Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, No. 361, Zhongshan East Road, Shijiazhuang 050017, China.
Cell Res. 2011 Oct;21(10):1487-508. doi: 10.1038/cr.2011.34. Epub 2011 Mar 8.
Abnormal proliferation of vascular smooth muscle cells (VSMCs) occurs in hypertension, atherosclerosis and restenosis after angioplasty, leading to pathophysiological vascular remodeling. As an important growth arrest gene, p21 plays critical roles in vascular remodeling. Regulation of p21 expression by retinoic acid receptor (RAR) and its ligand has important implications for control of pathological vascular remodeling. Nevertheless, the mechanism of RAR-mediated p21 expression in VSMCs remains poorly understood. Here, we show that, under basal conditions, RARα forms a complex with histone deacetylase 2 (HDAC2) and Krüppel-like factor 5 (Klf5) at the p21 promoter to inhibit its expression. Upon RARα agonist stimulation, HDAC2 is phosphorylated by CK2α. Phosphorylation of HDAC2, on the one hand, promotes its dissociation from RARα, thus allowing the liganded-RARα to interact with co-activators; on the other hand, it increases its interaction with Klf5, thus leading to deacetylation of Klf5. Deacetylation of Klf5 facilitates its dissociation from the p21 promoter, relieving its repressive effect on the p21 promoter. Interference with HDAC2 phosphorylation by either CK2α knockdown or the use of phosphorylation-deficient mutant of HDAC2 prevents the dissociation of Klf5 from the p21 promoter and impairs RAR agonist-induced p21 activation. Our results reveal a novel mechanism involving a phosphorylation-deacetylation cascade that functions to remove the basal repression complex from the p21 promoter upon RAR agonist treatment, allowing for optimum agonist-induced p21 expression.
血管平滑肌细胞（VSMCs）的异常增殖发生在高血压、动脉粥样硬化和血管成形术后再狭窄中，导致病理生理血管重塑。作为一个重要的生长抑制基因，p21 在血管重塑中起着关键作用。维甲酸受体（RAR）及其配体对 p21 表达的调节对控制病理性血管重塑具有重要意义。然而，RAR 介导的 VSMCs 中 p21 表达的机制仍知之甚少。在这里，我们表明，在基础条件下，RARα 在 p21 启动子处与组蛋白去乙酰化酶 2（HDAC2）和 Krüppel 样因子 5（Klf5）形成复合物，抑制其表达。在 RARα 激动剂刺激下，CK2α 使 HDAC2 磷酸化。一方面，HDAC2 的磷酸化促进其与 RARα 的解离，从而允许配体结合的 RARα 与共激活子相互作用；另一方面，它增加了与 Klf5 的相互作用，从而导致 Klf5 的去乙酰化。Klf5 的去乙酰化有助于其从 p21 启动子解离，从而解除其对 p21 启动子的抑制作用。通过 CK2α 敲低或使用 HDAC2 磷酸化缺陷突变体干扰 HDAC2 的磷酸化，可防止 Klf5 从 p21 启动子解离，并损害 RAR 激动剂诱导的 p21 激活。我们的结果揭示了一种新的机制，涉及一个磷酸化-去乙酰化级联反应，该反应在 RAR 激动剂处理时从 p21 启动子上除去基础抑制复合物，从而实现最佳的激动剂诱导的 p21 表达。
