Targeted disruption of the three Rb-related genes leads to loss of G 1 control and immortalization
Open accessAbstract
The retinoblastoma protein, pRB, and the closely related proteins p107 and p130 are important regulators of the mammalian cell cycle. Biochemical and genetic studies have demonstrated overlapping as well as distinct functions for the three proteins in cell cycle control and mouse development. However, the role of the pRB family as a whole in the regulation of cell proliferation, cell death, or cell differentiation is not known. We generated embryonic stem (ES) cells and other cell types mutant for all three genes. Triple knock-out mouse embryonic fibroblasts (TKO MEFs) had a shorter cell cycle than wild-type, single, or double knock-out control cells. TKO cells were resistant to G 1 arrest following DNA damage, despite retaining functional p53 activity. They were also insensitive to G 1 arrest signals following contact inhibition or serum starvation. Finally, TKO MEFs did not undergo senescence in culture and do possess some characteristics of transformed cells. Our results confirm the essential role of the Rb family in the control of the G 1 /S transition, place the three Rb family members downstream of multiple cell cycle control pathways, and further the link between loss of cell cycle control and tumorigenesis.
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Inactivation of Tp53, the genes encoding either one of the three Rb family members or Suv39h1 in already senescent cells enables cell cycle re-entry out of the terminal arrest condition.
“Conversely, inactivation of Tp53 , the genes encoding either one of the three Rb family members or Suv39h1 in already senescent cells enables cell cycle re- entry out of the terminal arrest condition 5,125,126 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [126]
The Abstract and “Convergence of growth arrest signals on the Rb family” (page not provided) report that mouse embryonic fibroblasts lacking all three Rb-family genes fail to undergo senescence or arrest in G1. They do not show that inactivating any one Rb-family gene in already senescent cells causes cell-cycle re-entry. The cited passages also do not establish that result for Tp53 or Suv39h1. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGenetic interference with senescence-essential factors, especially using inducible systems, underscored that, similar to other biological states, senescence is not necessarily irreversible.
“Of note, genetic interference with senescence- essential factors, especially using inducible systems, underscored that, similar to other biological states, senescence is not necessarily irreversible 125,126,149 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [126]
The “TKO MEFs are immortal” section reports that genetic loss of all three pRB-family genes allowed mouse embryonic fibroblasts to bypass senescence. It does not describe an inducible system or show that cells already in senescence resumed proliferation; bypassing senescence does not establish its reversibility. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMouse embryonic fibroblasts lacking p53 but not Ink4a (p16) or RB escape Ras-induced senescence.
“For example, mouse embryonic fibroblasts (MEFs) lacking p53 [72] but not Ink4a (p16) or RB [73,74,75] escape Ras-induced senescence.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [73]
RB family members have redundant activity in repressing replication genes during quiescence.
“Conversely, RB family members have redundant activity in repressing these genes during quiescence [73].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [73]
The RB proteins have redundant and/or compensatory functions.
“There is ample evidence that the RB proteins have redundant and/or compensatory functions (Sage et al., 2000).”
From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Sage et al., 2000
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Self-citation
- Authors
- Sage, J., Mulligan, G. J., Attardi, L. D., Miller, A., Chen, S., Williams, B., Theodorou, E., & Jacks, T.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-12-01
- Volume
- 14
- Issue
- 23
- Pages
- 3037-3050
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317090
- OpenAlex
- W2104775085
- Cited by
- 582
- References
- 12
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 12 · 2021: 12 · 2020: 11 · 2019: 7 · 2018: 15 · 2017: 12 · 2016: 11 · 2015: 15 · 2014: 13 · 2013: 22 · 2012: 26
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- retinoblastoma protein, p107, p130, G1/S transition, G1 cell cycle arrest, cell cycle regulation, cell immortalization, senescence, DNA damage resistance, contact inhibition, serum deprivation, p53, carcinogenesis, embryonic stem cells
- MeSH terms
- Animals, Cell Cycle, Cell Division, Cell Survival, Cell Transformation, Neoplastic, Cells, Cultured, DNA Damage, Doxorubicin, Mice, Inbred C57BL, Nuclear Proteins, Phosphoproteins, Proteins, Genes, ras, Retinoblastoma Protein, G1 Phase, Culture Media, Serum-Free, Mice, Knockout, Gene Targeting, Retinoblastoma-Like Protein p130, Retinoblastoma-Like Protein p107, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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