Glauser Dominique A, Schlegel Werner
Fondation pour Recherches Médicales, University of Geneva, Av de la Roseraie 64, Geneva, Switzerland.
J Endocrinol. 2007 May;193(2):195-207. doi: 10.1677/JOE-06-0191.
FOXO transcription factors critically control fundamental cellular processes, including metabolism, cell differentiation, cell cycle arrest, DNA repair, and other reactions to cellular stress. FOXO factors sense the balance between stimuli promoting growth and differentiation versus stress stimuli signaling damage. Integrated through the FOXO system, these divergent stimuli decide on cell fate, a choice between proliferation, differentiation, or apoptosis. In pancreatic beta cells, most recent evidence highlights complex FOXO-dependent responses to glucose, insulin, or other growth factors, which include regulatory feedback. In the short term, FOXO-dependent mechanisms help beta cells to accomplish their endocrine function, and may increase their resistance to oxidative stress due to transient hyperglycemia. In the long term, FOXO-dependent responses lead to the adaptation of beta cell mass, conditioning the future ability of the organism to produce insulin and cope with changes in fuel abundance. FOXO emerges as a key factor for the maintenance of a functional endocrine pancreas and represents an interesting element in the development of therapeutic approaches to treat diabetes. This review on the role of FOXO transcription factors in pancreatic beta cells has three parts. In Part I, FOXO transcription factors will be presented in general: structure, molecular mechanisms of regulation, cellular functions, and physiological roles. Part II will focus on specific data about FOXO factors in pancreatic beta cells. Lastly in Part III, it will be attempted to combine general and beta cell-specific knowledge with the aim to envisage globally the role of FOXO factors in beta cell-linked physiology and disease.
FOXO转录因子严格控制着包括新陈代谢、细胞分化、细胞周期停滞、DNA修复以及对细胞应激的其他反应等基本细胞过程。FOXO因子感知促进生长和分化的刺激与信号损伤的应激刺激之间的平衡。通过FOXO系统整合，这些不同的刺激决定细胞命运，即在增殖、分化或凋亡之间做出选择。在胰腺β细胞中，最新证据突出了对葡萄糖、胰岛素或其他生长因子的复杂的FOXO依赖性反应，其中包括调节反馈。在短期内，FOXO依赖性机制帮助β细胞完成其内分泌功能，并可能增加其对短暂高血糖引起的氧化应激的抵抗力。从长期来看，FOXO依赖性反应导致β细胞量的适应性变化，决定了生物体未来产生胰岛素和应对燃料丰度变化的能力。FOXO成为维持功能性内分泌胰腺的关键因素，并代表了糖尿病治疗方法开发中的一个有趣元素。这篇关于FOXO转录因子在胰腺β细胞中作用的综述分为三个部分。在第一部分，将总体介绍FOXO转录因子：结构、调节的分子机制、细胞功能和生理作用。第二部分将聚焦于胰腺β细胞中FOXO因子的具体数据。最后在第三部分，将尝试结合一般知识和β细胞特异性知识，以期全面设想FOXO因子在与β细胞相关的生理和疾病中的作用。
