Ramharack R, Wyborski R J, Spahr M A
Department of Vascular and Cardiac Diseases, Division of Warner-Lambert Company, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan, 48105, USA.
Biochem Biophys Res Commun. 1998 Apr 7;245(1):194-7. doi: 10.1006/bbrc.1998.8398.
Retinoids were previously shown to lower apolipoprotein(a) [apo(a)] mRNA levels, suggesting that the apo(a) promoter contains a retinoid response element (RRE). Scanning the apo(a) promoter for sequences related to the consensus RRE half-site (5'-PuG(G/T)TCA-3') uncovered four sites that could potentially function as RREs at -2915, -1875, -1036, and -407. The activity of these sites was assessed by their ability to compete with a very strong consensus DR5 RRE for binding to retinoic acid receptor (RARalpha) and retinoid X receptor (RXRalpha) heterodimers using electrophoretic mobility-shift assays. Only the -1036 site (5'-TGACCTTGTGATCC-'3) was an effective competitor of the DR5 RRE; therefore, it was designated as apo(a) RRE. Apo(a) RRE competed with DR5 RRE for RARalpha/RXRalpha binding with 1/10 the affinity of DR5 RRE, while a scrambled apo(a) RRE was inactive. These results suggested that apo(a) RRE is a potential candidate for mediating the effect retinoids have on apo(a) mRNA expression.
维甲酸类化合物先前已被证明可降低载脂蛋白(a)[apo(a)]的mRNA水平,这表明apo(a)启动子含有一个维甲酸反应元件(RRE)。扫描apo(a)启动子中与共有RRE半位点(5'-PuG(G/T)TCA-3')相关的序列,发现了四个可能在-2915、-1875、-1036和-407处作为RRE发挥作用的位点。通过电泳迁移率变动分析,评估这些位点与非常强的共有DR5 RRE竞争结合视黄酸受体(RARα)和视黄酸X受体(RXRα)异二聚体的能力,以此来评估这些位点的活性。只有-1036位点(5'-TGACCTTGTGATCC-'3)是DR5 RRE的有效竞争者;因此,它被指定为apo(a) RRE。Apo(a) RRE与DR5 RRE竞争RARα/RXRα结合,其亲和力为DR5 RRE的1/10,而一个打乱的apo(a) RRE则无活性。这些结果表明,apo(a) RRE是介导维甲酸类化合物对apo(a) mRNA表达影响的潜在候选者。