ArticleCell cycle (Georgetown, Tex.)2021
Activation of CDC25A phosphatase is limited by CDK2/cyclin A-mediated feedback inhibition.
Article in Cell cycle (Georgetown, Tex.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 52 citations in OpenAlex.
- WITHDRAWN: From CDK4/6 to CDK2 and KAT: Evolving therapeutic approaches in HR+/HER2- breast cancer.Breast (Edinburgh, Scotland) · 2026Article
- Article
- Targeting PCNA/PARP1 axis inhibits the malignant progression of hepatocellular carcinoma.Frontiers in pharmacology · 2025Article
- Alfalfa xenomiR-162 targets G protein subunit gamma 11 to regulate milk protein synthesis in bovine mammary epithelial cells.Animal bioscience · 2024Article
- Potential of CDC25 phosphatases in cancer research and treatment: key to precision medicine.Frontiers in pharmacology · 2024Review
- Mechanistic analysis of Tanshinone IIA's regulation of the ATM/GADD45/ORC signaling pathway to reduce myocardial ischemia-reperfusion injury.Frontiers in pharmacology · 2024Article
- Key molecular DNA damage responses of human cells to radiation.Frontiers in cell and developmental biology · 2024Review
- CDC25A inhibition suppresses cell proliferation and induces GMolecular medicine reports · 2023Article
- Cyclin A-CDK1 suppresses the expression of the CDK1 activator CDC25A to safeguard timely mitotic entry.The Journal of biological chemistry · 2023Article
- The Regulation of Cyclins and Cyclin-Dependent Kinases in the Development of Gastric Cancer.International journal of molecular sciences · 2023Review
- SRSF10 stabilizes CDC25A by triggering exon 6 skipping to promote hepatocarcinogenesis.Journal of experimental & clinical cancer research : CR · 2022Article
- Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer.Cancers · 2022Review
- Objective to identify and verify the regulatory mechanism of DTNBP1 as a prognostic marker for hepatocellular carcinoma.Scientific reports · 2022Article
- Adapalene Inhibits Prostate Cancer Cell ProliferationFrontiers in pharmacology · 2022Article
- Inhibition of Protein Synthesis Induced by CHK1 Inhibitors Discriminates Sensitive from Resistant Cancer Cells.ACS pharmacology & translational science · 2021Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Cyclin-dependent kinase (CDK) 1 complexed with cyclin B is a driver of mitosis, while CDK2 drives S phase entry and replicon initiation. CDK2 activity increases as cells progress through S phase, and its cyclin partner switches from cyclin E to cyclin A. Activation of CDK2 requires dephosphorylation of tyrosine-15 by CDC25A. DNA damage activates the checkpoint protein CHK1, which phosphorylates and degrades CDC25A to prevent activation of CDK2 and protect from cell cycle progression before damage is repaired. CHK1 inhibitors were developed to circumvent this arrest and enhance the efficacy of many cancer chemotherapeutic agents. CHK1 inhibition results in the accumulation of CDC25A and activation of CDK2. We demonstrate that inhibition of CDK2 or suppression of cyclin A also results in accumulation of CDC25A suggesting a feedback loop that prevents over activation of this pathway. The feedback inhibition of CDC25A targets phosphorylation of S88-CDC25A, which resides within a CDK consensus sequence. In contrast, it appears that CDK complexes with cyclin B (and possibly cyclin E) stabilize CDC25A in a feed-forward activation loop. While CDK2/cyclin A would normally be active at late S/G2, we propose that this feedback inhibitory loop prevents over activation of CDK2 in early S phase, while still leaving CDK2/cyclin E to catalyze replicon initiation. One importance of this observation is that a subset of cancer cell lines are very sensitive to CHK1 inhibition, which is mediated by CDK2/cyclin A activity in S phase cells. Hence, dysregulation of this feedback loop might facilitate sensitivity of the cells.
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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.