Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E
Open accessAbstract
The coordinated action of cell cycle progression and cell growth (an increase in cell size and cell mass) is critical for sustained cellular proliferation, yet the biochemical signals that control cell growth are poorly defined, particularly in mammalian systems. We find that cell growth and cell cycle progression are separable processes in mammalian cells and that growth to appropriate cell size requires mTOR- and PI3K-dependent signals. Expression of a rapamycin-resistant mutant of mTOR rescues the reduced cell size phenotype induced by rapamycin in a kinase-dependent manner, showing the evolutionarily conserved role of mTOR in control of cell growth. Expression of S6K1 mutants that possess partial rapamycin-resistant activity or overexpression of eIF4E individually and additively partially rescues the rapamycin-induced decrease in cell size. In the absence of rapamycin, overexpression of S6K1 or eIF4E increases cell size, and, when coexpressed, they cooperate to increase cell size further. Expression of a phosphorylation site-defective mutant of 4EBP1 that constitutively binds the eIF4E–Cap complex to inhibit translation initiation reduces cell size and blocks eIF4E effects on cell size. These data show that mTOR signals downstream to at least two independent targets, S6K1 and 4EBP1/eIF4E, that function in translational control to regulate mammalian cell size.
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mTORC1 is important for controlling cell size, with activated mTORC1 leading to larger cells.
“mTORC1 is also known to be important for controlling cell size, with activated mTORC1 leading to larger cells (Fingar et al., 2002).”
From Efficient genetic editing of human intestinal organoids using ribonucleoprotein-based CRISPR (2023) · cites this paper as Fingar et al., 2002
The Discussion reports that inhibiting mTOR reduces cell size, and the section “mTOR- and PI3K-mediated cell growth continues when cell cycle progression is blocked” reports that mTOR-dependent signaling is needed for cells to grow larger. The paper does not identify the signaling complex as mTORC1 or show that activating it makes cells larger; its direct evidence concerns inhibition and restoration of mTOR signaling. (LLM, conf=0.87)
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“This pathway is an important regulator of cell proliferation and metabolism (Hay and Sonenberg, 2004; Guertin and Sabatini, 2007). mTORC1 is also known to be important for controlling cell size, with activated mTORC1 leading to larger cells (Fingar et al., 2002).”
- Authors
- Fingar, D. C., Salama, S., Tsou, C., Harlow, E., & Blenis, J.
- Affiliations
- Harvard University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2002-06-15
- Volume
- 16
- Issue
- 12
- Pages
- 1472-1487
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC186342
- OpenAlex
- W2163583831
- Cited by
- 1,093
- References
- 5
- Citations by year
- 2026: 17 · 2025: 23 · 2024: 42 · 2023: 50 · 2022: 42 · 2021: 43 · 2020: 43 · 2019: 38 · 2018: 43 · 2017: 41 · 2016: 56 · 2015: 43 · 2014: 41 · 2013: 57 · 2012: 75
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Jane Coffin Childs Memorial Fund for Medical Research
- National Institutes of Health
- National Cancer Institute (CA69808, F32CA069808)
- 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 › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- cell size control, mTOR signaling, S6K1, 4E-BP1, eIF4E, PI3K signaling, cell growth, cell cycle progression, translational regulation, rapamycin resistance, translation initiation
- MeSH terms
- Animals, Carrier Proteins, Cell Cycle, Cell Division, Cell Line, Chromones, Flow Cytometry, HeLa Cells, Humans, Mitogens, Models, Biological, Morpholines, Mutation, Peptide Initiation Factors, Phenotype, Phosphoproteins, Plasmids, Precipitin Tests, Protein Kinases, Time Factors, Transfection, Protein Biosynthesis, Tumor Cells, Cultured, Immunoblotting, Signal Transduction, Up-Regulation, G1 Phase, G2 Phase, S Phase, Cell Cycle Proteins, Antigens, CD20, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Sirolimus, Eukaryotic Initiation Factor-4E, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Rats, TOR Serine-Threonine Kinases
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