Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry
Abstract
Cancer cells arise from normal cells through the acquisition of a series of mutations in oncogenes and tumour suppressor genes. Mouse models of human cancer often rely on germline alterations that activate or inactivate genes of interest. One limitation of this approach is that germline mutations might have effects other than somatic mutations, owing to developmental compensation. To model sporadic cancers associated with inactivation of the retinoblastoma (RB) tumour suppressor gene in humans, we have produced a conditional allele of the mouse Rb gene. We show here that acute loss of Rb in primary quiescent cells is sufficient for cell cycle entry and has phenotypic consequences different from germline loss of Rb function. This difference is explained in part by functional compensation by the Rb-related gene p107. We also show that acute loss of Rb in senescent cells leads to reversal of the cellular senescence programme. Thus, the use of conditional knockout strategies might refine our understanding of gene function and help to model human cancer more accurately.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In contrast to the senescence arrest of human fibroblasts, the senescence arrest of murine fibroblasts can be reversed by inactivating pRB.
“These mechanisms may explain another difference between rodent and human cells: in contrast to the senescence arrest of human fibroblasts (Beausejour et al., 2003), the senescence arrest of murine fibroblasts can be reversed by inactivating pRB (Sage et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Sage et al., 2003
RAS-induced senescent cells can resume cell proliferation upon acute inactivation of all three Rb family proteins.
“Indeed, a previous report showed that RAS-induced senescent cells can resume cell proliferation upon acute inactivation of all three Rb family proteins [40].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [40]
Cellular senescence can be reversible upon abrogation of the Rb or p53 pathways.
“As noted, cellular senescence can be reversible upon abrogation of the Rb or p53 pathways [40,41];”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [40]
Acute inactivation of RB is sufficient to promote proliferation in senescent mouse embryo fibroblasts.
“acute inactivation of RB is sufficient to promote proliferation in senescent mouse embryo fibroblasts (MEFs) (Sage et al., 2003)”
From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Sage et al., 2003
Mouse embryo fibroblast studies show that acute Rb ablation in quiescent cells leads to S phase entry and proliferation (Sage et al., 2003).
“In contrast, studies using mouse embryo fibroblasts show that acute ablation of Rb in quiescent cells leads to S phase entry and proliferation (Sage et al., 2003).”
From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Sage et al., 2003
Loss of RB may initiate cancer by allowing fully differentiated cells to re-enter the cell cycle.
“evidence indicates that loss of RB might initiate cancer by allowing fully differentiated cells to re-enter the cell cycle.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [31]
Acute loss of Rb causes cell cycle re-entry from quiescence in cultured mouse embryonic fibroblasts.
“acute loss of Rb results in cell cycle re-entry from quiescence in mouse embryonic fibroblasts in culture31.”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [31]
Dysfunctional telomeres are recognized as DNA double-strand breaks that impinge upon p53 and/or pRB tumor suppressor pathways, inducing p21 and p16 Ink4a to initiate replicative senescence.
“These results suggest that dysfunctional telomeres are recognized as DSBs that impinge upon p53 and/or pRB tumor suppressor pathways, to induce expression of their regulators p21 and p16 Ink4a to initiate replicative senescence24-26.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [26]
Cites
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · cited 1× · see citing works
“This result was confirmed in early-passage c Rb lox/lox MEFs induced to senesce prematurely with a retroviral construct expressing high levels of oncogenic Ras (H-Ras V12”
BackgroundSibling rivalry in the E2F family
Trimarchi, J. M., & Lees, J. A. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm714 · Cited by 1,158 · see citing works
The retinoblastoma tumour suppressor in development and cancer
Classon, M., & Harlow, E. (2002) · Nature Reviews Cancer · doi:10.1038/nrc950 · Cited by 738 · see citing works
Hurford, R. K., Cobrinik, D., Lee, M. H., & Dyson, N. (1997) · Genes & Development · doi:10.1101/gad.11.11.1447 · Cited by 431 · see citing works
Dannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H. (2000) · Genes & Development · doi:10.1101/gad.847700 · Cited by 413 · see citing works
Cellular senescence as a tumor-suppressor mechanism
Campisi, J. (2001) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)82148-6 · Cited by 390 · see citing works
Gire, V., & Wynford-Thomas, D. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1611 · Cited by 161 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,359 · see citing works
Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network
Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008) · Cell · doi:10.1016/j.cell.2008.03.039 · Cited by 2,086 · see citing works
“Although largely irreversible, upon acute inactivation of Rb or p53 genes senescence can be reversed (Beausejour et al., 2003; Dirac and Bernards, 2003; Sage et al., 2003).”
BackgroundSenescence surveillance of pre-malignant hepatocytes limits liver cancer development
Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011) · Nature · doi:10.1038/nature10599 · Cited by 1,621 · see citing works
Forging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104 · see citing works
Cellular mechanisms of tumour suppression by the retinoblastoma gene
Burkhart, D. L., & Sage, J. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2399 · Cited by 974 · see citing works
Self-citationKregel, K. C., & Zhang, H. J. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00327.2006 · Cited by 883 · see citing works
Genetic compensation: A phenomenon in search of mechanisms
El-Brolosy, M. A., & Stainier, D. Y. R. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006780 · Cited by 829 · see citing works
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Li, Z., Cai, X., Cai, C.-L., Wang, J., Zhang, W., Petersen, B. E., Yang, F.-C., & Xu, M. (2011) · Blood · doi:10.1182/blood-2010-12-325241 · Cited by 671 · see citing works
The dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588 · see citing works
Aging and Genome Maintenance: Lessons from the Mouse?
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H., & Vijg, J. (2003) · Science · doi:10.1126/science.1079161 · Cited by 553 · see citing works
Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S.-I., Tahara, H., Nakayama, K., Nakayama, K. I., Ide, T., Saya, H., & Hara, E. (2006) · Nature Cell Biology · doi:10.1038/ncb1491 · Cited by 528 · see citing works
Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity
Kinker, G. S., Greenwald, A. C., Tal, R., Orlova, Z., Cuoco, M. S., McFarland, J. M., Warren, A., Rodman, C., Roth, J. A., Bender, S. A., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-00726-6 · Cited by 445 · see citing works
CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors
Vora, S. R., Juric, D., Kim, N., Mino-Kenudson, M., Huynh, T., Costa, C., Lockerman, E. L., Pollack, S. F., Liu, M., Li, X., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.05.020 · Cited by 438 · see citing works
Rb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment
Walkley, C. R., Shea, J. M., Sims, N. A., Purton, L. E., & Orkin, S. H. (2007) · Cell · doi:10.1016/j.cell.2007.03.055 · Cited by 424 · see citing works
Senescence-associated inflammatory responses: aging and cancer perspectives
Lasry, A., & Ben-Neriah, Y. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.009 · Cited by 408 · see citing works
Telomere dysfunction and tumour suppression: the senescence connection
Deng, Y., Chan, S. S., & Chang, S. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2393 · Cited by 411 · see citing works
Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence
Chicas, A., Wang, X., Zhang, C., McCurrach, M., Zhao, Z., Mert, O., Dickins, R. A., Narita, M., Zhang, M., & Lowe, S. W. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.023 · Cited by 388 · see citing works
The RETINOBLASTOMA-RELATED Gene Regulates Stem Cell Maintenance in Arabidopsis Roots
Wildwater, M., Campilho, A., Perez-Perez, J. M., Heidstra, R., Blilou, I., Korthout, H., Chatterjee, J., Mariconti, L., Gruissem, W., & Scheres, B. (2005) · Cell · doi:10.1016/j.cell.2005.09.042 · Cited by 395 · see citing works
Oncogene-Induced Cell Senescence — Halting on the Road to Cancer
Mooi, W. J., & Peeper, D. S. (2006) · New England Journal of Medicine · doi:10.1056/nejmra062285 · Cited by 371 · see citing works
Choi, J., Southworth, L. K., Sarin, K. Y., Venteicher, A. S., Ma, W., Chang, W., Cheung, P., Jun, S., Artandi, M. K., Shah, N., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.0040010 · Cited by 336 · see citing works
The Requirement for Cyclin D Function in Tumor Maintenance
Choi, Y. J., Li, X., Hydbring, P., Sanda, T., Stefano, J., Christie, A. L., Signoretti, S., Look, A. T., Kung, A. L., von Boehmer, H., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.09.015 · Cited by 342 · see citing works
Mechanisms of cellular senescence in human and mouse cells.
Itahana, K., Campisi, J., & Dimri, G. P. (2004) · Biogerontology · doi:10.1023/b:bgen.0000017682.96395.10 · Cited by 338 · see citing works
Braun, B. S., Tuveson, D. A., Kong, N., Le, D. T., Kogan, S. C., Rozmus, J., Le Beau, M. M., Jacks, T. E., & Shannon, K. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307203101 · Cited by 299 · see citing works
Self-citationOhtani, N., Yamakoshi, K., Takahashi, A., & Hara, E. (2004) · The Journal of Medical Investigation · doi:10.2152/jmi.51.146 · Cited by 276 · see citing works
Oncogene-Induced Senescence: Putting the Brakes on Tumor Development
Braig, M., & Schmitt, C. A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4006 · Cited by 274 · see citing works
Cellular senescence and cancer treatment
Schmitt, C. A. (2007) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2006.08.005 · Cited by 254 · see citing works
Denchi, E. L., Attwooll, C., Pasini, D., & Helin, K. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.7.2660-2672.2005 · Cited by 195 · see citing works
Differentiated Horizontal Interneurons Clonally Expand to Form Metastatic Retinoblastoma in Mice
Ajioka, I., Martins, R. A. P., Bayazitov, I. T., Donovan, S., Johnson, D. A., Frase, S., Cicero, S. A., Boyd, K., Zakharenko, S. S., & Dyer, M. A. (2007) · Cell · doi:10.1016/j.cell.2007.09.036 · Cited by 184 · see citing works
Schvartzman, J.-M., Duijf, P. H. G., Sotillo, R., Coker, C., & Benezra, R. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.04.017 · Cited by 181 · see citing works
Tissue-specific and reversible RNA interference in transgenic mice
Dickins, R. A., McJunkin, K., Hernando, E., Premsrirut, P. K., Krizhanovsky, V., Burgess, D. J., Kim, S. Y., Cordon-Cardo, C., Zender, L., Hannon, G. J., et al. (2007) · Nature Genetics · doi:10.1038/ng2045 · Cited by 174 · see citing works
Viatour, P., Somervaille, T. C., Venkatasubrahmanyam, S., Kogan, S., McLaughlin, M. E., Weissman, I. L., Butte, A. J., Passegué, E., & Sage, J. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.07.009 · Cited by 178 · see citing works
Self-citationRegulation of DNA Methyltransferase 1 by the pRb/E2F1 Pathway
McCabe, M. T., Davis, J. N., & Day, M. L. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-2158 · Cited by 172 · see citing works
The search for the retinoblastoma cell of origin
Dyer, M. A., & Bremner, R. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1545 · Cited by 170 · see citing works
The role of cellular senescence and SASP in tumour microenvironment
Takasugi, M., Yoshida, Y., Hara, E., & Ohtani, N. (2023) · The FEBS Journal · doi:10.1111/febs.16381 · Cited by 144 · see citing works
Ruiz, S., Santos, M., Segrelles, C., Leis, H., Jorcano, J. L., Berns, A., Paramio, J. M., & Vooijs, M. (2004) · Development · doi:10.1242/dev.01148 · Cited by 147 · see citing works
Ink4a/Arf links senescence and aging
Sharpless, N. E. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2004.06.025 · Cited by 142 · see citing works
Sankaran, V. G., Orkin, & Walkley, C. R. (2008) · Genes & Development · doi:10.1101/gad.1627208 · Cited by 133 · see citing works
The Retinoblastoma Protein Regulates Pericentric Heterochromatin
Isaac, C. E., Francis, S. M., Martens, A. L., Julian, L. M., Seifried, L. A., Erdmann, N., Binné, U. K., Harrington, L., Sicinski, P., Bérubé, N. G., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.9.3659-3671.2006 · Cited by 128 · see citing works
Blais, A., van Oevelen, C. J. C., Margueron, R., Acosta-Alvear, D., & Dynlacht, B. D. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200705051 · Cited by 126 · see citing works
To clear, or not to clear (senescent cells)? That is the question
Lujambio, A. (2016) · BioEssays · doi:10.1002/bies.201670910 · Cited by 108 · see citing works
Liver-Specific pRB Loss Results in Ectopic Cell Cycle Entry and Aberrant Ploidy
Mayhew, C. N., Bosco, E. E., Fox, S. R., Okaya, T., Tarapore, P., Schwemberger, S. J., Babcock, G. F., Lentsch, A. B., Fukasawa, K., & Knudsen, E. S. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4221 · Cited by 101 · see citing works
Transcriptional regulation of cellular senescence
Lanigan, F., Geraghty, J. G., & Bracken, A. P. (2011) · Oncogene · doi:10.1038/onc.2011.34 · Cited by 95 · see citing works
RB signaling prevents replication-dependent DNA double-strand breaks following genotoxic insult
Bosco, E. E. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkg919 · Cited by 97 · see citing works
Weber, T., Corbett, M. K., Chow, L. M. L., Valentine, M. B., Baker, S. J., & Zuo, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708061105 · Cited by 89 · see citing works
Wei, W., Herbig, U., Wei, S., Dutriaux, A., & Sedivy, J. M. (2003) · The EMBO Reports · doi:10.1038/sj.embor.7400001 · Cited by 88 · see citing works
Singh, H. P., Wang, S., Stachelek, K., Lee, S., Reid, M. W., Thornton, M. E., Craft, C. M., Grubbs, B. H., & Cobrinik, D. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1808903115 · Cited by 78 · see citing works
The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence
Haferkamp, S., Tran, S. L., Becker, T. M., Scurr, L. L., Kefford, R. F., & Rizos, H. (2009) · Aging · doi:10.18632/aging.100051 · Cited by 77 · see citing works
Markers of cellular senescence.
Carnero, A. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_4 · Cited by 68 · see citing works
Walkley, C. R., & Orkin, S. H. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603389103 · Cited by 71 · see citing works
Camarda, G., Siepi, F., Pajalunga, D., Bernardini, C., Rossi, R., Montecucco, A., Meccia, E., & Crescenzi, M. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200408164 · Cited by 69 · see citing works
Zuo, S., Liu, C., Wang, J., Wang, F., Xu, W., Cui, S., Yuan, L., Chen, X., Fan, W., Cui, M., et al. (2012) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-012-1153-y · Cited by 58 · see citing works
Cellular senescence: a double‐edged sword in the fight against cancer
Ohtani, N., Takahashi, A., Mann, D. J., & Hara, E. (2012) · Experimental Dermatology · doi:10.1111/j.1600-0625.2012.01493.x · Cited by 57 · see citing works
Kong, L.-J., Meloni, A. R., & Nevins, J. R. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.02.016 · Cited by 48 · see citing works
Differential role of RB in response to UV and IR damage
Bosco, E. E. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki283 · Cited by 24 · see citing works
Stress-induced cellular senescence contributes to chronic inflammation and cancer progression.
KOBASHIGAWA, S., M. SAKAGUCHI, Y., MASUNAGA, S., & MORI, E. (2019) · Thermal Medicine · doi:10.3191/thermalmed.35.41 · Cited by 18 · see citing works
- Authors
- Sage, J., Miller, A. L., Pérez-Mancera, P. A., Wysocki, J. M., & Jacks, T.
- Affiliations
- Universidad de Salamanca (ES)
- Massachusetts Institute of Technology (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- Venue
- Nature
- Published
- 2003-07
- Volume
- 424
- Issue
- 6945
- Pages
- 223-228
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2034962229
- Cited by
- 538
- References
- 7
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 12 · 2021: 16 · 2020: 14 · 2019: 14 · 2018: 19 · 2017: 11 · 2016: 19 · 2015: 23 · 2014: 18 · 2013: 18 · 2012: 30
- FWCI
- 22.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Ophthalmology › Ocular Oncology and Treatments
- Keywords
- retinoblastoma gene, Rb, conditional knockout, cell cycle re-entry, quiescent cells, p107, cellular senescence, senescence reversal, tumor suppressor inactivation, developmental compensation, mouse tumor model
- MeSH terms
- Animals, Cell Cycle, Cell Line, Disease Models, Animal, Humans, Mice, Inbred C57BL, Nuclear Proteins, Genes, Retinoblastoma, Cyclins, Cellular Senescence, Gene Deletion, Germ-Line Mutation, Gene Targeting, Cyclin-Dependent Kinase Inhibitor p16, Retinoblastoma-Like Protein p107, Cyclin-Dependent Kinase Inhibitor p21, 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 ›
Are you an author, or do you see a problem with this page? Request a review
