Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
PLoS One. 2013 May 1;8(5):e63187. doi: 10.1371/journal.pone.0063187. Print 2013.
The microtubule-dependent molecular motor KIF23 (Kinesin family member 23) is one of two components of the centralspindlin complex assembled during late stages of mitosis. Formation of this complex is known as an essential step for cytokinesis. Here, we identified KIF23 as a new transcriptional target gene of the tumor suppressor protein p53. We showed that p53 reduces expression of KIF23 on the mRNA as well as the protein level in different cell types. Promoter reporter assays revealed that this repression results from downregulation of KIF23 promoter activity. CDK inhibitor p21(WAF1/CIP1) was shown to be necessary to mediate p53-dependent repression. Furthermore, we identified the highly conserved cell cycle genes homology region (CHR) in the KIF23 promoter to be strictly required for p53-dependent repression as well as for cell cycle-dependent expression of KIF23. Cell cycle- and p53-dependent regulation of KIF23 appeared to be controlled by differential binding of DREAM and MMB complexes to the CHR element. With this study, we describe a new mechanism for transcriptional regulation of KIF23. Considering the strongly supporting function of KIF23 in cytokinesis, its p53-dependent repression may contribute to the prevention of uncontrolled cell growth.
微管依赖性分子马达 KIF23(驱动蛋白家族成员 23)是在有丝分裂后期组装的中心纺锤体复合物的两个组成部分之一。该复合物的形成被认为是胞质分裂的一个必要步骤。在这里,我们确定 KIF23 是肿瘤抑制蛋白 p53 的一个新的转录靶基因。我们表明,p53 在不同细胞类型中均能在 mRNA 和蛋白水平上降低 KIF23 的表达。启动子报告基因检测表明,这种抑制是由于 KIF23 启动子活性的下调所致。CDK 抑制剂 p21(WAF1/CIP1)被证明是介导 p53 依赖性抑制所必需的。此外,我们还鉴定出 KIF23 启动子中高度保守的细胞周期基因同源区(CHR)是 p53 依赖性抑制以及 KIF23 细胞周期依赖性表达所必需的。KIF23 的细胞周期和 p53 依赖性调节似乎受 DREAM 和 MMB 复合物对 CHR 元件的差异结合的控制。通过这项研究,我们描述了 KIF23 转录调节的一种新机制。鉴于 KIF23 在胞质分裂中的重要支持作用,其 p53 依赖性抑制可能有助于防止失控的细胞生长。