Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The treatment of Cushing's disease is very complex and represents a challenge for clinicians. Transphenoidal surgical excision of adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma remains the treatment of choice but, unfortunately, the rate of cure at long-term follow-up is suboptimal and recurrences are high, even in the hands of skilled neurosurgeons. Other treatment options, such as bilateral adrenalectomy and pituitary radiotherapy, are currently in use but no treatment has proven fully satisfactory during the lengthy progress of this chronic and devastating disease. Nelson's syndrome and hypopituitarism are of particular concern as affected patients need lifelong hormone-replacement therapy and have notably increased mortality. Although medical treatment represents a second-line treatment option in patients with Cushing's disease, so far pharmacological therapy has been considered a transient and palliative treatment. Many drugs have been employed: they may act at the hypothalamic-pituitary level, decreasing ACTH secretion; at the adrenal level, inhibiting cortisol synthesis (steroidogenesis inhibitors); or at the peripheral level by competing with cortisol (glucocorticoid receptor antagonists). Recently, there has been renewed interest in the medical therapy of Cushing's disease and pituitary-directed drugs include old compounds commercially available for other diseases, such as cabergoline, and new promising compounds, such as pasireotide (SOM230) or retinoic acid. This review focuses on the tumor-directed pharmacological approaches for the management of Cushing's disease based on the recent identification of possibile targets at a pituitary level.
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PMID:Pituitary-directed medical treatment of Cushing's disease. 3074 97

Retinoic acid (RA), an active metabolite of Vitamin A, and bone morphogenetic protein 4 (BMP-4) pathways control the transcription of pro-opiomelanocortin (Pomc), the precursor of ACTH. We describe a novel mechanism by which RA and BMP-4 act together in the context of pituitary corticotroph tumoral cells to regulate Pomc transcription. BMP-4 and RA exert a potentiated inhibition on Pomc gene expression. This potentiation of the inhibitory action on Pomc transcription was blocked by the inhibitory SMADs of the BMP-4 pathway (SMAD6 and SMAD7), a negative regulator of BMP-4 signaling (TOB1) and a blocker of RA pathway (COUP-TFI). AtT-20 corticotrophinoma cells express RA receptors (RARB, RXRA and RXRG) which associate with factors of BMP-4 (SMAD4 and SMAD1) signaling cascade in transcriptional complexes that block Pomc transcription. COUP-TFI and TOB1 disrupt these complexes. Deletions and mutations of the Pomc promoter and a specific DNA-binding assay show that the complexes bind to the RARE site in the Pomc promoter. The enhanced inhibitory interaction between RA and BMP-4 pathways occurs also in another relevant corticotroph gene promoter, the corticotropin-releasing hormone receptor 1 (Crh-r1). The understanding of the molecules that participate in the control of corticotroph gene expression contribute to define more precise targets for the treatment of corticotrophinomas.
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PMID:Crosstalk of BMP-4 and RA signaling pathways on Pomc gene regulation in corticotrophs. 3139 4


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