与HIV-1疾病进展相关的CXCL12β 3'非翻译区G801A多态性（rs1801157）的分子表型

Molecular phenotype of CXCL12beta 3'UTR G801A polymorphism (rs1801157) associated to HIV-1 disease progression.

作者信息

Garcia-Moruja Carelia, Rueda Patricia, Torres Carmen, Alcamí José, Luque Francisco, Caruz Antonio

机构信息

Immunogenetics Unit and Human Molecular Pathology Unit, Experimental Biology Department, University of Jaén, Jaén, Spain.

出版信息

Curr HIV Res. 2009 Jul;7(4):384-9. doi: 10.2174/157016209788680543.

DOI:10.2174/157016209788680543

PMID:19601773

Abstract

OBJECTIVE

To investigate the molecular phenotype of the AIDS-onset delaying polymorphism in CXCL12beta 3'UTR (rs1801157).

METHODS

The 3 UTRs of the CXCL12beta isoform containing the A or G polymorphic variants were cloned downstream of the Luciferase gene under the control of the CXCL12 promoter. The plasmids were transfected in U373 and LC5 cells and the polymorphism phenotype was evaluated in terms of Luciferase activity and mRNA stability.

RESULTS

The 3'A genotype compared to 3'G leads to an increased luciferase activity in unstimulated and PMA+Ionomycin treated cells both in astrocytes (p = 0,0002, p = 0,02) and fibroblasts (p = 0,002, p = 0,03). The mRNA containing the 3'A variant have two-fold longer half-life compared to the 3'G variant (p = 6,99E(-7)).

CONCLUSIONS

CXCL12beta 3'A polymorphism, previously associated with resistance to AIDS progression and other diseases, leads to increased levels of CXCL12 mRNA, the results presented here demonstrate that this effect is a consequence of an enhanced mRNA stability. Our data contribute to characterize the CXCL12 as a potential pharmacological target in AIDS, autoimmune diseases and cancer.

摘要

目的

研究趋化因子配体12β（CXCL12β）3'非翻译区（rs1801157）中延缓艾滋病发病的多态性的分子表型。

方法

将含有A或G多态性变体的CXCL12β亚型的3'非翻译区克隆到荧光素酶基因的下游，该荧光素酶基因受CXCL12启动子控制。将质粒转染到U373和LC5细胞中，并根据荧光素酶活性和mRNA稳定性评估多态性表型。

结果

在星形胶质细胞（p = 0.0002，p = 0.02）和成纤维细胞（p = 0.002，p = 0.03）中，与3'G基因型相比，3'A基因型在未刺激的以及经佛波酯（PMA）+离子霉素处理的细胞中均导致荧光素酶活性增加。与3'G变体相比，含有3'A变体的mRNA半衰期延长了两倍（p = 6.99×10⁻⁷）。