The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways.

By Zhaohui Feng, Wenwei Hu, E. de Stanchina, A. Teresky, Shengkan Jin, S. Lowe, Arnold J. Levine. Cancer Research, 2007

629 citations recorded by the source corpus.

The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the beta1 and beta2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal-specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/3de28084a7f7d17610fda4e61ee8327b5afd0b80

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Citations in the corpus

Awakening guardian angels: drugging the p53 pathway (2009, background): “Other new targets of p53-induced transcription have been identified that are involved in protein translatio”
Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “Finally, it is worth noting that p53 also functions in a positive feedback loop with AMPK, whereby p53 can transcriptionally enhance the AMPK-dependent cellular stress response, while AMPK can catalyze the activation-initiating phosphorylation of p53 (69, 70).”
Mitochondria and Mitophagy: The Yin and Yang of Cell Death Control (2012, background): “Many products of these target genes, such as AMP-activated protein kinase, tuberous sclerosis protein 2, and sestrin1/2 converge on the mTOR pathway.(80,81) mTOR is a negative regulator of autophagy, and inhibition of this pathway results in the induction of autophagy.”
Blinded by the Light: The Growing Complexity of p53. (2009, background): “…(Jones et al., 2005). p53 then promotes a program of gene expression (including the induction of AMPK expression) to negatively regulate the kinase mTOR (mammalian target of rapamycin), a central node in the control of protein synthesis (Budanov and Karin, 2008; Feng et al., 2007a) (Figure 1).”
The genetics of the p53 pathway, apoptosis and cancer therapy (2008, background): “PRKAG2 is a non-catalytic subunit of the AMP-activated protein kinase (AMPK), which has been shown to phosphorylate p53 on an important serine residue (Ser 15) leading to p53 activatio”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Finally, the DNA damage-response pathway inhibits mTORC1 through the induction of p53 target genes, including the AMPK regulatory subunit (AMPKß), PTEN, and TSC2 itself, all of which increase TSC activity (Feng et al., 2007).”
p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. (2008, positive): “Although p53 can induce expression of several negative regulators of mTOR, including PTEN, TSC2, AMPKb1, and IGF-BP3, in a cell type-dependent manner (Feng et al., 2007), our results demonstrate that p53-mediated inhibition of mTOR depends mainly on Sesn1 and Sesn2 in mouse fibroblasts and certain h”
Transcriptional control of human p53-regulated genes (2008, background): “There is good evidence that the nature of the stress signal and the cell type can both affect the modulation of the transcriptional pattern of p53-responsive genes that respond with a transcriptional programm”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Finally, the DNA damage-response pathway inhibits mTORC1 through the induction of p53 target genes including the AMPK regulatory subunit (AMPKβ), PTEN, and TSC2 itself, all of which increase TSC activity (Feng et al., 2007).”