Tombran-Tink J, Lara N, Apricio S E, Potluri P, Gee S, Ma J-X, Chader G, Barnstable C J
Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO, USA.
Exp Eye Res. 2004 May;78(5):945-55. doi: 10.1016/j.exer.2003.12.013.
Both all-trans-retinoic acid (ATRA) and pigment epithelial-derived factor (PEDF) regulate cell proliferation and differentiation. Treatment of human Y-79 retinoblastoma and A-RPE 19 pigment epithelial cells with ATRA increased the levels of PEDF protein and RNA. Endothelial cells from bovine retina and human umbilical cord expressed PEDF and the levels were also increased by ATRA. Mouse Müller glial cells and rat C6 glioma cells showed at least a 2.5 fold increase in PEDF RNA levels after ATRA treatment, as measured by quantitative PCR. The PEDF promoter contains a retinoic acid receptor element (RARE). Plasmids containing a PEDF promoter regulating a luciferase gene were transfected into D407 and C6 cells and the luciferase activity measured after incubation in the presence or absence of ATRA. In both cell types ATRA increased the level of luciferase activity suggesting the RARE is functional. Dexamethasone was also effective at increasing PEDF RNA levels in both mouse Muller glial cells and C6 rat glioma cells. To test the effects of PEDF on retinoic acid function, expression of retinoic acid receptors in Y-79 and A-RPE 19 cells was measured by PCR. In Y79 cells, PEDF treatment increased the expression levels of RARalpha and RXRgamma receptors and in the A-RPE 19 cells it resulted in a decrease in expression of the RARbeta and RXRbeta receptors. This study clearly indicates an interaction between PEDF and ATRA. The cell differentiation activities of PEDF may operate through mechanisms orchestrated by retinoids, and the converse may also be true. The differentiation, anti-mitotic, and apoptotic actions of PEDF and ATRA may utilize parallel pathways that converge at key junctional transduction molecules to coordinate cellular quiescence and maintain tissue mass in the presence of signals that stimulate abnormal cell proliferation. It will be an interesting therapeutic strategy to co-administer PEDF and retinoic acid in developing protocols for neovascular diseases in the eye and in cancer.
全反式维甲酸（ATRA）和色素上皮衍生因子（PEDF）均能调节细胞增殖和分化。用ATRA处理人Y-79视网膜母细胞瘤细胞和A-RPE 19色素上皮细胞，可增加PEDF蛋白和RNA水平。牛视网膜和人脐带的内皮细胞表达PEDF，且ATRA也可使其水平升高。通过定量PCR检测，经ATRA处理后，小鼠Müller胶质细胞和大鼠C6胶质瘤细胞的PEDF RNA水平至少增加了2.5倍。PEDF启动子含有一个视黄酸受体元件（RARE）。将含有调控荧光素酶基因的PEDF启动子的质粒转染到D407和C6细胞中，并在有无ATRA的情况下孵育后测量荧光素酶活性。在这两种细胞类型中，ATRA均增加了荧光素酶活性水平，表明RARE具有功能。地塞米松在增加小鼠Muller胶质细胞和C6大鼠胶质瘤细胞中PEDF RNA水平方面也有效。为了测试PEDF对视黄酸功能的影响，通过PCR检测Y-79和A-RPE 19细胞中视黄酸受体的表达。在Y79细胞中，PEDF处理增加了RARα和RXRγ受体的表达水平，而在A-RPE 19细胞中，它导致RARβ和RXRβ受体的表达减少。这项研究清楚地表明了PEDF和ATRA之间的相互作用。PEDF的细胞分化活性可能通过类视黄醇精心编排的机制发挥作用，反之亦然。PEDF和ATRA的分化、抗有丝分裂和凋亡作用可能利用平行途径，这些途径在关键的连接转导分子处汇聚，以在刺激异常细胞增殖的信号存在的情况下协调细胞静止并维持组织质量。在制定眼部新血管疾病和癌症的治疗方案时，联合使用PEDF和视黄酸将是一种有趣的治疗策略。
