Control of glutamine metabolism by the tumor suppressor Rb
Open accessAbstract
Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in (13)C-glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate α-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly regulates a major energetic and anabolic pathway that is required for neoplastic growth.
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Deletion of Rb family proteins upregulates glutamine uptake and utilization via E2F-dependent upregulation of ASCT2 and GLS1.
“The deletion of Rb family proteins has been shown to upregulate the uptake and utilization of glutamine via the E2F-dependent upregulation of ASCT2 and GLS1”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Reynolds et al., 2014
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“For example, the glutamine transporter SLC1A5 was reported to be a direct target of RB transcriptional repression in mouse embryonic fibroblast cells (Reynolds et al., 2014).”
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“ASCT2 over-expression has been linked to the tumor suppressor pRb/E2F pathway [45].”
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“Other pathways have also been reported to regulate SLC1A5 expression, including c-Myc (42), N-Myc (37), Rb/E2F (43), EGF signaling (44), and RNF5 (45).”
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“There are two isoforms of GLS which are encoded by two genes in mammals, the kidney-type GLS1 and the liver-type GLS2.”
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“On the glutamine side, the glutamine transporter ASCT2 is an E2F3 target gene (12).”
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BackgroundRevisiting prostate cancer metabolism: From metabolites to disease and therapy
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“Concerning metabolism, the loss of Rb protein was shown to be a strong stimulator of glutamine metabolism in mouse embryonic fibroblasts by upregulating the expression of ASCT2 and glutaminase activity.(203) The control of PCa cells metabolism by Rb protein is highly unknown, but increased ASCT2 expression and glutami…”
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The role of the glutamine transporter ASCT2 in antineoplastic therapy
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Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis
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- Authors
- Reynolds, M. R., Lane, A. N., Robertson, B., Kemp, S., Liu, Y., Hill, B. G., Dean, D. C., & Clem, B. F.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Clem, B F
- Venue
- Oncogene
- Published
- 2013-01-28
- Volume
- 33
- Issue
- 5
- Pages
- 556-566
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3918885
- OpenAlex
- W2037338364
- Cited by
- 216
- References
- 42
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 21 · 2023: 17 · 2022: 16 · 2021: 24 · 2020: 19 · 2019: 18 · 2018: 12 · 2017: 14 · 2016: 12 · 2015: 20 · 2014: 17 · 2013: 5
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Food and Drug Administration (3P20RR018733-09-BFC)
- National Cancer Institute (R01CA166327)
- National Institute of General Medical Sciences (P30GM106396)
- National Center for Research Resources (RR-024489, P20RR024489, 1P20RR18733, P20RR018733)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- retinoblastoma protein, glutamine metabolism, ASCT2, glutamine transporter, GLS1, glutamine uptake, glutamate, TCA cycle, glutathione, alpha-ketoglutarate, cell proliferation, tumor suppressor, cell cycle regulation, mouse embryonic fibroblasts
- MeSH terms
- Adenosine Triphosphate, Animals, Biological Transport, Cell Cycle, Cells, Cultured, Fibroblasts, Glutamate-Cysteine Ligase, Glutaminase, Glutamine, Glutathione, Ketoglutaric Acids, Oxygen, Promoter Regions, Genetic, Minor Histocompatibility Antigens, Retinoblastoma Protein, Reactive Oxygen Species, Mice, Knockout, Amino Acid Transport System ASC, RNA Interference, RNA, Small Interfering, Cell Proliferation, E2F3 Transcription Factor, Retinoblastoma-Like Protein p130, Retinoblastoma-Like Protein p107, Mice
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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