The discrete roles of individual FOXO transcription factor family members in B-cell malignancies.
The discrete roles of individual FOXO transcription factor family members in B-cell malignancies.
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DOI：
10.3389/fimmu.2023.1179101
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发表时间：
2023
影响因子：
7.3
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中科院分区：
文献类型：
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FOXO（Forkhead box）是一个动态的转录因子家族，由FOXO 1、FOXO 3、FOXO 4和FOXO 6组成。作为环境依赖性转录激活因子和抑制因子，FOXO家族调节多种细胞过程，包括细胞周期停滞、凋亡、代谢、寿命和细胞命运决定。负责负调节FOXO活性的中心途径是磷脂酰肌醇-3-激酶（PI 3 K）-AKT信号传导途径，其使细胞存活和增殖。FOXO家族成员可以进一步由不同的激酶调节，两者都是正向的（例如，JNK，AMPK）和负性（例如，ERK-MAPK，CDK 2），具有进一步影响FOXO活性的额外翻译后修饰。有证据表明，FOXO通过转录程序调节几种细胞行为，包括细胞周期阻滞和细胞凋亡，表现为“真正的”肿瘤抑制因子。然而，另一种范式已经出现，这表明FOXO在“正常”和病理生理情况下都作为细胞稳态和/或抗性的介质起作用。不同的FOXO家族成员在正常的B细胞成熟和功能过程中发挥不同的作用，现在已经清楚FOXO在不同的B细胞恶性肿瘤中异常表达和突变。虽然活性FOXO功能通常与例如慢性淋巴细胞白血病中的疾病抑制相关，但FOXO表达与弥漫性大B细胞淋巴瘤中的疾病进展相关，这一观察结果也见于其他癌症。FOXO家族的相反功能推动了关于FOXO促进或阻碍疾病进展的情况以及靶向FOXO介导的过程是否能有效治疗B细胞恶性肿瘤的辩论。在这里，我们讨论了FOXO家族成员在B谱系细胞中的不同作用，影响FOXO功能的调节事件主要集中在翻译后修饰上，并考虑未来开发靶向FOXO活性的疗法的潜力。
Forkhead box (FOX) class O (FOXO) proteins are a dynamic family of transcription factors composed of four family members: FOXO1, FOXO3, FOXO4 and FOXO6. As context-dependent transcriptional activators and repressors, the FOXO family regulates diverse cellular processes including cell cycle arrest, apoptosis, metabolism, longevity and cell fate determination. A central pathway responsible for negative regulation of FOXO activity is the phosphatidylinositol-3-kinase (PI3K)-AKT signalling pathway, enabling cell survival and proliferation. FOXO family members can be further regulated by distinct kinases, both positively (e.g., JNK, AMPK) and negatively (e.g., ERK-MAPK, CDK2), with additional post-translational modifications further impacting on FOXO activity. Evidence has suggested that FOXOs behave as ‘bona fide’ tumour suppressors, through transcriptional programmes regulating several cellular behaviours including cell cycle arrest and apoptosis. However, an alternative paradigm has emerged which indicates that FOXOs operate as mediators of cellular homeostasis and/or resistance in both ‘normal’ and pathophysiological scenarios. Distinct FOXO family members fulfil discrete roles during normal B cell maturation and function, and it is now clear that FOXOs are aberrantly expressed and mutated in discrete B-cell malignancies. While active FOXO function is generally associated with disease suppression in chronic lymphocytic leukemia for example, FOXO expression is associated with disease progression in diffuse large B cell lymphoma, an observation also seen in other cancers. The opposing functions of the FOXO family drives the debate about the circumstances in which FOXOs favour or hinder disease progression, and whether targeting FOXO-mediated processes would be effective in the treatment of B-cell malignancies. Here, we discuss the disparate roles of FOXO family members in B lineage cells, the regulatory events that influence FOXO function focusing mainly on post-translational modifications, and consider the potential for future development of therapies that target FOXO activity.