ArticleCell death and differentiation2015
A novel autoregulatory loop between the Gcn2-Atf4 pathway and (L)-Proline [corrected] metabolism controls stem cell identity.
Article in Cell death and differentiation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 42 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
42 citing papers in PubMed, 68 citations in OpenAlex.
- Association between salivary microbiota-related amino acid metabolic dysregulation and tacrolimus-induced gingival overgrowth following kidney transplantation.BMC oral health · 2026Article
- Pirfenidone Sensitizes Hepatic Stellate Cells to Ferroptosis by Reprogramming Glutamine and Serine Metabolism for GSH Depletion.Antioxidants (Basel, Switzerland) · 2026Article
- TDG orchestrates ATF4-dependent gene transcription during retinoic acid-induced cell fate acquisition.Nucleic acids research · 2026Article
- Regulation of Translation of ATF4 mRNA: A Focus on Translation Initiation Factors and RNA-Binding Proteins.Cells · 2026Review
- Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.Science advances · 2025Article
- Both asparagine and proline are required to decreaseBiomedical reports · 2025Article
- The Modulation of Cell Plasticity by Budesonide: Beyond the Metabolic and Anti-Inflammatory Actions of Glucocorticoids.Pharmaceutics · 2025Review
- The new insight into the role of hydroxyproline in metabolism of cancer cells.Frontiers in cell and developmental biology · 2025Review
- Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors.GeroScience · 2024Article
- Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.International journal of molecular sciences · 2023Review
- Article
- Signalling pathway crosstalk stimulated by L-proline drives mouse embryonic stem cells to primitive-ectoderm-like cells.Development (Cambridge, England) · 2023Article
- An active metabolite of the anti-COVID-19 drug molnupiravir impairs mouse preimplantation embryos at clinically relevant concentrations.Reproductive toxicology (Elmsford, N.Y.) · 2023Article
- Budesonide Analogues Preserve Stem Cell Pluripotency and Delay 3D Gastruloid Development.Pharmaceutics · 2023Article
- Stabilization of cell-cell adhesions prevents symmetry breaking and locks in pluripotency in 3D gastruloids.Stem cell reports · 2022Article
- Review
- Cellular responses to halofuginone reveal a vulnerability of the GCN2 branch of the integrated stress response.The EMBO journal · 2022Article
- A stromal Integrated Stress Response activates perivascular cancer-associated fibroblasts to drive angiogenesis and tumour progression.Nature cell biology · 2022Article
- Amino Acid Homeostasis in Mammalian Cells with a Focus on Amino Acid Transport.The Journal of nutrition · 2022Article
- The regulatory mechanisms of proline and hydroxyproline metabolism: Recent advances in perspective.Frontiers in oncology · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Increasing evidence indicates that metabolism is implicated in the control of stem cell identity. Here, we demonstrate that embryonic stem cell (ESC) behaviour relies on a feedback loop that involves the non-essential amino acid L-Proline (L-Pro) in the modulation of the Gcn2-Eif2α-Atf4 amino acid starvation response (AAR) pathway that in turn regulates L-Pro biosynthesis. This regulatory loop generates a highly specific intrinsic shortage of L-Pro that restricts proliferation of tightly packed domed-like ESC colonies and safeguards ESC identity. Indeed, alleviation of this nutrient stress condition by exogenously provided L-Pro induces proliferation and modifies the ESC phenotypic and molecular identity towards that of mesenchymal-like, invasive pluripotent stem cells. Either pharmacological inhibition of the prolyl-tRNA synthetase by halofuginone or forced expression of Atf4 antagonises the effects of exogenous L-Pro. Our data provide unprecedented evidence that L-Pro metabolism and the nutrient stress response are functionally integrated to maintain ESC identity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.