p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment

Abstract

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.

Figure 1.

The interconnections between p53 and IGF-1/AKT/mTOR pathways. p53 negatively regulates IGF-1/AKT and mTOR pathways through its up-regulation of IGF-BP3, PTEN, TSC2, AMPK β1, and Sestrin1/2 in response to stress. mTORC1 activates the α-4 subunit of the PP2A phosphatase to dephosphorylate p53 on Ser15 to inactivate p53, whereas AMPK phosphorylates p53 on Ser15 to activate p53. AKT-MDM2-p53 forms a negative feedback loop to negatively regulate p53, whereas p53-PTEN-AKT-MDM2 forms a positive loop to positively regulate p53. Furthermore, p53 activates autophagy through its regulation of mTOR pathway and DRAM. This extensive communication and coordination between p53 and IGF-1/AKT/mTOR pathways slows down cell growth and division to prevent the accumulations of errors in response to stress and restores cellular homeostasis after stress is resolved.

Figure 2.

p53 regulation of the function of endosome compartment. In response to stress signals, p53 regulates the transcription of Chmp4C and Caveolin-1 to enhance endosome production and promote endosomal clearance of membrane receptors (e.g., EGFR) from cell surface, regulates the transcription of TSAP6 and Chmp4C to enhance exosome production, and regulates the transcription of DRAM to activate autophagy.