Wright State University, Boonshoft School of Medicine, Biochemistry & Molecular Biology Department, 3640 Colonel Glenn Hwy, Dayton, OH 45435, USA.
Am J Cancer Res. 2011;1(1):62-70.
The Fragile Histidine Triad gene or FHIT functions as tumor suppressor in many epithelial cell types. Although its tumor suppressive mechanism is the subject of intense study, less is known about how FHIT gene expression itself is regulated. Here we show that PI3 kinase and its downstream target AKT suppress FHIT gene expression in response to growth factor stimulation in actively cycling cells. Upon removal of mitogens from the culture environment, FHIT mRNA and protein levels are observed to increase as a result of derepression from these protooncogenic kinases. AKT signaling through the FOXO transcription factors appears to be the basis for FHIT gene regulation. Increases in FHIT gene expression are directly dependent on endogenous FOXO3a in MCF7 breast carcinoma cells as evidenced by experiments with RNAi targeting FOXO transcription factor family members. Thus, this is the first report demonstrating that FHIT gene expression is normally repressed in actively cycling cells through the PI3K/AKT/FOXO3a axis.
脆性组氨酸三联体基因（FHIT）在许多上皮细胞类型中作为肿瘤抑制因子发挥作用。尽管其肿瘤抑制机制是深入研究的主题，但关于 FHIT 基因表达本身是如何调控的知之甚少。在这里，我们表明，PI3 激酶及其下游靶标 AKT 在有丝分裂原刺激下抑制 FHIT 基因表达，从而抑制这些原癌基因激酶。在去除培养环境中的有丝分裂原后，由于从这些原癌基因激酶的去抑制，观察到 FHIT mRNA 和蛋白水平增加。通过 FOXO 转录因子的 AKT 信号似乎是 FHIT 基因调控的基础。在 MCF7 乳腺癌细胞中，通过针对 FOXO 转录因子家族成员的 RNAi 实验证明，FHIT 基因表达的增加直接依赖于内源性 FOXO3a。因此，这是第一个表明 FHIT 基因表达在有丝分裂细胞中通过 PI3K/AKT/FOXO3a 轴正常受到抑制的报告。
