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Ablation of the Retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth-restricting conditions
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The retinoblastoma suppressor pRB belongs to the family of so-called pocket proteins, which also includes p107 and p130. These proteins may functionally overlap in cell cycle control and tumor suppression. We have generated an isogenic set of embryonic stem (ES) cell lines carrying single or compound loss-of-function mutations in the Rb gene family, including a cell line completely devoid of all three pocket proteins. None of the knockout combinations affected the growth characteristics of ES cells; however, concomitant ablation of all three pocket proteins strongly impaired their differentiation capacity. For the generated genotypes, primary mouse embryonic fibroblasts (MEFs) also were obtained. While inactivation of Rb alone did not alleviate the senescence response of MEFs, pRB/p107-deficient MEFs, after having adapted to in vitro culturing, continued to proliferate at modest rate. Additional ablation of p130 rendered MEFs completely insensitive to senescence-inducing signals and strongly increased their proliferation rate. Although triple-knockout MEFs retained anchorage dependence, they lacked proper G 1 control and showed increased cell turnover under growth-inhibiting conditions.
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“In ES cells, ablation of all three RB family members (RB, p107 and p130) results in impaired differentiation and an increase in cell turnover under growth arrest conditions69.”
From Molecular regulation of stem cell quiescence (2013) · cites this paper as [69]
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Metadata
- Authors
- Dannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-12-01
- Volume
- 14
- Issue
- 23
- Pages
- 3051-3064
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317114
- OpenAlex
- W2001004678
- Cited by
- 413
- References
- 96
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 8 · 2020: 12 · 2019: 3 · 2018: 12 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 11 · 2013: 21 · 2012: 17
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Keywords
- retinoblastoma protein, p107, p130, pocket proteins, cellular senescence, cell immortalization, cell turnover, embryonic stem cells, mouse embryonic fibroblasts, differentiation capacity, loss-of-function mutations, tumor suppression
- MeSH terms
- Animals, Cell Adhesion, Cell Differentiation, Cell Division, Cell Line, Mice, Inbred C57BL, Mice, Nude, Nuclear Proteins, Phosphoproteins, Proteins, Stem Cells, Tumor Suppressor Protein p53, Retinoblastoma Protein, G1 Phase, Teratocarcinoma, Mice, Knockout, Tumor Suppressor Protein p14ARF, Retinoblastoma-Like Protein p130, Retinoblastoma-Like Protein p107, Mice
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