|ACTH receptor (MC2R) promoter variants associated with infantile spasms modulate MC2R expression and responsiveness to ACTH|
|Ding, Ying-Xue1,2; Zou, Li-Ping1,2; He, Bing5; Yue, Wei-Hua3,4; Liu, Zhan-Li1; Zhang, Dai3,4|
|关键词||adrenocorticotropin hormone infantile spasms melanocortin 2 receptor promoter variants responsiveness|
|刊名||PHARMACOGENETICS AND GENOMICS|
|WOS标题词||Science & Technology|
|类目[WOS]||Biotechnology & Applied Microbiology ; Genetics & Heredity ; Pharmacology & Pharmacy|
|研究领域[WOS]||Biotechnology & Applied Microbiology ; Genetics & Heredity ; Pharmacology & Pharmacy|
|关键词[WOS]||GENE-EXPRESSION ; MESSENGER-RNA ; ADRENOCORTICAL-CELLS ; CORTICOTROPIN ; MECHANISMS ; PROTEIN|
Objective Adrenocorticotropin hormone (ACTH) has been the standard treatment to infantile spasms (IS). However, the mechanism of ACTH therapy is still unclear. ACTH exerts the function via melanocortin 2 receptor (MC2R). Our previous study showed a common 4-single nucleotide polymorphism (SNP) haplotype TCCT at the MC2R promoter was strongly associated with responsiveness to ACTH therapy, where these 4 SNPs [rs1893219, rs1893220, rs2186944, and a novel SNP (T>C)] were mapped at position -853, -759, -7, and -2 bp based on the transcription start site of the MC2R gene. In this study, we further elucidated functional significances of the TCCT haplotype.
Methods To evaluate whether the TCCT haplotype influences MC2R transcription levels, the luciferase reporter vector was used by a transient transfection. Expression of rat MC2R cDNA driven by the TCCT-carrying or TCCC-carrying promoter was detected by the real-time quantitative reverse transcription-PCR. These assays were performed on cell lines cultured in absence or presence of ACTH.
Results In the baseline, the light intensity of the luciferase reporter assay driven by the TCCT promoter was four times higher than that by the TCCC promoter. The intensity was dramatically increased in the pGL3-TCCT after ACTH stimulation, compared to that in the pGL3-TCCC. MC2R expression assay showed a 5-fold increase in the TCCT promoter in presence of ACTH, compared with that in absence of ACTH.
Conclusion The results showed that the haplotype TCCT in MC2R promoter significantly led to increased MC2R expression and strong responses to ACTH, providing evidence of the molecular mechanism of ACTH therapy in IS. Pharmacogenetics and Genomics 20:71-76 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
|项目编号||30770747 ; 7081002 ; 7042024 ; 2003-2037 ; 200802074|
|资助机构||National Natural Science Foundation of China ; Beijing Municipal Natural Science Foundation ; Capital Development Foundation of Beijing ; Hygiene Industry-specific Research Projects of China|
|作者单位||1.Chinese Peoples Liberat Army Gen Hosp, Dept Pediat, Beijing 100853, Peoples R China|
2.Capital Med Univ, Dept Neurol, Beijing Childrens Hosp, Beijing, Peoples R China
3.Peking Univ, Inst Mental Hlth, Beijing 100871, Peoples R China
4.Minist Hlth, Key Lab Mental Hlth, Beijing, Peoples R China
5.Karolinska Inst, Div Matrix Biol, Dept Med Biochem & Biophys, Stockholm, Sweden
|Ding, Ying-Xue,Zou, Li-Ping,He, Bing,et al. ACTH receptor (MC2R) promoter variants associated with infantile spasms modulate MC2R expression and responsiveness to ACTH[J]. PHARMACOGENETICS AND GENOMICS,2010,20(2):71-76.|
|APA||Ding, Ying-Xue,Zou, Li-Ping,He, Bing,Yue, Wei-Hua,Liu, Zhan-Li,&Zhang, Dai.(2010).ACTH receptor (MC2R) promoter variants associated with infantile spasms modulate MC2R expression and responsiveness to ACTH.PHARMACOGENETICS AND GENOMICS,20(2),71-76.|
|MLA||Ding, Ying-Xue,et al."ACTH receptor (MC2R) promoter variants associated with infantile spasms modulate MC2R expression and responsiveness to ACTH".PHARMACOGENETICS AND GENOMICS 20.2(2010):71-76.|