Regulation and function of FoxO transcription factors in normal and cancer stem cells: what have we learned?
Regulation and function of FoxO transcription factors in normal and cancer stem cells: what have we learned?
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DOI：
10.2174/138945011796150325
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发表时间：
2011-07
影响因子：
3.2
通讯作者：
Xin Zhang;Maité Rielland;S. Yalcin;S. Ghaffari
中科院分区：
文献类型：
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作者：
Xin Zhang;Maité Rielland;S. Yalcin;S. Ghaffari
叉头FoxO转录因子发挥关键的生物学功能，以应对遗传毒性应激。在哺乳动物中，已知有四种FoxOs蛋白。FoxOs通过调节控制这些过程的基因来诱导细胞周期停滞、修复受损的DNA或启动凋亡。特别地，FoxO蛋白是通过调节几种抗氧化酶基因的表达来调节氧化应激的关键调节剂。FoxO的这种功能对于造血系统中的干细胞和祖细胞池以及可能的其他干细胞的调节是必需的。FoxO的总体功能与其作为肿瘤抑制剂的作用一致，如在动物模型中所示。因此，FoxO在各种癌细胞中受到抑制。然而，最近的报道强烈表明FoxO对于维持白血病干细胞至关重要。FoxOs的各种功能是由其家族成员的表达和活动的严格规定所协调的。在这里，我们讨论了最近的进展，特别是在正常和癌症干细胞中理解FoxOs的功能，以及这些蛋白质在各种细胞类型和组织中的调节，包括在体内原代细胞的生理环境中。这些研究强调了FoxO蛋白调节的重要性，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，对于设计基于癌症和FoxO具有关键功能的其他病变细胞中FoxO功能的靶向恢复/或抑制的新疗法至关重要。
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.