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学科主题: 精神卫生
题名:
ACTH receptor (MC2R) promoter variants associated with infantile spasms modulate MC2R expression and responsiveness to ACTH
作者: 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
发表日期: 2010-02-01
DOI: 10.1097/FPC.0b013e328333a172
卷: 20, 期:2, 页:71-76
收录类别: SCI
文章类型: Article
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
英文摘要:

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.

语种: 英语
所属项目编号: 30770747 ; 7081002 ; 7042024 ; 2003-2037 ; 200802074
项目资助者: National Natural Science Foundation of China ; Beijing Municipal Natural Science Foundation ; Capital Development Foundation of Beijing ; Hygiene Industry-specific Research Projects of China
WOS记录号: WOS:000274306700001
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59787
Appears in Collections:北京大学精神卫生研究所_期刊论文

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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

Recommended Citation:
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.
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