Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
J Am Coll Cardiol. 2013 Jan 15;61(2):143-7. doi: 10.1016/j.jacc.2012.08.1020. Epub 2012 Nov 28.
Because post-transcriptional mechanisms modulate levels of p16 (encoded by CDKN2A) and p15 (encoded by CDKN2B), we tested whether interferon-γ regulates the expression of these proteins and the effect of the 9p21 genotype.
The mechanism whereby the common variant at chromosome 9p21.3 confers risk for coronary artery disease (CAD) remains uncertain. A recent report proposed that 9p21.3 confers differential activation of adjacent genes in response to interferon-γ, and reported that mRNA levels of CDKN2B are reduced in response to interferon-γ.
Human umbilical vein endothelial cells (HUVECs), aortic smooth muscle cells, HeLa cells, HEK293 cells, and 16 human lymphoblastoid cell lines, all genotyped for the 9p21.3 locus, were treated with interferon-γ and analyzed by immunoblot.
In all cells tested--except HUVECs where expression was not modulated by interferon-γ--regardless of 9p21.3 genotype, interferon-γ increased the expression of p16 and p15. Northern blot analysis confirmed that interferon-γ has little effect on mRNA levels of CDKN2A and CDKN2B.
The 9p21.3 risk genotype does not affect the activation of cyclin-dependent kinase inhibitors p15 and p16 by interferon-γ. Thus, another mechanism is likely to account for the CAD risk associated with this locus.
由于转录后机制调节 p16（由 CDKN2A 编码）和 p15（由 CDKN2B 编码）的水平，我们测试了干扰素-γ 是否调节这些蛋白的表达以及 9p21 基因型的影响。
染色体 9p21.3 上常见变异体赋予冠心病（CAD）风险的机制仍不清楚。最近的一份报告提出，9p21.3 赋予相邻基因对干扰素-γ的反应的差异激活，并且报告说 CDKN2B 的 mRNA 水平响应干扰素-γ而降低。
用人脐静脉内皮细胞（HUVEC）、主动脉平滑肌细胞、HeLa 细胞、HEK293 细胞和 16 个人类淋巴母细胞系，所有这些细胞均对 9p21.3 基因座进行基因分型，用干扰素-γ处理并进行免疫印迹分析。
在所有测试的细胞中 - 除了 HUVEC 细胞，干扰素-γ对其表达没有调节作用 - 无论 9p21.3 基因型如何，干扰素-γ均增加了 p16 和 p15 的表达。Northern 印迹分析证实干扰素-γ对 CDKN2A 和 CDKN2B 的 mRNA 水平几乎没有影响。
9p21.3 风险基因型不会影响干扰素-γ对细胞周期蛋白依赖性激酶抑制剂 p15 和 p16 的激活。因此，可能还有另一种机制可以解释与该基因座相关的 CAD 风险。
