CONTEXT: ACTH stimulates adrenocortical steroid production through the melanocortin 2 receptor (MC2R). MC2R trafficking and signaling are dependent on the MC2R accessory protein (MRAP). The MRAP homolog MRAP2 also transports the MC2R to the cell surface but might prevent activation. OBJECTIVE: The objective of the investigation was to study the regulatory pathways of MRAP and MRAP2 and their contributions to ACTH responsiveness in human adrenal tissues. DESIGN AND SETTING: MRAP, MRAP2, and MC2R expression levels were studied in 32 human adrenocortical samples. Regulation of these mRNAs was investigated in 43 primary adrenal cultures, stimulated with ACTH, forskolin, angiotensin II (AngII), phorbol-12-myristate-13-acetate (PMA), or dexamethasone. The induction of cortisol, cAMP, and ACTH-responsive genes after treatment with ACTH was related to MRAP, MRAP2, and MC2R expression levels. RESULTS: MRAP and MRAP2 levels were lower in adrenocortical carcinomas (ACC) than in other adrenal tissues (P < 0.001). Patient ACTH and cortisol levels were associated with adrenal levels of MRAP and MC2R in adrenal hyperplasia samples (P < 0.05) but not in tumors. ACTH induced the expression of MRAP 11 ± 2.1-fold and MC2R 20 ± 3.8-fold in all adrenal tissue types (mean ± SEM, both P < 0.0001), whereas AngII augmented these mRNAs 4.0 ± 1.2-fold and 12.6 ± 3.2-fold (P < 0.0001) in all but the ACC. MRAP2 expression was suppressed by forskolin (-24 ± 15%, P = 0.013) and PMA (-22 ± 7%, P = 0.0007). MRAP, MRAP2, or MC2R levels were not associated with the induction of cortisol, cAMP, or gene expression by ACTH in vitro. CONCLUSION: MRAP and MC2R expression is induced by ACTH and AngII, which would facilitate cell surface receptor availability. Physiological expression levels of MRAP, MRAP2, and MC2R were not limiting for ACTH sensitivity.
CONTEXT: ACTH stimulates adrenocorticalsteroid production through the melanocortin 2 receptor (MC2R). MC2R trafficking and signaling are dependent on the MC2R accessory protein (MRAP). The MRAP homolog MRAP2 also transports the MC2R to the cell surface but might prevent activation. OBJECTIVE: The objective of the investigation was to study the regulatory pathways of MRAP and MRAP2 and their contributions to ACTH responsiveness in human adrenal tissues. DESIGN AND SETTING:MRAP, MRAP2, and MC2R expression levels were studied in 32 humanadrenocortical samples. Regulation of these mRNAs was investigated in 43 primary adrenal cultures, stimulated with ACTH, forskolin, angiotensin II (AngII), phorbol-12-myristate-13-acetate (PMA), or dexamethasone. The induction of cortisol, cAMP, and ACTH-responsive genes after treatment with ACTH was related to MRAP, MRAP2, and MC2R expression levels. RESULTS:MRAP and MRAP2 levels were lower in adrenocortical carcinomas (ACC) than in other adrenal tissues (P < 0.001). PatientACTH and cortisol levels were associated with adrenal levels of MRAP and MC2R in adrenal hyperplasia samples (P < 0.05) but not in tumors. ACTH induced the expression of MRAP 11 ± 2.1-fold and MC2R 20 ± 3.8-fold in all adrenal tissue types (mean ± SEM, both P < 0.0001), whereas AngII augmented these mRNAs 4.0 ± 1.2-fold and 12.6 ± 3.2-fold (P < 0.0001) in all but the ACC. MRAP2 expression was suppressed by forskolin (-24 ± 15%, P = 0.013) and PMA (-22 ± 7%, P = 0.0007). MRAP, MRAP2, or MC2R levels were not associated with the induction of cortisol, cAMP, or gene expression by ACTH in vitro. CONCLUSION:MRAP and MC2R expression is induced by ACTH and AngII, which would facilitate cell surface receptor availability. Physiological expression levels of MRAP, MRAP2, and MC2R were not limiting for ACTH sensitivity.
Authors: Jennifer B Permuth; Ailith Pirie; Y Ann Chen; Hui-Yi Lin; Brett M Reid; Zhihua Chen; Alvaro Monteiro; Joe Dennis; Gustavo Mendoza-Fandino; Hoda Anton-Culver; Elisa V Bandera; Maria Bisogna; Louise Brinton; Angela Brooks-Wilson; Michael E Carney; Georgia Chenevix-Trench; Linda S Cook; Daniel W Cramer; Julie M Cunningham; Cezary Cybulski; Aimee A D'Aloisio; Jennifer Anne Doherty; Madalene Earp; Robert P Edwards; Brooke L Fridley; Simon A Gayther; Aleksandra Gentry-Maharaj; Marc T Goodman; Jacek Gronwald; Estrid Hogdall; Edwin S Iversen; Anna Jakubowska; Allan Jensen; Beth Y Karlan; Linda E Kelemen; Suzanne K Kjaer; Peter Kraft; Nhu D Le; Douglas A Levine; Jolanta Lissowska; Jan Lubinski; Keitaro Matsuo; Usha Menon; Rosemary Modugno; Kirsten B Moysich; Toru Nakanishi; Roberta B Ness; Sara Olson; Irene Orlow; Celeste L Pearce; Tanja Pejovic; Elizabeth M Poole; Susan J Ramus; Mary Anne Rossing; Dale P Sandler; Xiao-Ou Shu; Honglin Song; Jack A Taylor; Soo-Hwang Teo; Kathryn L Terry; Pamela J Thompson; Shelley S Tworoger; Penelope M Webb; Nicolas Wentzensen; Lynne R Wilkens; Stacey Winham; Yin-Ling Woo; Anna H Wu; Hannah Yang; Wei Zheng; Argyrios Ziogas; Catherine M Phelan; Joellen M Schildkraut; Andrew Berchuck; Ellen L Goode; Paul D P Pharoah; Thomas A Sellers Journal: Hum Mol Genet Date: 2016-07-04 Impact factor: 6.150
Authors: Ben Gibbison; Francesca Spiga; Jamie J Walker; Georgina M Russell; Kirsty Stevenson; Yvonne Kershaw; Zidong Zhao; David Henley; Gianni D Angelini; Stafford L Lightman Journal: Crit Care Med Date: 2015-04 Impact factor: 7.598
Authors: Johannes Hofland; Leo J Hofland; Peter M van Koetsveld; Jacobie Steenbergen; Wouter W de Herder; Casper H van Eijck; Ronald R de Krijger; Francien H van Nederveen; Maarten O van Aken; Johannes W de Groot; Thera P Links; Frank H de Jong; Richard A Feelders Journal: Orphanet J Rare Dis Date: 2013-09-13 Impact factor: 4.123