ArticleMolecular endocrinology (Baltimore, Md.)2012
Overexpression of hepatocyte nuclear factor-4α initiates cell cycle entry, but is not sufficient to promote β-cell expansion in human islets.
Article in Molecular endocrinology (Baltimore, Md.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 49 citations in OpenAlex.
- The protein deacetylase SIRT2 exerts metabolic control over adaptive β cell proliferation.The Journal of clinical investigation · 2025Article
- Cell cycle visualization tools to study cardiomyocyte proliferation in real-time.Open biology · 2024Review
- DNA hypomethylation activates Cdk4/6 and Atr to induce DNA replication and cell cycle arrest to constrain liver outgrowth in zebrafish.Nucleic acids research · 2024Article
- Failure to repair endogenous DNA damage in β-cells causes adult-onset diabetes in mice.Aging biology · 2023Article
- An Overfeeding-Induced Obesity Mouse Model Reveals Necessity for Sin3a in Postnatal Peak β-Cell Mass Acquisition.Diabetes · 2022Article
- Mitogen Synergy: An Emerging Route to Boosting Human Beta Cell Proliferation.Frontiers in cell and developmental biology · 2021Review
- Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence.Oncogene · 2020Article
- The supply chain of human pancreatic β cell lines.The Journal of clinical investigation · 2019Review
- Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases.World journal of gastroenterology · 2019Review
- Article
- Endogenous Pancreatic β Cell Regeneration: A Potential Strategy for the Recovery of β Cell Deficiency in Diabetes.Frontiers in endocrinology · 2019Review
- Glucocorticoids and checkpoint tyrosine kinase inhibitors stimulate rat pancreatic beta cell proliferation differentially.PloS one · 2019Article
- Pancreatic β Cell Regeneration as a Possible Therapy for Diabetes.Cell metabolism · 2018Review
- A Pdx-1-Regulated Soluble Factor Activates Rat and Human Islet Cell Proliferation.Molecular and cellular biology · 2016Article
- A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform.Journal of visualized experiments : JoVE · 2016Article
- Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement.Transplantation · 2016Article
- SerpinB1 Promotes Pancreatic β Cell Proliferation.Cell metabolism · 2016Article
- Exploiting Expression of Hippo Effector, Yap, for Expansion of Functional Islet Mass.Molecular endocrinology (Baltimore, Md.) · 2015Article
- Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.Nature communications · 2015Article
- Early and Late G1/S Cyclins and Cdks Act Complementarily to Enhance Authentic Human β-Cell Proliferation and Expansion.Diabetes · 2015Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
The transcription factor HNF4α (hepatocyte nuclear factor-4α) is required for increased β-cell proliferation during metabolic stress in vivo. We hypothesized that HNF4α could induce proliferation of human β-cells. We employed adenoviral-mediated overexpression of an isoform of HNF4α (HNF4α8) alone, or in combination with cyclin-dependent kinase (Cdk)6 and Cyclin D3, in human islets. Heightened HNF4α8 expression led to a 300-fold increase in the number of β-cells in early S-phase. When we overexpressed HNF4α8 together with Cdk6 and Cyclin D3, β-cell cycle entry was increased even further. However, the punctate manner of bromodeoxyuridine incorporation into HNF4α(High) β-cells indicated an uncoupling of the mechanisms that control the concise timing and execution of each cell cycle phase. Indeed, in HNF4α8-induced bromodeoxyuridine(+,punctate) β-cells we observed signs of dysregulated DNA synthesis, cell cycle arrest, and activation of a double stranded DNA damage-associated cell cycle checkpoint mechanism, leading to the initiation of loss of β-cell lineage fidelity. However, a substantial proportion of β-cells stimulated to enter the cell cycle by Cdk6 and Cyclin D3 alone also exhibited a DNA damage response. HNF4α8 is a mitogenic signal in the human β-cell but is not sufficient for completion of the cell cycle. The DNA damage response is a barrier to efficient β-cell proliferation in vitro, and we suggest its evaluation in all attempts to stimulate β-cell replication as an approach to diabetes treatment.
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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.