Cellular mechanisms of tumour suppression by the retinoblastoma gene

In the paper

“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.”

What the sources say

• Not checked yetcites [11] Morris, E. J. & Dyson, N. J. Retinoblastoma protein partners. Adv. Cancer Res. 82, 1–54 (2001). source
• Not checked yetcites [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

In the paper

“it is well-accepted that loss of RB is the initiating event in these familial retinal tumours, as well as in sporadic cases15–17.”

What the sources say

• Not checked yetcites [15] Knudson, A. G., Jr. Genetic predisposition to cancer. Cancer Detect Prev. 7, 1–8 (1984).
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [8] Cobrinik, D. Pocket proteins and cell cycle control. Oncogene 24, 2796–2809 (2005). source
• Not checked yetcites [9] Claudio, P. P., Tonini, T. & Giordano, A. The retinoblastoma family: twins or distant cousins? Genome Biol. 3, reviews3012 (2002). source
• Not checked yetcites [10] Classon, M. & Dyson, N. p107 and p130: versatile proteins with interesting pockets. Exp. Cell Res. 264, 135–147. (2001). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [21] Doorbar, J. Molecular biology of human papillomavirus infection and cervical cancer. Clin. Sci. 110, 525–541 (2006). source

In the paper

“RB has also been shown to participate in and potentially modulate the structure and location of heterochromatin formation in senescent cells40”

What the sources say

• Not checked yetcites [40] Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003). source

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [56] Dyer, M. A. & Bremner, R. The search for the retinoblastoma cell of origin. Nature Rev. Cancer 5, 91–101 (2005). source
• Not checked yetcites [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.

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [54] Ferguson, K. L. & Slack, R. S. The Rb pathway in neurogenesis. Neuroreport 12, A55–A62 (2001). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [11] Morris, E. J. & Dyson, N. J. Retinoblastoma protein partners. Adv. Cancer Res. 82, 1–54 (2001). source
• Not checked yetcites [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 yetcites [62] Iavarone, A. et al. Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages. Nature 432, 1040–1045 (2004). source
• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [67] Krutzfeldt, M. et al. Selective ablation of retinoblastoma protein function by the RET finger protein. Mol. Cell 18, 213–224 (2005). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“In normal adult hepatocytes, which are often tetraploid, acute deletion of Rb results in cell cycle re-entry and increased aneuploidy43.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Strikingly, these transgenic mice develop focal hyperplastic lesions and mammary tumours, probably because the survival of differentiated mammary epithelial cells is extended after pregnancy86.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [94] Pickering, M. T. & Kowalik, T. F. Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation. Oncogene 25, 746–755 (2006). source

In the paper

“It has been suggested that this type of chromosomal instability is linked to the progression of benign eye lesions to malignant retinoblastoma17.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [95] Mathew, R., Karantza-Wadsworth, V. & White, E. Role of autophagy in cancer. Nature Rev. Cancer 7, 961–967 (2007). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [93] Weinstein, I. B. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis 21, 857–864 (2000). source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

In the paper

“Both chromatin remodelling and DNA methylation have been linked to tumorigenesis119,120.”

What the sources say

• Not checked yetcites [119] Lund, A. H. & van Lohuizen, M. Epigenetics and cancer. Genes Dev. 18, 2315–2335 (2004). source
• Not checked yetcites [120] McCabe, D. C. & Caudill, M. A. DNA methylation, genomic silencing, and links to nutrition and cancer. Nutr. Rev. 63, 183–195 (2005). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [108] Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007). source

In the paper

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

In the paper

“Through this pathway, the presence of RB leads to downregulation of SKP2 and therefore stabilization of p27, which inhibits cyclin-E-associated kinase activity129.”

What the sources say

• Not checked yetcites [129] Alexander, K. & Hinds, P. W. Requirement for p27(KIP1) in retinoblastoma protein-mediated senescence. Mol. Cell. Biol. 21, 3616–3631 (2001). source

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [105] Zheng, L. & Lee, W. H. Retinoblastoma tumor suppressor and genome stability. Adv. Cancer Res. 85, 13–50 (2002). source
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“The cellular response to the presence or absence of RB might depend on complex regulatory networks that are poorly understood146.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [87] Symonds, H. et al. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 78, 703–711 (1994). source
• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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