ArticleMolecular biology of the cell2018
Cholesterol depletion enhances TGF-β Smad signaling by increasing c-Jun expression through a PKR-dependent mechanism.
Article in Molecular biology of the cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 19 citations in OpenAlex.
- Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review).International journal of molecular medicine · 2025Review
- Molecular mechanisms underlying the effects of statins on bone metabolism: an evolving paradigm of statins delivery modalities for bone regeneration.Pharmacological reports : PR · 2025Review
- A monocyte-derived blood transcriptomic signature reveals systemic immunosuppression in HCC and partial reversal following curative therapy.Frontiers in immunology · 2025Article
- Association of higher potency statin use with risk of osteoporosis and fractures in patients with stroke in a Korean nationwide cohort study.Scientific reports · 2024Article
- A two-way street - cellular metabolism and myofibroblast contraction.NPJ Regenerative medicine · 2024Review
- Cholesterol modulates type I/II TGF-β receptor complexes and alters the balance between Smad and Akt signaling in hepatocytes.Communications biology · 2024Article
- The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells.Nature communications · 2023Article
- Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-β.Microbiology spectrum · 2023Article
- Autophagy is induced and modulated by cholesterol depletion through transcription of autophagy-related genes and attenuation of flux.Cell death discovery · 2021Article
- Mechanistic Insights Delineating the Role of Cholesterol in Epithelial Mesenchymal Transition and Drug Resistance in Cancer.Frontiers in cell and developmental biology · 2021Review
- Toward a Membrane-Centric Biology.Frontiers in immunology · 2020Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Transforming growth factor-β (TGF-β) plays critical roles in numerous physiological and pathological responses. Cholesterol, a major plasma membrane component, can have pronounced effects on signaling responses. Cells continually monitor cholesterol content and activate multilayered transcriptional and translational signaling programs, following perturbations to cholesterol homeostasis (e.g., statins, the commonly used cholesterol-reducing drugs). However, the cross-talk of such programs with ligand-induced signaling responses (e.g., TGF-β signaling) remained unknown. Here, we studied the effects of a mild reduction in free (membrane-associated) cholesterol on distinct components of TGF-β-signaling pathways. Our findings reveal a new regulatory mechanism that enhances TGF-β-signaling responses by acting downstream from receptor activation. Reduced cholesterol results in PKR-dependent eIF2α phosphorylation, which enhances c-Jun translation, leading in turn to higher levels of JNK-mediated c-Jun phosphorylation. Activated c-Jun enhances transcription and expression of Smad2/3. This leads to enhanced sensitivity to TGF-β stimulation, due to increased Smad2/3 expression and phosphorylation. The phospho/total Smad2/3 ratio remains unchanged, indicating that the effect is not due to altered receptor activity. We propose that cholesterol depletion induces overactivation of PKR, JNK, and TGF-β signaling, which together may contribute to the side effects of statins in diverse disease settings.
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