ArticleCell death and differentiation2016
An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress.
Article in Cell death and differentiation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 22 citations in OpenAlex.
- Cell-cycle targeted cancer therapy: clinical advances, biological gaps, and the emergence of selective CDK4 inhibitors.Journal of hematology & oncology · 2026Review
- Tumor cell cycle regulation: integrated perspective of stage characteristics, regulatory networks, and signaling pathway intervention strategies.Molecular biomedicine · 2026Review
- Structural analysis of the impact of germline mutations of p16 in melanoma prone families.Molecular diversity · 2025Article
- Comprehensive profiling of RNA modification-related genes identifies RNA mExperimental & molecular medicine · 2025Article
- Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon.Molecules (Basel, Switzerland) · 2023Review
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- Extracellular Vesicles fromInternational journal of molecular sciences · 2022Article
- An Unanticipated Modulation of Cyclin-Dependent Kinase Inhibitors: The Role of Long Non-Coding RNAs.Cells · 2022Review
- Polyphenols: Chemoprevention and therapeutic potentials in hematological malignancies.Frontiers in nutrition · 2022Review
- Reviewing cancer's biology: an eclectic approach.Journal of the Egyptian National Cancer Institute · 2021Review
- Cellular senescence or stemness: hypoxia flips the coin.Journal of experimental & clinical cancer research : CR · 2021Review
- Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology.Cellular and molecular life sciences : CMLS · 2021Review
- Mitogen Synergy: An Emerging Route to Boosting Human Beta Cell Proliferation.Frontiers in cell and developmental biology · 2021Review
- Review
- Emerging Roles for Ciz1 in Cell Cycle Regulation and as a Driver of Tumorigenesis.Biomolecules · 2016Review
- Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Coordinately Modulates Cell Cycle Regulatory Genes and Intrinsic and Extrinsic Apoptotic Pathway Genes to Induce Apoptosis in Human Glioblastoma, Medulloblastoma, and Acute Lymphoblastic Leukemia Cells.Iranian journal of pharmaceutical research : IJPRArticle
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Cell-cycle inhibitors of the Ink4 and Cip/Kip families are involved in cellular senescence and tumor suppression. These inhibitors are individually dispensable for the cell cycle and inactivation of specific family members results in increased proliferation and enhanced susceptibility to tumor development. We have now analyzed the consequences of eliminating a substantial part of the cell-cycle inhibitory activity in the cell by generating a mouse model, which combines the absence of both p21(Cip1) and p27(Kip1) proteins with the endogenous expression of a Cdk4 R24C mutant insensitive to Ink4 inhibitors. Pairwise combination of Cdk4 R24C, p21-null and p27-null alleles results in frequent hyperplasias and tumors, mainly in cells of endocrine origin such as pituitary cells and in mesenchymal tissues. Interestingly, complete abrogation of p21(Cip1) and p27(Kip1) in Cdk4 R24C mutant mice results in a different phenotype characterized by perinatal death accompanied by general hypoplasia in most tissues. This phenotype correlates with increased replicative stress in developing tissues such as the nervous system and subsequent apoptotic cell death. Partial inhibition of Cdk4/6 rescues replicative stress signaling as well as p53 induction in the absence of cell-cycle inhibitors. We conclude that one of the major physiological activities of cell-cycle inhibitors is to prevent replicative stress during development.
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