Wang Chiung-Min, Liu Runhua, Wang Lizhong, Nascimento Leticia, Brennan Victoria C, Yang Wei-Hsiung
Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
Department of Genetics and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Int J Mol Sci. 2014 Jun 10;15(6):10233-51. doi: 10.3390/ijms150610233.
Transcription factor Forkhead Box Protein M1 (FOXM1) is a well-known master regulator in controlling cell-cycle pathways essential for DNA replication and mitosis, as well as cell proliferation. Among the three major isoforms of FOXM1, FOXM1B is highly associated with tumor growth and metastasis. The activities of FOXM1B are modulated by post-translational modifications (PTMs), such as phosphorylation, but whether it is modified by small ubiquitin-related modifier (SUMO) remains unknown. The aim of the current study was to determine whether FOXM1B is post-translationally modified by SUMO proteins and also to identify SUMOylation of FOXM1B on its target gene transcription activity. Here we report that FOXM1B is clearly defined as a SUMO target protein at the cellular levels. Moreover, a SUMOylation protease, SENP2, significantly decreased SUMOylation of FOXM1B. Notably, FOXM1B is selectively SUMOylated at lysine residue 463. While SUMOylation of FOXM1B is required for full repression of its target genes MiR-200b/c and p21, SUMOylation of FOXM1B is essential for full activation of JNK1 gene. Overall, we provide evidence that FOXM1B is post-translationally modified by SUMO and SUMOylation of FOXM1B plays a functional role in regulation of its target gene activities.
转录因子叉头框蛋白M1（FOXM1）是一种著名的主要调节因子，可控制DNA复制、有丝分裂以及细胞增殖所必需的细胞周期途径。在FOXM1的三种主要亚型中，FOXM1B与肿瘤生长和转移高度相关。FOXM1B的活性受翻译后修饰（PTM）调控，如磷酸化，但它是否被小泛素相关修饰物（SUMO）修饰尚不清楚。本研究的目的是确定FOXM1B是否被SUMO蛋白进行翻译后修饰，并确定FOXM1B在其靶基因转录活性上的SUMO化修饰情况。在此我们报告，在细胞水平上，FOXM1B被明确界定为一种SUMO靶蛋白。此外，一种SUMO化蛋白酶SENP2显著降低了FOXM1B的SUMO化修饰。值得注意的是，FOXM1B在赖氨酸残基463处被选择性SUMO化修饰。虽然FOXM1B的SUMO化修饰对于其靶基因MiR - 200b/c和p21的完全抑制是必需的，但FOXM1B的SUMO化修饰对于JNK1基因的完全激活至关重要。总体而言，我们提供了证据表明FOXM1B被SUMO进行翻译后修饰，且FOXM1B的SUMO化修饰在调控其靶基因活性中发挥功能性作用。
