␥2 In Preadipocytesmentioning

confidence: 99%

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Noon

Clark

King

2004

Journal of Biological Chemistry

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Adrenocorticotropic hormone can stimulate lipolysis and suppress leptin expression in murine adipocytes. These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis. In this study, we have characterized the mc2-r promoter in the murine adipocyte, one of the few extra-adrenal sites of expression and a cell type that lacks steroidogenic factor 1 (SF-1), a transcription factor that is required for mc2-r expression in adrenal cells. Transcriptional regulation of the mc2-r in the absence of SF-1 was investigated by 5 deletion analysis of the murine mc2-r promoter in both undifferentiated and differentiated 3T3-L1 cells. The results revealed the presence of a 59-base pair regulatory region within the promoter containing an adipocytespecific enhancer. The ability of this region to confer enhanced activity in the adipocyte was mapped to a peroxisome proliferator-response element (PPRE)-like sequence that bound to peroxisome proliferator-activated receptor ␥ (PPAR␥) and its heterodimeric partner retinoid X receptor ␣ (RXR␣) in adipocyte nuclear extracts. Co-transfection of PPAR␥2/RXR␣ with the pMC2-R(؊112/؉105)GL3 reporter resulted in transcriptional activation in preadipocytes, and this response required an intact PPRE. Mutation of the PPRE to prevent PPAR␥/RXR␣ binding resulted in a complete abrogation of the pMC2-R(؊112/؉105)GL3 reporter activity in day 3 differentiated 3T3-L1 cells, demonstrating a key role played by this site in regulating MC2-R expression in the murine adipocyte. These data highlight a novel mechanism for mc2-r transcription, which may have significance in both adrenal and extra-adrenal sites of expression.The melanocortin 2 receptor (MC2-R) 1,2 is a seven-transmembrane G-protein coupled receptor best known for its role in the adrenal cortex where it couples the actions of adrenocorticotropic hormone (ACTH) to steroidogenesis and increased glucocorticoid output (1). Although the key role of MC2-R in the hypothalamo-pituitary-adrenal axis has been the focus of the majority of publications to date, it is also expressed in a number of extra-adrenal sites including the murine adipocyte, fetal testis, human skin, and sympathetic ganglia (2-5).Early studies using the murine 3T3-L1 cell line, a widely used model of adipogenesis, demonstrated the appearance of high affinity ACTH binding sites following treatment of growth-arrested cells with a mixture of adipogenic agents including insulin, dexamethasone, and 3-isobutyl-1-methyl-xanthine (6). Subsequent characterization of the melanocortin receptors expressed by 3T3-L1 adipocytes revealed the presence of both the MC2 and MC5-R. However, a pharmacological analysis showed that the actions of ACTH were mediated solely through the MC2-R in this cell line (2). ACTH exerts a potent lipolytic effect on the murine adipocyte via the cAMP pathway (7, 8) and has more recently been shown to suppress the expression and secretion of the appetite regulating hormone leptin in differentiated 3...

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Section: The Mmc2-r Promoter Responds To Rxr␣/ppar␥2 In Preadipocytesmentioning

confidence: 99%

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Noon

Clark

King

2004

Journal of Biological Chemistry

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“…In an in vivo experiment, innoculating mice with corticotroph AtT20 tumour cells, treating with extremely high dose of rosiglitazone (150 mg/kg/day) prevented the development of tumours. In mice with already established corticotroph tumours, rosiglitazone treatment decreased tumour volume in 75% of cases and prevented signs of hypercortisolaemia in all cases, with 75% reduction in ACTH level and 96% reduction in cortisol levels (58). These observations caused great interest but are yet to impact on clinical practice.…”

Section: Ppar-γ Receptor Agonistsmentioning

confidence: 98%

“…In 2002, the nuclear hormone receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ) was identified in ACTH-secreting pituitary tumour (58). In an in vivo experiment, innoculating mice with corticotroph AtT20 tumour cells, treating with extremely high dose of rosiglitazone (150 mg/kg/day) prevented the development of tumours.…”

Section: Ppar-γ Receptor Agonistsmentioning

confidence: 99%

Pharmacological management of Cushing's syndrome: an update

Dang

Trainer

2007

Arq Bras Endocrinol Metab

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The treatment of choice for Cushing's syndrome remains surgical. The role for medical therapy is twofold. Firstly it is used to control hypercortisolaemia prior to surgery to optimize patient's preoperative state and secondly, it is used where surgery has failed and radiotherapy has not taken effect. The main drugs used inhibit steroidogenesis and include metyrapone, ketoconazole, and mitotane. RESUMOManejo Farmacológico da Síndrome de Cushing: Uma Atualização. O tratamento de escolha para a síndrome de Cushing ainda é a cirurgia. O papel da terapia medicamentosa é duplo: ele é usado para controlar o hipercortisolismo antes da cirurgia e otimizar o estado pré-operatório do paciente e, adicionalmente, quando ocorre falha cirúrgica e a radioterapia ainda não se mostrou efetiva. Os principais medicamentos são empregados para inibir a esteroidogênese e incluem: metirapona, cetoconazol e mitotano. Medicamentos visando o eixo hipotálamo-hipofisário têm sido investigados, mas seu papel na prática clínica permanece limitado, embora o agonista PPAR-γ e análogo de somatostatina, som-230 (pasireotídeo), requeira estudos adicionais. A única droga que age perifericamente no receptor glicocorticóide é a mifepristona (RU486). O manejo da síndrome de Cushing deve envolver uma combinação terapêutica atuando em diferentes vias da hipercortisolemia, mas o monitoramento dessa terapia ainda permanece um desafio. (Arq Bras Endocrinol Metab

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“…54 When it comes to canine studies, some phytochemicals, like green tea catechin and ipriflavone, showed a similar bioavailability compared with humans. 32,38 However, the bioavailability of most phytochemicals in dogs has not been studied in detail. In contrast to dietary compounds, Dalvie et al 20 reported that glucuronidation was the primary route of metabolism in humans and dogs when they were administrated the MMP inhibitor CP-544439.…”

Section: Dietary Compounds and Cancer Chemopreventionmentioning

confidence: 99%

Review Paper: Cancer Chemopreventive Compounds and Canine Cancer

2009

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Abstract. Canine cancer has become more prevalent in recent years because of increased life expectancy and greater attention to the health of pets. The range of cancers seen in dogs is as diverse as that in human patients, and despite more intensive therapeutic interventions, fatality rates remain unacceptably high in both species. Chemoprevention is therefore an important means of confronting this disease. Because domestic pets share our environment, greater cross-application and study of the protumorigenic and antitumorigenic factors in our shared environment will benefit all species, leading to the development of new families of less toxic antitumorigenic compounds based on novel and established molecular targets. Currently, the most interesting cancer preventive agents are nonsteroidal antiinflammatory drugs, peroxisome proliferator-activated receptor-c ligands, and dietary compounds. This article provides an overview of what is known about how these agents affect molecular signaling in neoplastic disease, with reference to reported application and/or study in dogs where available.

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Functional PPAR-γ receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas

Cited by 222 publications

References 38 publications

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Pharmacological management of Cushing's syndrome: an update

Review Paper: Cancer Chemopreventive Compounds and Canine Cancer

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