Disease relevance of Mc2r

• Targeted ablation of pituitary pre-proopiomelanocortin cells by herpes simplex virus-1 thymidine kinase differentially regulates mRNAs encoding the adrenocorticotropin receptor and aldosterone synthase in the mouse adrenal gland [1].
• We have, therefore, examined the expression and function of the ACTH receptor (the melanocortin 2 receptor, MC2-R) in human and mouse primary islet tIssue and in the MIN6 mouse insulinoma cell line [2].
• However, adrenal ACTH-R mRNA, as well as adrenal mass, per unit body weight was greater in FR than in AL rats (diet main effect, P < 0.001) [3].
• For in vitro analyses we co-transfected mouse Y1 adrenocortical carcinoma cells with the luciferase reporter gene vector pGL3 containing full-length constructs of human (h) or mouse (m) ACTH-R promoter together with a DAX-1 expression plasmid [4].
• In non-functional adrenal adenomas and adrenocortical carcinomas, ACTH-R expression is low [4].

Psychiatry related information on Mc2r

• Protein levels of P450c21 and the ACTH receptor were increased in Dax-1(-/Y) mice and intermediate in SF-1(+/-): Dax-1(-/Y) mice following chronic food deprivation [5].

High impact information on Mc2r

• In addition to their antimicrobial and cytotoxic properties, some defensins act as opsonins, while others inhibit protein kinase C, bind specifically to the ACTH receptor and block steroidogenesis or act as selective chemoattractants for monocytes [6].
• That this binding might result from one peptide being an "internal image" of the other was strongly suggested by the observation that antibody to the peptide that was encoded by the complementary RNA for ACTH recognized the adrenal cell ACTH receptor [7].
• Mutation of the PPRE to prevent PPARgamma/RXRalpha 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 [8].
• These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis [8].
• A mutant MC2R in which the single consensus PKA phosphorylation site has been mutated (S208A) when expressed in MC2R-negative Y6 cells is also unable to desensitize [9].

Chemical compound and disease context of Mc2r

• None of the antisera displayed any effect in these assays, nor did they bind to blotted MSH/ACTH receptor protein from Cloudman S91 melanoma cells or to ACTH antibodies [10].

Biological context of Mc2r

• The analysis of the cDNA 5'-end showed an untranslated region of 321 bp, and the ACTH-R gene was demonstrated to be composed of two exons of 113 and 112 bp lying upstream of the single coding exon [11].
• CONCLUSION: MC2-R expression is associated with a less aggressive adrenal tumor phenotype and anti-proliferative effects can be amplified through stimulation with physiological doses of ACTH [12].
• SF1(A172) and SF1(S172) exhibit little or no difference in transcriptional activity in SF1-dependent reporter gene assays, suggesting that SF1(S172) per se is not directly responsible for the loss of MC2R expression [13].
• In this study, we show that a luciferase reporter plasmid driven by 1,800 bp of the proximal promoter region of the MC2R was expressed poorly in the mutant cells compared with parent Y1 cells [14].
• In Crhr1-/- mice, intravenous ACTH administration failed to stimulate corticosterone secretion despite a significant upregulation of ACTH receptor mRNA levels in the adrenal cortex of these mutants [15].

Anatomical context of Mc2r

• Subsequent real-time PCR studies confirmed that Mc2r was expressed in the fetal testis at 100-fold higher levels than in the adult testis [16].
• Using RT-PCR and Northern blot hybridization, high levels of MC2 receptor messenger RNA (mRNA) were found in all adipose tissues examined in the mouse, whereas MC5 receptor mRNA was found in a subset of these [17].
• In conclusion we have cloned a mouse ACTH receptor gene and demonstrated for the first time its expression and functional effect in HeLa cells [18].
• In blood cells, MC5R was detected at all stages examined, while MC2R was detected at none [19].
• MC2R was observed in the brain and spinal cord from E11.5 to E13.5, while MC5R was detected only in the telencephalon and only from E16.5 to E18 [19].

Associations of Mc2r with chemical compounds

• The adrenal cortex showed a strong signal for the ACTH receptor mRNA in both the zona fasciculata and the zona glomerulosa, sites that are involved in the mediation of the action of ACTH on the synthesis and release of glucocorticoids and aldosterone [20].
• Daily administration of dexamethasone (DEX) (0.5 mg/100 g body weight.d) for 6 d in mice, decreased steroidogenic function of adrenal as shown by inhibition of the 36-kDa ACTH receptor protein expression, and decreased plasma corticosterone level [control from 465 +/- 35 ng/ml to 114 +/- 18 ng/ml in DEX group (P < 0.001)] [21].
• ACTH receptor-mediated induction of leukocyte cyclic AMP [22].
• A molecular weight (Mr) of 225 000 was determined for the complete ACTH receptor as analyzed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis [23].
• These data are interpreted to suggest that Y6 and OS3 cells are defective in a process or component that links the principal binding regions of the ACTH receptor to the catalytic subunit of the adenylate cyclase system [24].

Physical interactions of Mc2r

• We have used the chromatin immunoprecipitation assay to examine the temporal formation of ACTH-dependent transcription complexes on the Mc2r gene promoter [25].
• Our results demonstrate that ACTH-dependent signaling cascades modulate the temporal dynamics of SF-1-dependent complex assembly on the Mc2r promoter [25].

Enzymatic interactions of Mc2r

• Presence of functional MC2-R was demonstrated by RT-PCR and Western blot using an antibody for phosphorylated CREB [12].

Regulatory relationships of Mc2r

• We have described a family of adrenocortical tumor cell mutants (including clones OS3, Y6, and 10r9) that are resistant to ACTH because they fail to express the gene encoding the ACTH receptor (MC2R) [13].
• A dominant negative GRK2 inhibited internalization whilst the protein kinase A (PKA) consensus site mutant MC2R (S208A) internalized normally [26].
• ACTH induces c-fos proto-oncogene in fibroblasts expressing the ACTH receptor [27].

Other interactions of Mc2r

• The mouse adrenocorticotropin receptor gene: cloning and characterization of its promoter and evidence for a role for the orphan nuclear receptor steroidogenic factor 1 [11].
• An examination of potential compensatory mechanism(s) revealed an increase in adrenal weight, selective elevation of melanocortin 2 receptor mRNA, and a coincident increase in SRC-2 and SRC-3 expression in SRC-1-/- adrenals [28].
• The melanocortin pathway: effects of voluntary exercise on the melanocortin-4 receptor knockout mice and ACTH(1-24) ligand structure activity relationships at the melanocortin-2 receptor [29].
• Agonist activated adrenocorticotropin receptor internalizes via a clathrin-mediated G protein receptor kinase dependent mechanism [26].
• Apparently, the ACTH-R in Balb 3T3 cells induces the c-fos gene by a pathway independent of cAMP/protein kinase A and ERK/MAP Kinase [27].

Analytical, diagnostic and therapeutic context of Mc2r

• However, ACTH 1-24 treatment of group B and C mice significantly reduced tumor weight in MC2-R positive tumors in a dose dependent manner (P = 0.03), while no significant difference in tumor mass was observed in MC2-R negative tumors [12].
• As demonstrated by semiquantitative RT-PCR, MC2-R mRNA levels increased from E11.5 until birth, while the highest adrenal secretory protease (AsP) expression was detected at E13.5 with a decrease thereafter [30].
• In addition, adrenocorticotropin-hormone (ACTH) receptor (melanocortin-2-receptor (MC2-R)) expression was examined by in situ hybridization (ISH) and co-localized with 3beta-HSD [30].
• The ACTH receptor gene appears to be present in these mutants as determined by Southern blot hybridization analysis and can be activated following the growth of the mutant cells as tumors in mice, suggesting that the ACTH receptor gene is modified in a reversible manner [31].
• Immobilization stress triggered a large increase in MC-2 receptor mRNA in SCG [32].

References