Abstract
Glucose is a direct energy source for eukaryotic cells, and its deficiency elicits complex stress responses and diverse cellular outcomes. Although several signaling pathways involved have been identified, how they coordinately dictate the cell fate remains obscure. We propose a minimal network model for the cellular response to glucose restriction, characterizing the glucose uptake and signaling of the AMPK, Akt, mTOR, and p53 pathways. We demonstrate that in the presence of sufficient growth factors and amino acids, cells may undergo proliferation, senescence, or apoptosis, depending on the extracellular glucose level. AMPK is first activated upon glucose limitation, activating p53 to induce cell-cycle arrest; possibly, cells resume proliferation after timely glucose restoration. For long-term energy stress, cell senescence is maintained by low/intermediate levels of p53 and persistent activation of mTOR and Akt, or cells commit apoptosis when the proteins undergo biphasic dynamics, e.g., p53 switches from intermediate levels to high levels while mTOR and Akt become inactivated in the later phase. The biphasic dynamics of p53 are associated with flipping of two bistable switches. Appropriate mTOR levels are required for optimal cell-fate decision. This work suggests that senescence and apoptosis occur sequentially in glucose-depleted cells, and a theoretical framework is provided for exploring the cellular response to energy stress.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.