Wang Fang, Zhu Yu, Huang Yan, McAvoy Sarah, Johnson William B, Cheung Tak Hong, Chung Tony Kwok Hung, Lo Keith Wing Kit, Yim So Fan, Yu May M Y, Ngan Hextan Y S, Wong Yick Fu, Smith David I
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Oncogene. 2005 Jun 2;24(24):3875-85. doi: 10.1038/sj.onc.1208546.
Human Kruppel-like factor 2 (KLF2) is a Cys(2)/His(2) zinc-finger-containing transcriptional factor, which is involved in multiple cellular pathways. Utilizing gene expression profiling to identify aberrantly expressed genes in ovarian cancer, we found that KLF2 was significantly and specifically downregulated in ovarian tumors. After reintroducing KLF2 into ovarian cancer cell lines, we observed decreased cell growth and increased sensitivity to DNA damage-induced apoptosis. Analysis of genes that could be potential targets of KLF2 revealed that KLF2 negatively regulated WEE1 expression. WEE1 encodes a tyrosine kinase that regulates the G2/M cell cycle transition. Expression of KLF2 markedly repressed the transcription of WEE1 by directly binding to an SP1/CPBP motif located between -252 bp and the start codon of the WEE1 promoter. Both activation and zinc-finger domains of KLF2 were required for this suppression of Wee1 expression. In addition, we demonstrated that Wee1 expression prevents cancer cells from undergoing apoptosis in response to DNA damage; however, this resistance was abolished by coexpression of KLF2, which inhibits WEE1 transcription. Thus, the level of WEE1 is regulated by KLF2 and enhanced KLF2 expression sensitizes cells to DNA damage-induced apoptosis.
人类 Kruppel 样因子 2（KLF2）是一种含 Cys(2)/His(2)锌指结构的转录因子，参与多种细胞信号通路。通过基因表达谱分析以鉴定卵巢癌中异常表达的基因，我们发现 KLF2 在卵巢肿瘤中显著且特异性地下调。将 KLF2 重新导入卵巢癌细胞系后，我们观察到细胞生长减缓，且对 DNA 损伤诱导的凋亡敏感性增加。对可能是 KLF2 潜在靶标的基因分析表明，KLF2 负向调节 WEE1 的表达。WEE1 编码一种调节 G2/M 细胞周期转换的酪氨酸激酶。KLF2 的表达通过直接结合位于 WEE1 启动子 -252 bp 与起始密码子之间的 SP1/CPBP 基序，显著抑制 WEE1 的转录。KLF2 的激活域和锌指结构域对于这种对 Wee1 表达的抑制都是必需的。此外，我们证明 Wee1 的表达可防止癌细胞在 DNA 损伤时发生凋亡；然而，这种抗性可通过共表达抑制 WEE1 转录的 KLF2 而消除。因此，WEE1 的水平受 KLF2 调控，增强 KLF2 的表达可使细胞对 DNA 损伤诱导的凋亡敏感。
