Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul 143-747, Republic of Korea.
Biochem Biophys Res Commun. 2011 Jan 7;404(1):239-44. doi: 10.1016/j.bbrc.2010.11.100. Epub 2010 Nov 24.
Retinoic acid (RA) plays a role in cancer therapy. However, its long-term treatment is hindered by the acquired resistance which is not fully understood. Our previous study indicated that the transcriptional activity of RA receptor (RAR) is enhanced by association of MED25 with CREB-binding protein (CBP) through the PTOV domain, which is also present in prostate tumor over-expressed protein 1 (PTOV1). Here, we show that MED25 and PTOV1 reciprocally regulate RAR transcriptional activity through competitive bindings to CBP and opposite regulation of CBP recruitment to the RA-responsive gene promoter. Finally, we demonstrate that MED25 and PTOV1 differentially modulate RA sensitivity in cancer cells depending on their expression levels, suggesting a potential molecular mechanism underlying RA resistance which frequently emerges during cancer treatments.
维甲酸（RA）在癌症治疗中发挥作用。然而，其长期治疗受到获得性耐药的阻碍，目前对此还不完全了解。我们之前的研究表明，通过 PTOV 结构域，MED25 与 CREB 结合蛋白（CBP）的结合增强了 RA 受体（RAR）的转录活性，而 PTOV 结构域也存在于前列腺肿瘤过表达蛋白 1（PTOV1）中。在这里，我们表明 MED25 和 PTOV1 通过与 CBP 的竞争性结合以及对 CBP 募集到 RA 反应基因启动子的相反调节，相互调节 RAR 的转录活性。最后，我们证明 MED25 和 PTOV1 根据其表达水平差异调节癌细胞对 RA 的敏感性，这表明在癌症治疗过程中经常出现的 RA 耐药的潜在分子机制。
