Department of Radiation Oncology, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08903, USA.
Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a001057. doi: 10.1101/cshperspect.a001057.
In response to various stress signals, which introduce infidelity into the processes of cell growth and division, p53 initiates cell-cycle arrest, apoptosis, or senescence to maintain fidelity throughout the cell cycle. Although these functions are traditionally thought of as the major functions of the p53 protein for tumor suppression, recent studies have revealed some additional novel functions of the p53 pathway. These include the down-regulation of two central cell-growth pathways, the IGF/AKT-1 and mTOR pathways, and the up-regulation of the activities of the endosomal compartment. The IGF-1/AKT and mTOR pathways are two evolutionarily conserved pathways that play critical roles in regulation of cell proliferation, survival, and energy metabolism. In response to stress, p53 transcribes a group of critical negative regulators in these two pathways, including IGF-BP3, PTEN, TSC2, AMPK beta1, and Sestrin1/2, which leads to the reduction in the activities of these two pathways. Furthermore, p53 transcribes several critical genes regulating the endosomal compartment, including TSAP6, Chmp4C, Caveolin-1, and DRAM, and increases exosome secretion, the rate of endosomal removal of growth factor receptors (e.g., EGFR) from cell surface, and enhances autophagy. These activities all function to slow down cell growth and division, conserve and recycle cellular resources, communicate with adjacent cells and dendritic cells of the immune system, and inform other tissues of the stress signals. This coordinated regulation of IGF-1/AKT/mTOR pathways and the endosomal compartment by the p53 pathway integrates the molecular, cellular, and systemic levels of activities and prevents the accumulations of errors in response to stress and restores cellular homeostasis after stress.
针对细胞生长和分裂过程中引入的各种应激信号，p53 会启动细胞周期停滞、细胞凋亡或衰老，以保持整个细胞周期的保真度。尽管这些功能传统上被认为是 p53 蛋白抑制肿瘤的主要功能，但最近的研究揭示了 p53 途径的一些其他新功能。这些功能包括下调两个核心细胞生长途径，即 IGF/AKT-1 和 mTOR 途径，以及上调内体区室的活性。IGF-1/AKT 和 mTOR 途径是两个进化上保守的途径，在调节细胞增殖、存活和能量代谢方面发挥着关键作用。在应激反应中，p53 转录了这两个途径中的一组关键负调控因子，包括 IGF-BP3、PTEN、TSC2、AMPK beta1 和 Sestrin1/2，这导致这两个途径的活性降低。此外，p53 转录了几个调节内体区室的关键基因，包括 TSAP6、Chmp4C、Caveolin-1 和 DRAM，并增加了外泌体的分泌、生长因子受体（如 EGFR）从细胞膜表面被内体去除的速度，并增强了自噬。这些活动都有助于减缓细胞生长和分裂，节约和回收细胞资源，与相邻细胞和免疫系统的树突状细胞进行通讯，并向其他组织报告应激信号。p53 途径对 IGF-1/AKT/mTOR 途径和内体区室的协调调节整合了分子、细胞和系统水平的活动，并防止了应激反应中错误的积累，恢复了细胞的内稳态。
