Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Nur77 (Nr4a1) gene, encoding the orphan nuclear receptor NUR77 (NR4A1), is an immediate early response gene whose expression is rapidly induced by a variety of physiologic stimuli. Nur77 is expressed in several organs, including the classic steroidogenic tissues: gonads and adrenal. In MA-10 Leydig cells, NUR77 has been shown to regulate expression of several genes involved in steroidogenesis and male sex differentiation. In Leydig cells, androgen biosynthesis is controlled primarily by the pituitary gonadotropin luteinizing hormone (LH) acting via its receptor (LH-R), which in turn activates the adenylate cyclase/cyclic adenosine monophosphate (cAMP) signaling pathway. Even though Nur77 expression is induced both at the mRNA and protein levels in response to LH/forskolin/cAMP in Leydig cells, the mechanisms involved remain largely unknown. Here, we report that cAMP-mediated induction of Nur77 expression at the protein, mRNA, and promoter levels in MA-10 cells involves different mechanisms. We found that increased NUR77 protein requires transcription and translation, whereas increased Nur77 mRNA does not require de novo protein synthesis, and would therefore rely on transcription factors already present in the cell. In addition, our detailed analysis of the Nur77 promoter in MA-10 cells revealed that distinct regulatory elements are involved in basal and cAMP-induced Nur77 transcription. Finally, we found that maximal cAMP-mediated increase in Nur77 promoter activity involves a Ca(2+)/calmodulin kinase (CaMK)-dependent pathway and that Ca(2+)/calmodulin kinase I regulates Nur77 promoter activity in Leydig cells. Thus, our findings demonstrate the involvement of various mechanisms in the regulation of Nur77 expression in MA-10 Leydig cells, including a previously uncharacterized CaMK pathway.
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PMID:cAMP-induced expression of the orphan nuclear receptor Nur77 in MA-10 Leydig cells involves a CaMKI pathway. 1883 29

Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics.
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PMID:A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. 2452 88