ArticleProceedings of the National Academy of Sciences of the United States of America2016
Model-driven experimental approach reveals the complex regulatory distribution of p53 by the circadian factor Period 2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 99 citations in OpenAlex.
- PER2 knockdown drives immunotherapy resistance in gastric cancer via metabolic reprogramming of myeloid-derived suppressor cells.Cancer & metabolism · 2026Article
- The interplay between circadian rhythm components and apoptosis in health and disease.Human cell · 2026Review
- Circadian clock-gut microbiota axis in pulmonary hypertension: linking gut-lung crosstalk, immune timing and vascular remodeling.Frontiers in physiology · 2026Review
- How cells tame noise while maintaining ultrasensitive transcriptional responses.PLoS computational biology · 2025Article
- Clock genes in pancreatic disease progression: from circadian regulation to dysfunction.Annals of medicine · 2025Review
- Daytime-Dependent Effects of Thiamine on the Thiamine Pool and Pyruvate Dehydrogenase Regulation in the Brain and Heart.International journal of molecular sciences · 2025Article
- Regulation of Stemness by NR1D2 in Colorectal Cancer.Biomedicines · 2025Article
- Combining lineage correlations and a small molecule inhibitor to detect circadian control of the cell cycle.iScience · 2025Article
- The Influence of Circadian Rhythms on DNA Damage Repair in Skin Photoaging.International journal of molecular sciences · 2024Review
- Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response.Aging and disease · 2024Review
- Robotic Actuation-Mediated Quantitative Mechanogenetics for Noninvasive and On-Demand Cancer Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- The circadian clock as a potential biomarker and therapeutic target in pancreatic cancer.Molecular and cellular biochemistry · 2024Review
- Article
- Telling time in tumor samples reveals diversity of clock disruption.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Tumor circadian clock strength influences metastatic potential and predicts patient prognosis in luminal A breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Circadian clock crosstalks with autism.Brain and behavior · 2023Article
- Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.Cells · 2023Review
- A general model-based causal inference method overcomes the curse of synchrony and indirect effect.Nature communications · 2023Article
- Review
- Period2 is associated with immune cell infiltration and is a potential diagnostic and prognostic marker for hepatocellular carcinoma.Frontiers in molecular biosciences · 2023Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The circadian clock and cell cycle networks are interlocked on the molecular level, with the core clock loop exerting a multilevel regulatory role over cell cycle components. This is particularly relevant to the circadian factor Period 2 (Per2), which modulates the stability of the tumor suppressor p53 in unstressed cells and transcriptional activity in response to genotoxic stress. Per2 binding prevents Mdm2-mediated ubiquitination of p53 and, therefore, its degradation, and oscillations in the peaks of Per2 and p53 were expected to correspond. However, our findings showed that Per2 and p53 rhythms were significantly out-of-phase relative to each other in cell lysates and in purified cytoplasmic fractions. These seemingly conflicting experimental data motivated the use of a combined theoretical and experimental approach focusing on the role played by Per2 in dictating the phase of p53 oscillations. Systematic modeling of all possible regulatory scenarios predicted that the observed phase relationship between Per2 and p53 could be simulated if (i) p53 was more stable in the nucleus than in the cytoplasm, (ii) Per2 associates to various ubiquitinated forms of p53, and (iii) Per2 mediated p53 nuclear import. These predictions were supported by a sevenfold increase in p53's half-life in the nucleus and by in vitro binding of Per2 to the various ubiquitinated forms of p53. Last, p53's nuclear shuttling was significantly favored by ectopic expression of Per2 and reduced because of Per2 down-regulation. Our combined theoretical/mathematical approach reveals how clock regulatory nodes can be inferred from oscillating time course data.
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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.