The Regulation of AMPK β1, 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
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Abstract
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 β1 and β2 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. [Cancer Res 2007;67(7):3043–53]
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p53 activation is able to inhibit the activity of mTOR through a pathway involving the subsequent activation of TSC1 and TSC2.
“Furthermore, reports showed that p53 activation is able to inhibit the activity of mTOR through a pathway involving the subsequent activation of TSC gene products TSC1 and TSC2, which are tumour suppressors and negative regulators of mTOR [78, 103–105].”
From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [103]
PRKAB1 is targeted by p53 and encodes for AMP-activated protein kinase beta-1 subunit, which is involved in phosphorylation and inactivation of acetyl-coenzyme A carboxylase and β-hydroxy β-methylglutaryl-coenzyme A reductase, key enzymes involved in regulating de novo biosynthesis of fatty acids and cholesterol.
“PRKAB1 is also targeted by p53 and encodes for AMP-activated protein kinase beta-1 subunit, which is involved in phosphorylation and inactivation of acetyl-coenzyme A carboxylase and β-hydroxy β-methylglutaryl-coenzyme A reductase, key enzymes involved in regulating de novo biosynthesis of fatty acids and cholesterol.201”
From Census and evaluation of p53 target genes (2017) · cites this paper as [201]
AMPK, which p53 activates by direct activation of PRKAB1, blocks the mammalian target of rapamycin (mTOR) pathway, and leads to autophagy.
“AMPK, which p53 activates by direct activation of PRKAB1, blocks the mammalian target of rapamycin (mTOR) pathway, and leads to autophagy.201, 210”
From Census and evaluation of p53 target genes (2017) · cites this paper as [201]
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- Authors
- Feng, Z., Hu, W., de Stanchina, E., Teresky, A. K., Jin, S., Lowe, S., & Levine, A. J.
- Affiliations
- Rutgers Cancer Institute (US)
- 2Cold Spring Harbor Laboratories, Cold Spring Harbor, New York; and
- Cold Spring Harbor Laboratory (US)
- Institute for Advanced Study (US)
- Venue
- Cancer Research
- Published
- 2007-04-01
- Volume
- 67
- Issue
- 7
- Pages
- 3043-3053
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2101428185
- Cited by
- 633
- References
- 50
- Citations by year
- 2026: 8 · 2025: 24 · 2024: 22 · 2023: 22 · 2022: 29 · 2021: 48 · 2020: 36 · 2019: 47 · 2018: 45 · 2017: 34 · 2016: 36 · 2015: 32 · 2014: 35 · 2013: 44 · 2012: 44
- FWCI
- 13.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- p53, TSC2, PTEN, IGFBP-3, glucose deprivation, p53 phosphorylation, apoptosis, cell cycle arrest, tissue-specific gene regulation, mouse embryonic fibroblasts, stress signaling
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, Animals, Cell Transformation, Neoplastic, Female, Glucose, Humans, Insulin-Like Growth Factor I, Male, Mice, Inbred C57BL, Multienzyme Complexes, Organ Specificity, Protein Kinases, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Adenovirus E1B Proteins, Mice, Knockout, ras Proteins, Insulin-Like Growth Factor Binding Proteins, Tumor Suppressor Proteins, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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