CoChat
Sign Up
Cited by 975Cancer-related Molecular PathwaysChromatin Remodeling and CancerOcular Oncology and Treatments

Cellular mechanisms of tumour suppression by the retinoblastoma gene

Open access
Burkhart, Deborah L., Sage, Julien·2008·Nature Reviews Cancer
DOI 10.1038/nrc2399PMC PMC6996492
Open this paper in CoChat — free account

Abstract

The retinoblastoma (RB) tumour suppressor gene is functionally inactivated in a broad range of paediatric and adult cancers, and a plethora of cellular functions and partners have been identified for the RB protein. Data from human tumours and studies from mouse models indicate that loss of RB function contributes to both cancer initiation and progression. However, we still do not know the identity of the cell types in which RB normally prevents cancer initiation in vivo, and the specific functions of RB that suppress distinct aspects of the tumorigenic process are poorly understood.

Integrity signals

Registry

Crossref · 10.1038/nrc2399

Cites

221 of 221 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 226 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Mouse genetic studies confirm that RB is crucial in preventing initiation of small-cell lung carcinoma.

    “mouse genetic studies have confirmed that RB is crucial in preventing the initiation of this lung cancer sub-type24”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Meuwissen, R. et al. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 4, 181–189 (2003). Describes a mouse model of human SCLC, the only adult tumour type in which loss of RB function occurs in most, if not all cases. source

      Not checked in the free run.

  • Premisecitation

    p130, rather than RB, binds to promoters of genes in G0 cells.

    “Whereas p130, rather than RB, binds to the promoters of genes in G0 cells28–30”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28] Smith, E. J., Leone, G., DeGregori, J., Jakoi, L. & Nevins, J. R. The accumulation of an E2F-p130 transcriptional repressor distinguishes a G0 cell state from a G1 cell state. Mol. Cell. Biol. 16, 6965–6976 (1996). source

      Not checked in the free run.

    • cites [29] Balciunaite, E. et al. Pocket protein complexes are recruited to distinct targets in quiescent and proliferating cells. Mol. Cell. Biol. 25, 8166–8178 (2005). source

      Not checked in the free run.

    • cites [30] Takahashi, Y., Rayman, J. B. & Dynlacht, B. D. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 14, 804–816 (2000). source

      Not checked in the free run.

  • Premisecitation

    Upstream regulators of RB are involved in cancer initiation in patients across several organs.

    “upstream regulators of RB have been involved in cancer initiation in patients, both in familial and sporadic cases, and in several organs and tissues25–27.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] Ranade, K. et al. Mutations associated with familial melanoma impair p16INK4 function. Nature Genet. 10, 114–116 (1995). source

      Not checked in the free run.

    • cites [26] Zuo, L. et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet. 12, 97–99 (1996). source

      Not checked in the free run.

    • cites [27] Berman, H. et al. Genetic and epigenetic changes in mammary epithelial cells identify a subpopulation of cells involved in early carcinogenesis. Cold Spring Harb. Symp. Quant. Biol. 70, 317–327 (2005). source

      Not checked in the free run.

  • Premisecitation

    Experiments with genetically modified mice demonstrate that loss of Rb is a causal event in many cancer types.

    “the high penetrance of pituitary and thyroid tumours in Rb+/− mice and the development of other tumours in mice that have been subjected to tissue-specific Rb deletion using the Cre–lox system demonstrate that loss of Rb is a causal event in many cancer types7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Wikenheiser-Brokamp, K. A. Retinoblastoma family proteins: insights gained through genetic manipulation of mice. Cell Mol. Life Sci. 63, 767–780 (2006). source

      Not checked in the free run.

  • Premisecitation

    RB is an adaptor protein that recruits chromatin remodelling enzymes to control specific target genes and modify chromatin structure chromosome-wide.

    “Furthermore, RB is also an adaptor protein that recruits chromatin remodelling enzymes to control the expression of specific target genes and to modify chromatin structure at a chromosome-wide level13,14”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Gonzalo, S. & Blasco, M. A. Role of Rb family in the epigenetic definition of chromatin. Cell Cycle 4, 752–755 (2005). source

      Not checked in the free run.

    • cites [14] Brehm, A. & Kouzarides, T. Retinoblastoma protein meets chromatin. Trends Biochem. Sci. 24, 142–145 (1999). source

      Not checked in the free run.

  • May combine two claims. 44
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    RB is a transcriptional co-factor that can bind and either antagonize or potentiate numerous transcription factors.

    “RB is now viewed as a transcriptional co-factor that can bind to and either antagonize or potentiate the function of numerous transcription factors11,12.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Morris, E. J. & Dyson, N. J. Retinoblastoma protein partners. Adv. Cancer Res. 82, 1–54 (2001). source

      Not checked in the free run.

    • cites [12] Macaluso, M., Montanari, M. & Giordano, A. Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes. Oncogene 25, 5263–5267 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of RB is the initiating event in familial and sporadic retinoblastoma.

    “it is well-accepted that loss of RB is the initiating event in these familial retinal tumours, as well as in sporadic cases15–17.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Knudson, A. G., Jr. Genetic predisposition to cancer. Cancer Detect Prev. 7, 1–8 (1984).

      Not checked in the free run.

    • cites [16] Corson, T. W. & Gallie, B. L. One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes Chromosomes Cancer 46, 617–634 (2007). source

      Not checked in the free run.

    • cites [17] Dimaras, H. et al. Loss of RB1 induces non-proliferative retinoma; increasing genomic instability correlates with progression to retinoblastoma. Hum. Mol. Genet. (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RB controls p27 stability through APC/C, contributing to G1 arrest, so E2Fs are not the only mediators of RB's G1-S control.

    “Recent studies have also demonstrated that control of the stability of the p27 cell cycle inhibitor (which is encoded by CDKN1B) by RB, through the interaction of RB with the anaphase-promoting complex/cyclosome (APC/C), is an important part of the capacity of RB to arrest cells in G1; therefore, E2Fs are not the sole mediators of the capacity of RB to control the G1–S transition5,6.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Ji, P. et al. An Rb–Skp2–p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant. Mol. Cell 16, 47–58 (2004). source

      Not checked in the free run.

    • cites [6] Binne, U. K. et al. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nature Cell Biol. 9, 225–232 (2007). References 5 and 6 demonstrate that the role of RB in cell cycle control is not solely mediated through its interactions with E2F transcription factors. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RB belongs to a family with p107 and p130, which are structurally and functionally related, share the same pathway, but have distinct functions in specific contexts.

    “In mammalian cells, RB belongs to a family of three proteins that also includes p107 and p130, which are structurally and functionally related to RB and belong to the same cellular pathway, but display distinct functions from RB in specific contexts4,7–10”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [4] Dannenberg, J. H. & te Riele, H. P. The retinoblastoma gene family in cell cycle regulation and suppression of tumorigenesis. Results Probl. Cell Differ. 42, 183–225 (2006). source

      Not checked in the free run.

    • cites [7] Wikenheiser-Brokamp, K. A. Retinoblastoma family proteins: insights gained through genetic manipulation of mice. Cell Mol. Life Sci. 63, 767–780 (2006). source

      Not checked in the free run.

    • cites [8] Cobrinik, D. Pocket proteins and cell cycle control. Oncogene 24, 2796–2809 (2005). source

      Not checked in the free run.

    • cites [9] Claudio, P. P., Tonini, T. & Giordano, A. The retinoblastoma family: twins or distant cousins? Genome Biol. 3, reviews3012 (2002). source

      Not checked in the free run.

    • cites [10] Classon, M. & Dyson, N. p107 and p130: versatile proteins with interesting pockets. Exp. Cell Res. 264, 135–147. (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RB has multiple cellular roles beyond the G1 checkpoint, including control of differentiation, regulation of apoptosis, maintenance of permanent cell cycle arrest, and preservation of chromosomal stability.

    “It is now believed that RB has many cellular roles in addition to serving as a G1 checkpoint, including control of cellular differentiation during embryogenesis and in adult tissues, regulation of apoptotic cell death, maintenance of permanent cell cycle arrest and preservation of chromosomal stability3,4.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Zheng, L. & Lee, W. H. The retinoblastoma gene: a prototypic and multifunctional tumor suppressor. Exp. Cell Res. 264, 2–18 (2001). source

      Not checked in the free run.

    • cites [4] Dannenberg, J. H. & te Riele, H. P. The retinoblastoma gene family in cell cycle regulation and suppression of tumorigenesis. Results Probl. Cell Differ. 42, 183–225 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In HPV-induced cervical cancers, the virus initiates cancer in dividing basal epithelial cells, preventing normal cell cycle exit and maturation.

    “in HPV-induced cervical cancers, the virus initiates cancer in dividing cells in the basal layer of the epithelium, preventing their normal cell cycle exit and maturation21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Doorbar, J. Molecular biology of human papillomavirus infection and cervical cancer. Clin. Sci. 110, 525–541 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RB participates in and potentially modulates heterochromatin formation in senescent cells.

    “RB has also been shown to participate in and potentially modulate the structure and location of heterochromatin formation in senescent cells40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In cycling progenitor cells, loss of RB may accelerate proliferation and prevent normal G1 cell cycle exit associated with differentiation.

    “In these cells, loss of RB might accelerate proliferation and prevent normal cell cycle exit in G1, which is associated with differentiation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In muscle cells, loss of Rb function can result in no cell cycle re-entry or in re-entry followed by a G2 block, depending on culture conditions.

    “In muscle cells, loss of Rb function can result in no cell cycle re-entry45,46 or in cell cycle re-entry followed by a block in G2 (REF. 47), depending on the culture conditions.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Camarda, G. et al. A pRb-independent mechanism preserves the postmitotic state in terminally differentiated skeletal muscle cells. J. Cell Biol. 167, 417–423 (2004). source

      Not checked in the free run.

    • cites [46] Huh, M. S., Parker, M. H., Scime, A., Parks, R. & Rudnicki, M. A. Rb is required for progression through myogenic differentiation but not maintenance of terminal differentiation. J. Cell Biol. 166, 865–876 (2004). source

      Not checked in the free run.

    • cites [47] Blais, A., van Oevelen, C. J., Margueron, R., Acosta-Alvear, D. & Dynlacht, B. D. Retinoblastoma tumor suppressor protein-dependent methylation of histone H3 lysine 27 is associated with irreversible cell cycle exit. J. Cell Biol. 179, 1399–1412 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rb inactivation in mouse retinal progenitors causes cell-autonomous defects in cell cycle exit, differentiation defects, proliferation in differentiating cells, and increased cell death.

    “Rb inactivation in mouse retinal progenitors results in cell-autonomous defects in cell cycle exit, specific differentiation defects, proliferation in differentiating cells and increased cell death.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [50] Chen, D. et al. Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma. Cancer Cell 5, 539–551 (2004). source

      Not checked in the free run.

    • cites [51] MacPherson, D. et al. Cell type-specific effects of Rb deletion in the murine retina. Genes Dev. 18, 1681–1694 (2004). source

      Not checked in the free run.

    • cites [55] Zhang, J. et al. Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nature Genet. 36, 351–360 (2004). source

      Not checked in the free run.

    • cites [56] Dyer, M. A. & Bremner, R. The search for the retinoblastoma cell of origin. Nature Rev. Cancer 5, 91–101 (2005). source

      Not checked in the free run.

    • cites [57] Pacal, M. & Bremner, R. Insights from animal models on the origins and progression of retinoblastoma. Curr. Mol. Med. 6, 759–781 (2006). References 50, 51 and 55, and the two reviews 56 and 57 describe the first breedable mouse models of retinoblastoma and investigate the mechanisms of tumorigenesis in the retina.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the cochlea, Rb deletion increases proliferation of precursor cells; mature mechanosensory hair cells can re-enter the cell cycle but fail to complete division.

    “In the cochlea, Rb deletion allows increased proliferation of precursor cells, and although mature mechanosensory hair cells are capable of re-entering the cell cycle, they fail to complete cellular division48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Weber, T. et al. Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells. Proc. Natl Acad. Sci. USA 105, 781–785 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the brain, RB levels increase as progenitor cells undergo cell cycle exit, and loss of Rb delays cell cycle exit.

    “In the brain, RB levels increase as progenitor cells normally undergo cell cycle exit and loss of Rb results in delayed cell cycle exit in these cells44,49,53,54.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [44] Slack, R. S., El-Bizri, H., Wong, J., Belliveau, D. J. & Miller, F. D. A critical temporal requirement for the retinoblastoma protein family during neuronal determination. J. Cell Biol. 140, 1497–1509 (1998). source

      Not checked in the free run.

    • cites [49] Ferguson, K. L. et al. Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development. EMBO J. 21, 3337–3346. (2002). source

      Not checked in the free run.

    • cites [53] Callaghan, D. A. et al. Neural precursor cells differentiating in the absence of Rb exhibit delayed terminal mitosis and deregulated E2F 1 and 3 activity. Dev. Biol. 207, 257–270 (1999). source

      Not checked in the free run.

    • cites [54] Ferguson, K. L. & Slack, R. S. The Rb pathway in neurogenesis. Neuroreport 12, A55–A62 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cell cycle re-entry in terminally differentiated cells due to loss of RB is context-dependent and usually insufficient to initiate cancer.

    “Therefore, cell cycle re-entry in terminally differentiated cells owing to loss of RB function might be context-dependent and most of the time insufficient to initiate cancer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    RB promotes differentiation of multiple lineages by binding and regulating tissue-specific transcription factors, inhibitors of differentiation such as ID2 and EID1, and general transcription factors and chromatin modifiers.

    “RB promotes the differentiation of multiple lineages by binding and regulating tissue-specific transcription factors11,42 and inhibitors of differentiation such as ID2 and EID1 (REFS 62–65), as well as general transcription factors and chromatin modifiers66,67.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [11] Morris, E. J. & Dyson, N. J. Retinoblastoma protein partners. Adv. Cancer Res. 82, 1–54 (2001). source

      Not checked in the free run.

    • cites [42] Skapek, S. X., Pan, Y. R. & Lee, E. Y. Regulation of cell lineage specification by the retinoblastoma tumor suppressor. Oncogene 25, 5268–5276 (2006). source

      Not checked in the free run.

    • cites [62] Iavarone, A. et al. Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature 432, 1040–1045 (2004). source

      Not checked in the free run.

    • cites [63] Lasorella, A., Noseda, M., Beyna, M., Yokota, Y. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000). Describes a crucial link between MYC signalling and RB function, and provides mechanistic evidence that the interactions between ID2 and RB might regulate the proliferation and differentiation of cells. source

      Not checked in the free run.

    • cites [64] Miyake, S. et al. Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle. Mol. Cell. Biol. 20, 8889–8902 (2000). source

      Not checked in the free run.

    • cites [65] MacLellan, W. R., Xiao, G., Abdellatif, M. & Schneider, M. D. A novel Rb- and p300-binding protein inhibits transactivation by MyoD. Mol. Cell. Biol. 20, 8903–8915 (2000). source

      Not checked in the free run.

    • cites [66] Benevolenskaya, E. V., Murray, H. L., Branton, P., Young, R. A. & Kaelin, W. G., Jr. Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol. Cell 18, 623–635 (2005). source

      Not checked in the free run.

    • cites [67] Krutzfeldt, M. et al. Selective ablation of retinoblastoma protein function by the RET finger protein. Mol. Cell 18, 213–224 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rb-mutant haematopoietic stem cells induced to enter the cell cycle under stress may fail to re-enter quiescence and can undergo enforced differentiation.

    “Rb-mutant HSCs that are induced to enter the cell cycle under conditions that induce cellular stress might not be able to properly re-enter a quiescent state and can undergo enforced differentiation32–34.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32] Daria, D. et al. The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress. Blood 111, 1894–1902 (2008). source

      Not checked in the free run.

    • cites [33] Walkley, C. R. & Orkin, S. H. Rb is dispensable for self-renewal and multilineage differentiation of adult hematopoietic stem cells. Proc. Natl Acad. Sci. USA 103, 9057–9062 (2006). source

      Not checked in the free run.

    • cites [34] Walkley, C. R., Shea, J. M., Sims, N. A., Purton, L. E. & Orkin, S. H. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 129, 1081–1095 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In these hepatocytes, E2F activity activates Ddb2, and loss of RB may increase DNA repair activity of mutant cells.

    “In these hepatocytes, E2F activity has been shown to activate Ddb2 (damage-specific DNA binding 2), a gene that is crucial for DNA repair, and loss of RB might therefore increase the DNA repair activity of mutant cells82.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Prost, S., Lu, P., Caldwell, H. & Harrison, D. E2F regulates DDB2: consequences for DNA repair in Rb-deficient cells. Oncogene 26, 3572–3581 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In normal adult hepatocytes, acute deletion of Rb results in cell cycle re-entry and increased aneuploidy.

    “In normal adult hepatocytes, which are often tetraploid, acute deletion of Rb results in cell cycle re-entry and increased aneuploidy43.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Mayhew, C. N. et al. Liver-specific pRB loss results in ectopic cell cycle entry and aberrant ploidy. Cancer Res. 65, 4568–4577 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNA damage increases acetylation of human RB at lysines 873 and 874, decreasing RB phosphorylation by cyclin-Cdk complexes and increasing repression of E2F1.

    “DNA damage increases the acetylation of human RB at lysines 873 and 874, which decreases RB phosphorylation by cyclin–Cdk (cyclin-dependent kinase) complexes and therefore increases its repression over E2F1 (REF. 77).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Markham, D., Munro, S., Soloway, J., O'Connor, D. P. & La Thangue, N. B. DNA-damage-responsive acetylation of pRb regulates binding to E2F-1. EMBO Rep. 7, 192–198 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Rb-deficient cells, UV-induced lesions fail to induce cell cycle arrest, but DNA repair mechanisms are rapidly engaged.

    “In Rb-deficient cells, UV-induced lesions fail to induce cell cycle arrest, unlike in Rb wild-type cells; however, DNA repair mechanisms are rapidly engaged81.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Bosco, E. E. & Knudsen, E. S. Differential role of RB in response to UV and IR damage. Nucleic Acids Res. 33, 1581–1592 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These transgenic mice develop focal hyperplastic lesions and mammary tumours, probably because survival of differentiated mammary epithelial cells is extended after pregnancy.

    “Strikingly, these transgenic mice develop focal hyperplastic lesions and mammary tumours, probably because the survival of differentiated mammary epithelial cells is extended after pregnancy86.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Jiang, Z. & Zacksenhaus, E. Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma. J. Cell Biol. 156, 185–198 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RB could promote cancer under certain conditions by increasing survival, supported by transgenic mice expressing constitutively active Rb in mammary epithelium.

    “The idea that RB could promote cancer under certain conditions by increasing survival is supported by experiments in transgenic mice expressing a phosphorylation-resistant, constitutively active allele of Rb in the mammary gland epithelium.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Jiang, Z. & Zacksenhaus, E. Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma. J. Cell Biol. 156, 185–198 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Presence of RB in tumour cells could promote differentiation and restrict proliferative potential, possibly explaining why RB must be lost during progression to poorly differentiated tumours.

    “the presence of RB in tumour cells could in theory promote their differentiation and thereby restrict their proliferative potential, which might explain why RB must be lost during the progression from a well differentiated to a poorly differentiated tumour.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Decreased INK4A and E1A both inhibit protein interactions mediated through the RB pocket region, suggesting RB structure or modifications may distinctly regulate individual functions.

    “Both decreased INK4A and presence of E1A result in inhibition of protein interactions that are mediated through the RB pocket region, suggesting the structure and/or specific modifications of RB might distinctly regulate individual functions”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [92] Seifried, L. A. et al. pRB-E2F1 complexes are resistant to adenovirus E1A-mediated disruption. J. Virol. 82, 4511–4520 (2008). source

      Not checked in the free run.

    • cites [94] Pickering, M. T. & Kowalik, T. F. Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation. Oncogene 25, 746–755 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Chromosomal instability is suggested to be linked to progression of benign eye lesions to malignant retinoblastoma.

    “It has been suggested that this type of chromosomal instability is linked to the progression of benign eye lesions to malignant retinoblastoma17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Dimaras, H. et al. Loss of RB1 induces non-proliferative retinoma; increasing genomic instability correlates with progression to retinoblastoma. Hum. Mol. Genet. (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most tumour types display RB alterations later in tumour progression, and familial retinoblastoma patients are not strongly predisposed to many other tumours.

    “the vast majority of tumour types only display RB alterations later in tumour progression (TABLE 1) and that patients with familial retinoblastoma are not strongly predisposed to a wide variety of other tumours73.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Kleinerman, R. A. et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J. Clin. Oncol. 23, 2272–2279 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Wild-type RB may slow tumour cell proliferation by acting as a checkpoint at G1-S, S phase, and G2-M; loss of this checkpoint could contribute to proliferation with genomic abnormalities.

    “Wild-type RB activity might normally slow down the proliferation of tumour cells by acting as a checkpoint not only at the G1–S transition but also during S phase and at the G2–M transition, and loss of this checkpoint could contribute to the ability of a tumour cell to proliferate in the presence of genomic abnormalities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Autophagy induced in hypoxia can initially allow survival of a hypoxic cell by enabling metabolism, but extended autophagy can result in cell death.

    “Autophagy, which is induced in hypoxic conditions, can initially allow survival of a hypoxic cell by enabling metabolism to continue; however, extended autophagy can eventually result in cell death95.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nature Rev. Cancer 7, 961–967 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Functional inactivation of RB by phosphorylation or viral oncoproteins may not induce the same amount of cell death as deletion of RB, potentially explaining selection of upstream pathway mutations in some cancers.

    “it is possible that functional inactivation of RB by phosphorylation or by viral oncoproteins does not induce the same amount of cell death as deletion of RB, potentially explaining why mutations in upstream members of the pathway are selected in some cancers92,93.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [92] Seifried, L. A. et al. pRB-E2F1 complexes are resistant to adenovirus E1A-mediated disruption. J. Virol. 82, 4511–4520 (2008). source

      Not checked in the free run.

    • cites [93] Weinstein, I. B. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis 21, 857–864 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Double-strand breaks activate ATM and CHK2, which phosphorylates RB at serine 612, forming an RB-E2F1 complex that inhibits E2F1 target genes necessary for apoptosis such as Apaf1 and Trp73.

    “Double-strand breaks activate the kinases ATM (ataxia telangiectasia mutated) and CHK2 (checkpoint homologue 2), which phosphorylates RB at serine 612, resulting in the formation of a RB–E2F1 complex that can inhibit E2F1-specific target genes that are necessary for apoptosis, such as Apaf1 and Trp73 (REF. 76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Inoue, Y., Kitagawa, M. & Taya, Y. Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage. EMBO J. 26, 2083–2093 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Mutations in RB may participate in genomic instability by inducing DNA replication defects and abnormal chromosomal segregation, enabling tumour progression.

    “mutations in RB might participate in this phenotype by inducing defects during DNA replication and abnormal chromosomal segregation in mitosis101–103, which could result in abnormal expression of other cancer genes, enabling tumour progression.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [101] Foijer, F., Wolthuis, R. M., Doodeman, V., Medema, R. H. & te Riele, H. Mitogen requirement for cell cycle progression in the absence of pocket protein activity. Cancer Cell 8, 455–466 (2005). source

      Not checked in the free run.

    • cites [102] Eguchi, T., Takaki, T., Itadani, H. & Kotani, H. RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene. Oncogene 26, 509–520 (2007). source

      Not checked in the free run.

    • cites [103] Kennedy, B. K., Barbie, D. A., Classon, M., Dyson, N. & Harlow, E. Nuclear organization of DNA replication in primary mammalian cells. Genes Dev. 14, 2855–2868 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Presence of RB in tumour cells may prevent E2F-mediated apoptosis after DNA damage and prevent elimination of tumour cells.

    “Through these mechanisms, the presence of RB in tumour cells might prevent E2F-mediated apoptosis in response to DNA damage, and might prevent the elimination of tumour cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Among the E2F family, apoptosis induction is largely mediated by E2F1, and its repression by RB involves domains distinct from those controlling cell cycle progression.

    “among the E2F family, induction of apoptosis is a function largely mediated by E2F1 and its repression is mediated by specific RB and E2F1 protein domains that are distinct from those through which RB interacts with E2F1, E2F2, E2F3 and E2F4 to control cell cycle progression78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Dick, F. A. Structure-function analysis of the retinoblastoma tumor suppressor protein — is the whole a sum of its parts? Cell Div. 2, 26 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Loss of RB may increase autophagy-mediated cell death, and presence of RB may be beneficial to early tumours under some conditions.

    “So, similar to apoptosis, loss of RB might increase autophagy-mediated cell death, and presence of RB might be beneficial to early tumours under some conditions”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chromatin remodelling and DNA methylation are linked to tumorigenesis.

    “Both chromatin remodelling and DNA methylation have been linked to tumorigenesis119,120.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [119] Lund, A. H. & van Lohuizen, M. Epigenetics and cancer. Genes Dev. 18, 2315–2335 (2004). source

      Not checked in the free run.

    • cites [120] McCabe, D. C. & Caudill, M. A. DNA methylation, genomic silencing, and links to nutrition and cancer. Nutr. Rev. 63, 183–195 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNMT1, an E2F target and RB-E2F binding partner, is upregulated in human cancers and in response to loss of RB.

    “DNA methyltransferase DNMT1, which is both an E2F target112 and a RB–E2F protein binding partner118, has been shown to be upregulated in human cancers and in response to loss of RB.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [112] McCabe, M. T., Davis, J. N. & Day, M. L. Regulation of DNA methyltransferase 1 by the pRb/E2F1 pathway. Cancer Res. 65, 3624–3632 (2005). source

      Not checked in the free run.

    • cites [118] Robertson, K. D. et al. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nature Genet. 25, 338–342 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many chromatin modifiers bind RB through the LXCXE domain; an LXCXE mutant retaining E2F binding but not regulating pericentric heterochromatin contributes to chromosome missegregation and genomic instability.

    “Many chromatin modifiers bind to RB through the LXCXE binding domain (BOX 2), and recent evidence has demonstrated that an LXCXE mutant that retains E2F-binding capability, and therefore has no effect on MAD2 levels, still contributes to chromosome missegregation and genomic instability through its failure to regulate appropriate pericentric heterochromatin formation109.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Isaac, C. E. et al. The retinoblastoma protein regulates pericentric heterochromatin. Mol. Cell. Biol. 26, 3659–3671 (2006). Describes one of the first in vivo models to use a knock-in mouse to understand the cellular function of individual protein residues of RB. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MAD2 levels are increased in Rb-deficient cells, correlating with increased activating E2F, and MAD2 overexpression is sufficient to induce aneuploidy and tumour formation in transgenic mice.

    “MAD2 levels are increased in Rb-deficient cells, correlating with increased levels of activating E2F, and overexpression of MAD2 is sufficient to induce aneuploidy and tumour formation in transgenic mice108.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These epigenetic changes may abnormally inactivate tumour suppressors and activate oncogenes without physical mutation.

    “These epigenetic changes might result in abnormal inactivation of tumour suppressors and activation of oncogenes without the physical mutation of these genes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the RB-SKP2-p27 pathway, RB lowers SKP2, stabilizes p27, and thereby inhibits cyclin E-associated kinase activity.

    “Through this pathway, the presence of RB leads to downregulation of SKP2 and therefore stabilization of p27, which inhibits cyclin-E-associated kinase activity129.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Alexander, K. & Hinds, P. W. Requirement for p27(KIP1) in retinoblastoma protein-mediated senescence. Mol. Cell. Biol. 21, 3616–3631 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Loss of RB may contribute to angiogenesis during tumour progression in vivo, though it may not be sufficient for a full angiogenic response.

    “So, although loss of RB might not be sufficient to trigger a full angiogenic response, it might participate in this crucial stage of tumour progression in vivo.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Tumours acquire mutations that enhance endothelial cell recruitment and new blood vessel formation to overcome hypoxia.

  • May combine two claims.

    Premisecitation

    Rb-deficient cells fail to properly arrest in G1 upon DNA damage and may replicate mutated DNA, leading to accumulation of mutations.

    “Rb-deficient cells fail to properly arrest in G1 upon DNA damage and might replicate mutated DNA, leading to the accumulation of mutations102,105,111,116.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [102] Eguchi, T., Takaki, T., Itadani, H. & Kotani, H. RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene. Oncogene 26, 509–520 (2007). source

      Not checked in the free run.

    • cites [105] Zheng, L. & Lee, W. H. Retinoblastoma tumor suppressor and genome stability. Adv. Cancer Res. 85, 13–50 (2002). source

      Not checked in the free run.

    • cites [111] Knudsen, E. S., Sexton, C. R. & Mayhew, C. N. Role of the retinoblastoma tumor suppressor in the maintenance of genome integrity. Curr. Mol. Med. 6, 749–757 (2006).

      Not checked in the free run.

    • cites [116] Harrington, E. A., Bruce, J. L., Harlow, E. & Dyson, N. pRB plays an essential role in cell cycle arrest induced by DNA damage. Proc. Natl Acad. Sci. USA 95, 11945–11950 (1998). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p16 mutations are absent in SCLC but common in non-SCLC.

    “A clear example that RB and p16 mutations are not equivalent comes from the observations that RB is mutated in most, if not all cases of SCLC, whereas p16 mutations are never found in this lung cancer type but are prevalent in non-SCLC, a different type of lung cancer167.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] Kaye, F. J. RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer. Oncogene 21, 6908–6914 (2002). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Higher E2F3 activity in metastatic tumour cells may be indirectly linked to their greater motility.

    “A similar increase in E2F3 activity in metastatic tumour cells could be indirectly related to the capacity of these cells to be more motile.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Loss of RB causes inappropriate neuronal migration in the developing mouse cortex, and this phenotype depends on E2F3 activity.

    “Loss of RB has been shown to produce inappropriate migration of neurons in the developing mouse cortex141, a phenotype that is dependent on E2F3 activity69.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [141] Ferguson, K. L. et al. A cell-autonomous requirement for the cell cycle regulatory protein, Rb, in neuronal migration. EMBO J. 24, 4381–4391 (2005). source

      Not checked in the free run.

    • cites [69] McClellan, K. A. et al. Unique requirement for Rb/E2F3 in neuronal migration: evidence for cell cycle-independent functions. Mol. Cell. Biol. 27, 4825–4843 (2007). References 68 and 69 describe a novel function of RB in controlling cell migration, distinct from its role in the cell cycle, and show that E2F transcription factors might mediate this novel function of RB in vivo. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    The cellular response to RB presence or absence may depend on complex regulatory networks that are poorly understood.

    “The cellular response to the presence or absence of RB might depend on complex regulatory networks that are poorly understood146.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Calzone, L., Gelay, A., Zinovyev, A., Radvanyl, F. & Barillot, E. A comprehensive modular map of molecular interactions in RB/E2F pathway. Mol. Syst. Biol. 4, 173 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    RB promotes terminal differentiation and cell-cycle arrest in progenitor cells undergoing maturation.

    “Some of these functions seem difficult to reconcile with others: RB promotes terminal differentiation and cell cycle arrest in progenitor cells undergoing maturation, but it is also important for maintaining reversible cell cycle arrest in quiescent stem cells that must not permanently withdraw from the cell cycle and differentiate.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Loss of RB may increase apoptotic and autophagic cell death and DNA lesion repair.

    “But, loss of RB might also increase apoptotic and autophagic cell death and the ability to repair DNA lesions81,84, which might not be beneficial to tumour cells.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [81] Bosco, E. E. & Knudsen, E. S. Differential role of RB in response to UV and IR damage. Nucleic Acids Res. 33, 1581–1592 (2005). source

      Not checked in the free run.

    • cites [84] Bosco, E. E. et al. RB signaling prevents replication-dependent DNA double-strand breaks following genotoxic insult. Nucleic Acids Res. 32, 25–34 (2004). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    T121 is thought to specifically inactivate the three Rb family members.

    “The Van Dyke group has published a series of elegant studies in mice expressing a truncated form of the SV40 large T oncoprotein, T121, which is thought to specifically inactivate the three Rb family members87,154–160.”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [87] Symonds, H. et al. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 78, 703–711 (1994). source

      Not checked in the free run.

    • cites [154] Yin, C., Knudson, C. M., Korsmeyer, S. J. & Van Dyke, T. Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature 385, 637–640 (1997). source

      Not checked in the free run.

    • cites [155] Pan, H. et al. Key roles for E2F1 in signaling p53-dependent apoptosis and in cell division within developing tumors. Mol. Cell 2, 283–292 (1998). source

      Not checked in the free run.

    • cites [156] Lu, X. et al. Selective inactivation of p53 facilitates mouse epithelial tumor progression without chromosomal instability. Mol. Cell. Biol. 21, 6017–6030 (2001). source

      Not checked in the free run.

    • cites [157] Xiao, A., Wu, H., Pandolfi, P. P., Louis, D. N. & Van Dyke, T. Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation. Cancer Cell 1, 157–168 (2002). source

      Not checked in the free run.

    • cites [158] Simin, K. et al. pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. PLoS Biol. 2, E22 (2004). source

      Not checked in the free run.

    • cites [159] Hill, R., Song, Y., Cardiff, R. D. & Van Dyke, T. Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell 123, 1001–1011 (2005). source

      Not checked in the free run.

    • cites [160] Hill, R., Song, Y., Cardiff, R. D. & Van Dyke, T. Heterogeneous tumor evolution initiated by loss of pRb function in a preclinical prostate cancer model. Cancer Res. 65, 10243–10254 (2005). source

      Not checked in the free run.

48 of 48

  • The paper relies on this without support.

    Cellular senescence suppresses tumours in vivo in response to oncogenic stress.

    “Cellular senescence acts to suppress tumours in vivo in response to oncogenic stress”

  • The paper relies on this without support.

    Loss of Rb is sufficient to initiate tumorigenesis in the pituitary, thyroid and adrenal glands.

    “Furthermore, it is striking that the mechanisms of cancer initiation in the pituitary, thyroid and adrenal glands, in which loss of Rb is sufficient for tumorigenesis, are still largely unknown.”

  • The paper relies on this without support.

    p107 and p130 are rarely mutated in human cancers and resemble RB in many respects.

    “In particular, comparing the structure of RB with those of p107 and p130, which are rarely mutated in human cancers and yet are similar to RB in many ways, might help to identify mutant forms of RB that can distinguish specific cellular functions of RB.”

  • The paper relies on this without support.

    High levels of cyclin–Cdk complexes may not fully phosphorylate and inactivate RB.

    “In addition, even high levels of cyclin–Cdk complexes might be insufficient to fully phosphorylate — and functionally inactivate — RB.”

  • The paper relies on this without support.

    Tumours acquire mutations that enhance endothelial cell recruitment and new blood vessel formation to overcome hypoxia.

    “In order to over-come the growth-limiting effects of hypoxia, tumours select for mutations that increase their ability to recruit endothelial cells to form novel blood vessels in a process termed angiogenesis.”
5 of 5

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?

  • Continuous Cdk-mediated inactivation of pRb family proteins is required for cell cycle progression because active pocket proteins sequester E2F factors and repress replication and division genes.

    “Continuous Cdk-mediated inactivation of pRb family proteins is a prerequisite for cell cycle progression, because active (hypo-phosphorylated) pocket-proteins drive cell cycle exit by sequestering E2F family transcription factors and repressing the genes required for DNA replication and cell division.3”

    From Senescence from G2 arrest, revisited (2015) · cites this paper as [3]

  • Loss-of-function mutations in RB or its signaling network are considered necessary for cancer development.

    “Loss-of-function mutations in the retinoblastoma gene product (RB) or its signaling network are considered requisite for cancer development”

    From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Burkhart and Sage, 2008

  • Somatic mutations in p107 or p130 are rare in human cancers.

    “somatic mutations affecting p107 or p130 are rare in human cancers (Burkhart and Sage, 2008)”

    From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Burkhart and Sage, 2008

  • RB's importance as a tumor suppressor is evident from frequent inactivating mutations in RB or its pathway in human cancer; the RB pathway is thought to be disabled in virtually all tumor cells (Burkhart and Sage, 2008).

    “The importance of RB as a tumor suppressor gene is evident by the frequency of inactivating mutations that target RB or its pathway in human cancer; indeed, the RB pathway is thought to be disabled in virtually all tumor cells (Burkhart and Sage, 2008).”

    From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Burkhart and Sage, 2008

  • CDK4/6 phosphorylates RB to prime it for inactivation by other CDKs later in G1, releasing E2F transcription factors to induce S-phase genes.

    “Together, these results implied that the role of CDK4/6 was to phosphorylate RB, priming it for inactivation by other CDKs later in G1, and releasing E2F transcription factors from RB constraint to allow their coordinate induction of a suite of genes whose activities are jointly required for initiation of S phase [reviewed in detail in (16) (29-31)].”

    From Targeting CDK4 and CDK6: From Discovery to Therapy (2016) · cites this paper as [16]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Oesophageal cancer claim cites an endometrial cancer study

    Minor

    The cited reference 99 is identified in the paper as a study of endometrial carcinoma, not oesophageal cancer. The same reference is also cited for a claim about gastrointestinal cancers.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Burkhart, D. L., & Sage, J.
Affiliations
Stanford Medicine (US)
Corresponding author
Sage, Julien
ORCID
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2008-07-24
Volume
8
Issue
9
Pages
671-682
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/nrc2399
PMC
PMC6996492
OpenAlex
W2071333117
Cited by
974
References
221
Citations by year
2026: 20 · 2025: 45 · 2024: 32 · 2023: 47 · 2022: 54 · 2021: 75 · 2020: 61 · 2019: 48 · 2018: 49 · 2017: 58 · 2016: 53 · 2015: 57 · 2014: 66 · 2013: 73 · 2012: 90
FWCI
4.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA114102)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Health Sciences › Medicine › Ophthalmology › Ocular Oncology and Treatments
Keywords
retinoblastoma gene, retinoblastoma protein, tumor suppression, tumor suppressor, tumor initiation, tumor progression, Rb inactivation, childhood cancer, mouse tumor model
MeSH terms
Animals, Cell Cycle, Cell Differentiation, Humans, Mutation, Neoplasm Invasiveness, Neoplasms, Neovascularization, Pathologic, Protein Binding, RNA Processing, Post-Transcriptional, Stem Cells, Genes, Tumor Suppressor, Genes, Retinoblastoma

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

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