p53 Regulation of the IGF-1/AKT/mTOR Pathways and the Endosomal Compartment
- 18 November 2009
- journal article
- review article
- Published by Cold Spring Harbor Laboratory in Cold Spring Harbor Perspectives in Biology
- Vol. 2 (2), a001057
- https://doi.org/10.1101/cshperspect.a001057
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 β1, 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.Keywords
This publication has 80 references indexed in Scilit:
- The LKB1 tumor suppressor negatively regulates mTOR signalingCancer Cell, 2004
- Exosomes: endosomal-derived vesicles shipping extracellular messagesCurrent Opinion in Cell Biology, 2004
- Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progressionOncogene, 2004
- S6K1−/−/S6K2−/− Mice Exhibit Perinatal Lethality and Rapamycin-Sensitive 5′-Terminal Oligopyrimidine mRNA Translation and Reveal a Mitogen-Activated Protein Kinase-Dependent S6 Kinase PathwayMolecular and Cellular Biology, 2004
- The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stressProceedings of the National Academy of Sciences, 2004
- Activation of the RAS/Cyclic AMP Pathway Suppresses a TOR Deficiency in YeastMolecular and Cellular Biology, 2004
- mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4EMolecular and Cellular Biology, 2004
- Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressorProceedings of the National Academy of Sciences, 2003
- Minireview: The AMP-Activated Protein Kinase Cascade: The Key Sensor of Cellular Energy StatusEndocrinology, 2003
- TSC2 Mediates Cellular Energy Response to Control Cell Growth and SurvivalCell, 2003