Department of Development and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Curr Drug Targets. 2011 Aug;12(9):1267-83. doi: 10.2174/138945011796150325.
Forkhead FoxO transcription factors exert critical biological functions in response to genotoxic stress. In mammals four FoxOs proteins are known. FoxOs induce cell cycle arrest, repair damaged DNA, or initiate apoptosis by modulating genes that control these processes. In particular, FoxO proteins are critical regulators of oxidative stress by modulating the expression of several anti-oxidant enzyme genes. This function of FoxO is essential for the regulation of stem and progenitor cell pool in the hematopoietic system and possibly other stem cells. Overall functions of FoxOs are consistent with their role as tumor suppressors as has been shown in animal models. As such, FoxOs are suppressed in various cancer cells. However, recent reports strongly suggest that FoxOs are critical for the maintenance of leukemic stem cells. The diverse functions of FoxOs are orchestrated by tight regulations of expression and activity of its family members. Here we discuss the recent progress in understanding the function of FoxOs specifically in normal and cancer stem cells and what is known about the regulation of these proteins in various cell types and tissues including in the physiological setting of primary cells in vivo. These studies underscore the importance of regulation of FoxO proteins and whether these factors play distinct or redundant functions. Understanding how FoxOs are modulated is critical for devising novel therapies based on targeted restoration/or inhibition of FoxO function in cancer and in other diseased cells in which FoxOs have a key function.
叉头框转录因子在应对遗传毒性应激时发挥着关键的生物学功能。在哺乳动物中，已知有四种 FoxO 蛋白。FoxO 通过调节控制这些过程的基因，诱导细胞周期停滞、修复受损的 DNA 或启动细胞凋亡。特别是，FoxO 蛋白通过调节几种抗氧化酶基因的表达，是氧化应激的关键调节剂。FoxO 的这一功能对于造血系统和可能其他干细胞中的干细胞和祖细胞库的调节至关重要。FoxO 的总体功能与其作为肿瘤抑制因子的作用一致，这在动物模型中已经得到证实。因此，FoxO 在各种癌细胞中受到抑制。然而，最近的报告强烈表明，FoxO 对于维持白血病干细胞至关重要。FoxO 家族成员的表达和活性受到严格调控，从而实现了其多样化的功能。在这里，我们讨论了最近在理解 FoxO 特别是在正常和癌症干细胞中的功能方面的进展，以及这些蛋白质在各种细胞类型和组织中的调节情况，包括在体内原代细胞的生理环境中。这些研究强调了调节 FoxO 蛋白的重要性，以及这些因子是否发挥独特或冗余的功能。了解 FoxO 是如何被调节的，对于设计基于靶向恢复/抑制 FoxO 功能的癌症和其他 FoxO 具有关键功能的疾病细胞的新型疗法至关重要。
