Cellular mechanisms of tumour suppression by the retinoblastoma gene

In the paper

“mouse genetic studies have confirmed that RB is crucial in preventing the initiation of this lung cancer sub-type24”

What the sources say

• Not checked yetcites [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

In the paper

“Whereas p130, rather than RB, binds to the promoters of genes in G0 cells28–30”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [25] Ranade, K. et al. Mutations associated with familial melanoma impair p16INK4 function. Nature Genet. 10, 114–116 (1995). source
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• 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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [14] Brehm, A. & Kouzarides, T. Retinoblastoma protein meets chromatin. Trends Biochem. Sci. 24, 142–145 (1999). source

In the paper

“human papillomavirus (HPV) is thought to initiate cervical carcinoma and squamous cell carcinoma of the head and neck in part by inactivating RB through expression of the E7 oncoprotein21,22”

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
• Not checked yetcites [22] Perez-Ordonez, B., Beauchemin, M. & Jordan, R. C. Molecular biology of squamous cell carcinoma of the head and neck. J. Clin. Pathol. 59, 445–453 (2006). source

In the paper

“Loss of RB also increases the risk of osteosarcoma development in children and teenagers18–20.”

What the sources say

• Not checked yetcites [18] Friend, S. H. et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323, 643–646 (1986). source
• Not checked yetcites [19] Bookstein, R. & Lee, W. H. Molecular genetics of the retinoblastoma suppressor gene. Crit. Rev. Oncog. 2, 211–227 (1991).
• Not checked yetcites [20] Deshpande, A. & Hinds, P. W. The retinoblastoma protein in osteoblast differentiation and osteosarcoma. Curr. Mol. Med. 6, 809–817 (2006).

In the paper

“RB is inactivated in more than 90% of human small-cell lung carcinomas (SCLC)”

What the sources say

• Not checked yetcites [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

In the paper

“In Arabidopsis roots, loss of the RB homologue RBR leads to expansion of stem cells in the stem cell pool, seemingly without affecting their self-renewal potential and their proliferative status but by preventing their differentiation36.”

What the sources say

• Not checked yetcites [36] Wildwater, M. et al. The RETINOBLASTOMA-RELATED gene regulates stem cell maintenance in Arabidopsis roots. Cell 123, 1337–1349 (2005). Provides the first description of a role for RB in maintaining a stem cell pool in vivo. source

In the paper

“loss of Rb results in cell cycle re-entry in mature hepatocytes43.”

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

“Because it is difficult to imagine how both alleles of the RB gene can become mutated in non-cycling cells in vivo, this model in which cells lose RB function before they differentiate and are induced to re-enter the cell cycle after they differentiate might be more representative of what is happening during cancer initiation in differentiated cells.”

In the paper

“recent evidence suggests that the activity of these factors also controls cellular differentiation in RB-mutant cells68,69.”

What the sources say

• Not checked yetcites [68] Chen, D. et al. Rb-mediated neuronal differentiation through cell-cycle-independent regulation of E2f3a. PLoS Biol. 5, e179 (2007). 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

“Deletion of Rb in the skin results in a decrease in the number of label-retaining, slowly cycling cells in the stem cell compartment35.”

What the sources say

• Not checked yetcites [35] Ruiz, S. et al. Unique and overlapping functions of pRb and p107 in the control of proliferation and differentiation in epidermis. Development 131, 2737–2748 (2004). source

In the paper

“indicating that failure to exit the cell cycle properly as they differentiate is a mechanism by which mutant Rb cells can begin to become tumour cells50,51,55–57.”

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

“was recently illustrated in the retina of mice genetically engineered to develop retinoblastoma52.”

What the sources say

• Not checked yetcites [52] Ajioka, I. et al. Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell 131, 378–390 (2007). Describes the first example of a fully differentiated cell (a neuron) that re-enters the cell cycle to initiate cancer. source

In the paper

“cells that lose RB function before cell cycle exit and retain the ability to differentiate might also exhibit an increased capacity to re-enter the cell cycle and initiate cancer in the presence of certain stimuli”

What the sources say

• 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 [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

In the paper

“acute loss of Rb results in cell cycle re-entry from quiescence in mouse embryonic fibroblasts in culture31.”

What the sources say

• Not checked yetcites [31] Sage, J., Miller, A. L., Perez-Mancera, P. A., Wysocki, J. M. & Jacks, T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228 (2003). source

In the paper

“The role of RB in promoting cellular differentiation during embryonic development and in adult lineages has been well characterized in mutant mice and in vitro systems20,42,58–61.”

What the sources say

• Not checked yetcites [20] Deshpande, A. & Hinds, P. W. The retinoblastoma protein in osteoblast differentiation and osteosarcoma. Curr. Mol. Med. 6, 809–817 (2006).
• 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 [58] Khidr, L. & Chen, P. L. RB, the conductor that orchestrates life, death and differentiation. Oncogene 25, 5210–5219 (2006). source
• Not checked yetcites [59] Nguyen, D. X. & McCance, D. J. Role of the retinoblastoma tumor suppressor protein in cellular differentiation. J. Cell Biochem. 94, 870–879 (2005). source
• Not checked yetcites [60] Thomas, D. M., Yang, H. S., Alexander, K. & Hinds, P. W. Role of the retinoblastoma protein in differentiation and senescence. Cancer Biol. Ther. 2, 124–130 (2003). source
• Not checked yetcites [61] Classon, M. & Harlow, E. The retinoblastoma tumour suppressor in development and cancer. Nature Rev. Cancer 2, 910–917 (2002). source

In the paper

“some mutant forms of RB from families with low penetrance retinoblastoma were deficient in E2F binding but retained the ability to induce the differentiation of tumour cells.”

What the sources say

• Not checked yetcites [70] Sidle, A. et al. Activity of the retinoblastoma family proteins, pRB, p107, and p130, during cellular proliferation and differentiation. Crit. Rev. Biochem. Mol. Biol. 31, 237–271 (1996). source
• Not checked yetcites [71] Sellers, W. R. et al. Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth. Genes Dev. 12, 95–106 (1998). A classical example dissecting the mechanisms of retinoblastoma development by studying various mutants of RB; these observations highlight the fact that a pro-differentiation activity of RB that is independent of E2F acts as a tumour suppressor mechanism. source
• Not checked yetcites [72] Thomas, D. M. et al. The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol. Cell 8, 303–316 (2001). source

In the paper

“loss of RB function might result in chromatin remodelling in differentiated cells, allowing the expression of cell cycle genes and resulting in the de-differentiation of the mutant cells41,42.”

What the sources say

• Not checked yetcites [41] Ferreira, R., Naguibneva, I., Pritchard, L. L., Ait-Si-Ali, S. & Harel-Bellan, A. The Rb/chromatin connection and epigenetic control: opinion. Oncogene 20, 3128–3133. (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

In the paper

“In neurons, however, loss of RB, or even inactivation of the entire Rb gene family, does not allow these cells to re-enter the cell cycle44.”

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

In the paper

“Although cancer initiation from quiescent stem cells and post-mitotic differentiated cells upon loss of RB can take place, loss of RB function is more likely to initiate cancer from cycling progenitor cells.”

In the paper

“evidence indicates that loss of RB might initiate cancer by allowing fully differentiated cells to re-enter the cell cycle.”

What the sources say

• Not checked yetcites [31] Sage, J., Miller, A. L., Perez-Mancera, P. A., Wysocki, J. M. & Jacks, T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228 (2003). source
• Not checked yetcites [39] Beausejour, C. M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222 (2003). source

In the paper

“data from several groups indicate that loss of Rb in haematopoietic stem cells (HSCs) does not increase their proliferation”

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

“UV treatment of RB-deficient cancer cells results in apoptosis, similar to that seen with other types of DNA damage83”

What the sources say

• Not checked yetcites [83] Billecke, C. A. et al. Lack of functional pRb results in attenuated recovery of mRNA synthesis and increased apoptosis following UV radiation in human breast cancer cells. Oncogene 21, 4481–4489 (2002). source

In the paper

“This suggests that retention of the ability to induce differentiation might be sufficient to prevent fully penetrant retinoblastoma”

In the paper

“in adult mouse fibroblasts loss of Rb deregulates S phase, resulting in polyploidy106.”

What the sources say

• Not checked yetcites [106] Srinivasan, S. V., Mayhew, C. N., Schwemberger, S., Zagorski, W. & Knudsen, E. S. RB loss promotes aberrant ploidy by deregulating levels and activity of DNA replication factors. J. Biol. Chem. 282, 23867–23877 (2007). source

In the paper

“These observations suggest that there might be a disadvantage to losing RB too early during tumour development in some contexts.”

In the paper

“In both of these cases, presence of RB seems to be beneficial to tumour progression, which is counterintuitive given the role of RB as a potent tumour suppressor”

In the paper

“if cancer cells carry a mutation that protects them from apoptosis, such as inactivation of p53, before losing RB, then the tumour will benefit from the loss of the other tumour suppressive functions of RB (described below) and cancer will progress.”

In the paper

“RB–E2F complexes are thought normally to restrict the expression of MAD2 (REF. 107), a spindle checkpoint component.”

What the sources say

• Not checked yetcites [107] Hernando, E. et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430, 797–802 (2004). source

In the paper

“similar observations have been made for osteosarcoma70–72.”

What the sources say

• Not checked yetcites [70] Sidle, A. et al. Activity of the retinoblastoma family proteins, pRB, p107, and p130, during cellular proliferation and differentiation. Crit. Rev. Biochem. Mol. Biol. 31, 237–271 (1996). source
• Not checked yetcites [71] Sellers, W. R. et al. Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth. Genes Dev. 12, 95–106 (1998). A classical example dissecting the mechanisms of retinoblastoma development by studying various mutants of RB; these observations highlight the fact that a pro-differentiation activity of RB that is independent of E2F acts as a tumour suppressor mechanism. source
• Not checked yetcites [72] Thomas, D. M. et al. The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol. Cell 8, 303–316 (2001). source

In the paper

“abnormal proliferation that is induced by loss of RB is often accompanied by increased cell death, through p53-dependent and independent mechanisms49,57,87–91.”

What the sources say

• 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 [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 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 [88] Chau, B. N. & Wang, J. Y. Coordinated regulation of life and death by RB. Nature Rev. Cancer 3, 130–138 (2003). source
• Not checked yetcites [89] Borges, H. L., Hunton, I. C. & Wang, J. Y. Reduction of apoptosis in Rb-deficient embryos via Abl knockout. Oncogene 26, 3868–3877 (2007). source
• Not checked yetcites [90] Moroni, M. C. et al. Apaf-1 is a transcriptional target for E2F and p53. Nature Cell Biol. 3, 552–558 (2001). source
• Not checked yetcites [91] Simpson, M. T. et al. Caspase 3 deficiency rescues peripheral nervous system defect in retinoblastoma nullizygous mice. J. Neurosci. 21, 7089–7098 (2001). source

In the paper

“RB seems to have a separate function in the ATR (ATM and RAD3-related) pathway, which responds to single-stranded DNA resulting from stalled replication forks and induces DNA repair.”

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

“E2F1 activity is an important mediator of p53-dependent apoptosis in response to loss of RB74,75”

What the sources say

• Not checked yetcites [74] Tsai, K. Y. et al. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol. Cell 2, 293–304 (1998). source
• Not checked yetcites [75] Macleod, K. F., Hu, Y. & Jacks, T. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. EMBO J. 15, 6178–6188 (1996). source

In the paper

“Expression and loss of heterozygosity studies indicate that loss of RB function is associated with the progression of human cancers, in addition to its role in cancer initiation (TABLE 1).”

What the sources say

• Not checked yetcites TABLE 1

In the paper

“In primary Rb-null mouse hepatocytes, cyclob-utane pyrimidine dimers are removed more quickly than in wild-type cells following UV irradiation82.”

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

“These diverse results suggest that the role of RB in the response to DNA damage might depend significantly on cellular context.”

In the paper

“loss of several of the cellular functions attributed to RB might directly participate in tumour progression.”

In the paper

“RB has pro-survival functions that might seem paradoxical to its role as a tumour suppressor.”

In the paper

“an increase in double-strand breaks is observed in Rb–/– mouse adult fibroblasts treated with DNA-damaging chemotherapeutic drugs84.”

What the sources say

• 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

“suggests that different regions or modifications of the RB protein mediate its control over cell cycle progression and differentiation”

In the paper

“loss of INK4A (which is encoded by CDKN2A and is also known as p16) or expression of E1A is insufficient to disrupt RB inhibition of E2F1-dependent apoptosis92,94.”

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

“E2F3 can also induce cell death in Rb-deficient cells in vivo79,80.”

What the sources say

• Not checked yetcites [79] Ziebold, U., Reza, T., Caron, A. & Lees, J. A. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev. 15, 386–391 (2001). source
• Not checked yetcites [80] Saavedra, H. I. et al. Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb. Cell Growth Differ. 13, 215–225 (2002).

In the paper

“Recent work has demonstrated that the presence of functional RB might prevent autophagy in response to hypoxia through its inhibition of E2F target genes97,98.”

What the sources say

• Not checked yetcites [97] Tracy, K. et al. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol. Cell. Biol. 27, 6229–6242 (2007). source
• Not checked yetcites [98] Polager, S., Ofir, M. & Ginsberg, D. E2F1 regulates autophagy and the transcription of autophagy genes. Oncogene 14 April 2008 (doi:10.1038/onc.2008.117). source

In the paper

“Altered RB expression has been observed to be correlated with higher grade, poorly differentiated gastrointestinal cancers99.”

What the sources say

• Not checked yetcites [99] Sanseverino, F. et al. pRb2/p130 and VEGF expression in endometrial carcinoma in relation to angiogenesis and histopathologic tumor grade. Cancer Biol. Ther. 5, 84–88 (2006). source

In the paper

“In mouse embryonic stem cells, in which there is no active G1 checkpoint, Rb deficiency leads to increased chromosomal alterations104,105”

What the sources say

• Not checked yetcites [104] Zheng, L., Flesken-Nikitin, A., Chen, P. L. & Lee, W. H. Deficiency of Retinoblastoma gene in mouse embryonic stem cells leads to genetic instability. Cancer Res. 62, 2498–2502 (2002).
• Not checked yetcites [105] Zheng, L. & Lee, W. H. Retinoblastoma tumor suppressor and genome stability. Adv. Cancer Res. 85, 13–50 (2002). source

In the paper

“RB might help maintain genomic stability by regulating the expression of, and associating with, chromatin remodelling complexes, thereby regulating chromatin structure, in particular at centromeres and telomeres109–112.”

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
• Not checked yetcites [110] Gonzalo, S. et al. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nature Cell Biol. 7, 420–428 (2005). 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 [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

In the paper

“This is mediated, at least in part, through the formation of senescence-specific heterochromatin at cell cycle gene loci40.”

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

“A recent report indicates that loss of RB function is associated with increased levels of cyclooxygenase 2 (COX2) and an increased chance of recurring invasive basal-like breast cancer138.”

What the sources say

• Not checked yetcites [138] Gauthier, M. L. et al. Abrogated response to cellular stress identifies DCIS associated with subsequent tumor events and defines basal-like breast tumors. Cancer Cell 12, 479–491 (2007). source

In the paper

“Another mechanism by which loss of RB might promote angiogenesis in these pituitary tumours is through the loss of inhibition of ID2 (REF. 132).”

What the sources say

• Not checked yetcites [132] Lasorella, A., Rothschild, G., Yokota, Y., Russell, R. G. & Iavarone, A. Id2 mediates tumor initiation, proliferation, and angiogenesis in Rb mutant mice. Mol. Cell. Biol. 25, 3563–3574 (2005). source

In the paper

“Moreover, deletion of Rb in a mouse model of Trp53-deficient squamous cell carcinoma demonstrates increased vascularization when compared to similar Trp53–/– tumours136.”

What the sources say

• Not checked yetcites [136] Martinez-Cruz, A. B. et al. Spontaneous squamous cell carcinoma induced by the somatic inactivation of retinoblastoma and Trp53 tumor suppressors. Cancer Res. 68, 683–692 (2008). source

In the paper

“Recent experiments in Drosophila melanogaster and human cells also indicate that RB might normally promote chromosomal condensation and preserve chromosomal stability through a direct interaction with a condensin protein115.”

What the sources say

• Not checked yetcites [115] Longworth, M. S., Herr, A., Ji, J. Y. & Dyson, N. J. RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes Dev. 22, 1011–1024 (2008). source

In the paper

“Expression of several of the Id proteins has been associated with tumour progression and several genetic studies suggest that the presence of Id factors is necessary for tumour vascularization through regulation of pro-angiogenic factors133,134.”

What the sources say

• Not checked yetcites [133] Ruzinova, M. B. & Benezra, R. Id proteins in development, cell cycle and cancer. Trends Cell Biol. 13, 410–418 (2003). source
• Not checked yetcites [134] Benezra, R., Rafii, S. & Lyden, D. The Id proteins and angiogenesis. Oncogene 20, 8334–8341 (2001). source

In the paper

“COX2 overexpression has been observed in various epithelial cancers and has been demonstrated to increase motility of breast cancer cells in culture139, as well as invasiveness of colon cancer cells140.”

What the sources say

• Not checked yetcites [139] Singh, B., Berry, J. A., Shoher, A., Ramakrishnan, V. & Lucci, A. COX-2 overexpression increases motility and invasion of breast cancer cells. Int. J. Oncol. 26, 1393–1399 (2005).
• Not checked yetcites [140] Tsujii, M., Kawano, S. & DuBois, R. N. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc. Natl Acad. Sci. USA 94, 3336–3340 (1997). source

In the paper

“Therefore, loss of RB function allows a tumour cell to bypass the cell cycle arrest that is associated with both replication and oncogene-induced senescence during cancer progression.”

In the paper

“COX2 overexpression has been observed in various epithelial cancers and has been demonstrated to increase motility of breast cancer cells in culture139, as well as invasiveness of colon cancer cells140.”

What the sources say

• Not checked yetcites [139] Singh, B., Berry, J. A., Shoher, A., Ramakrishnan, V. & Lucci, A. COX-2 overexpression increases motility and invasion of breast cancer cells. Int. J. Oncol. 26, 1393–1399 (2005).

In the paper

“Altered RB expression patterns have been observed in poorly differentiated, metastatic hepatocellular carcinomas137, and correlative analyses have suggested that changes in RB expression are significantly associated with invasion and metastasis of oesophageal cancers99.”

What the sources say

• Not checked yetcites [99] Sanseverino, F. et al. pRb2/p130 and VEGF expression in endometrial carcinoma in relation to angiogenesis and histopathologic tumor grade. Cancer Biol. Ther. 5, 84–88 (2006). source

In the paper

“loss of RB function might also alter the epigenetic definition of the genome through misregulation of chromatin remodelling enzymes117 and DNA modifiers.”

What the sources say

• Not checked yetcites [117] Siddiqui, H., Fox, S. R., Gunawardena, R. W. & Knudsen, E. S. Loss of RB compromises specific heterochromatin modifications and modulates HP1α dynamics. J. Cell Physiol. 211, 131–137 (2007). source

In the paper

“This senescent cell cycle arrest depends on the presence of functional RB128 and is in part mediated by the RB–SKP2 (S-phase kinase-associated protein 2)–p27 pathway.”

What the sources say

• Not checked yetcites [128] Young, A. P. et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nature Cell Biol. 10, 361–369 (2008). source

In the paper

“COX2 overexpression has been observed in various epithelial cancers and has been demonstrated to increase motility of breast cancer cells in culture139, as well as invasiveness of colon cancer cells140.”

What the sources say

• Not checked yetcites [140] Tsujii, M., Kawano, S. & DuBois, R. N. Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc. Natl Acad. Sci. USA 94, 3336–3340 (1997). source

In the paper

“loss of Rb can lead to chromosome segregation defects through the misregulation of genes that are important for processes such as centrosome duplication113,114 and DNA replication106.”

What the sources say

• Not checked yetcites [113] Iovino, F., Lentini, L., Amato, A. & Di Leonardo, A. RB acute loss induces centrosome amplification and aneuploidy in murine primary fibroblasts. Mol. Cancer 5, 38 (2006). source
• Not checked yetcites [114] Meraldi, P., Lukas, J., Fry, A. M., Bartek, J. & Nigg, E. A. Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nature Cell Biol. 1, 88–93 (1999). source
• Not checked yetcites [106] Srinivasan, S. V., Mayhew, C. N., Schwemberger, S., Zagorski, W. & Knudsen, E. S. RB loss promotes aberrant ploidy by deregulating levels and activity of DNA replication factors. J. Biol. Chem. 282, 23867–23877 (2007). source

In the paper

“strong evidence places RB–E2F activity and associated chromatin-regulating complexes, such as SUV39H1, as a key regulators of senescence in cells in culture121–124.”

What the sources say

• Not checked yetcites [121] Sage, J. Making young tumors old: a new weapon against cancer? Sci. Aging Knowledge Environ. pe25 (2005). source
• Not checked yetcites [122] Collado, M., Blasco, M. A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223–233 (2007). source
• Not checked yetcites [123] Courtois-Cox, S., Jones, S. L. & Cichowski, K. Many roads lead to oncogene-induced senescence. Oncogene 27, 2801–2089 (2008). source
• Not checked yetcites [124] Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). source

In the paper

“Expression of several of the Id proteins has been associated with tumour progression and several genetic studies suggest that the presence of Id factors is necessary for tumour vascularization through regulation of pro-angiogenic factors133,134.”

What the sources say

• Not checked yetcites [133] Ruzinova, M. B. & Benezra, R. Id proteins in development, cell cycle and cancer. Trends Cell Biol. 13, 410–418 (2003). source
• Not checked yetcites [134] Benezra, R., Rafii, S. & Lyden, D. The Id proteins and angiogenesis. Oncogene 20, 8334–8341 (2001). source

In the paper

“This senescent cell cycle arrest depends on the presence of functional RB128 and is in part mediated by the RB–SKP2 (S-phase kinase-associated protein 2)–p27 pathway.”

What the sources say

• Not checked yetcites [128] Young, A. P. et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nature Cell Biol. 10, 361–369 (2008). source

In the paper

“Furthermore, the RB family controls the length of telomeres and mediates the cellular signals to induce senescence in cells with shortened telomeres125–127.”

What the sources say

• Not checked yetcites [125] Garcia-Cao, M., Gonzalo, S., Dean, D. & Blasco, M. A. A role for the Rb family of proteins in controlling telomere length. Nature Genet. 32, 415–419 (2002). source
• Not checked yetcites [126] Kong, L. J., Meloni, A. R. & Nevins, J. R. The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1. Mol. Cell 22, 63–71 (2006). source
• Not checked yetcites [127] Wei, W., Herbig, U., Wei, S., Dutriaux, A. & Sedivy, J. M. Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts. EMBO Rep. 4, 1061–1066 (2003). source

In the paper

“Emerging evidence shows that vascular endothelial growth factor (VEGF) and other angiogenic factors that are secreted by tumour cells to recruit endothelial cells are transcriptional targets of the RB–E2F pathway130.”

What the sources say

• Not checked yetcites [130] Gabellini, C., Del Bufalo, D. & Zupi, G. Involvement of RB gene family in tumor angiogenesis. Oncogene 25, 5326–5332 (2006). source

In the paper

“A recent report indicates that loss of RB function is associated with increased levels of cyclooxygenase 2 (COX2) and an increased chance of recurring invasive basal-like breast cancer138.”

What the sources say

• Not checked yetcites [138] Gauthier, M. L. et al. Abrogated response to cellular stress identifies DCIS associated with subsequent tumor events and defines basal-like breast tumors. Cancer Cell 12, 479–491 (2007). source

In the paper

“For example, pituitary tumours arising in Rb-mutant mice have high levels of VEGF131.”

What the sources say

• Not checked yetcites [131] Chien, W. M. et al. Differential gene expression of p27Kip1 and Rb knockout pituitary tumors associated with altered growth and angiogenesis. Cell Cycle 6, 750–757 (2007). source

In the paper

“Additionally, RB might relay receptor-mediated mitogenic signals to develop an angiogenic response135.”

What the sources say

• Not checked yetcites [135] Dasgupta, P. et al. Disruption of the Rb–Raf-1 interaction inhibits tumor growth and angiogenesis. Mol. Cell. Biol. 24, 9527–9541 (2004). source

In the paper

“Altered RB expression patterns have been observed in poorly differentiated, metastatic hepatocellular carcinomas137, and correlative analyses have suggested that changes in RB expression are significantly associated with invasion and metastasis of oesophageal cancers99.”

What the sources say

• Not checked yetcites [137] Hui, A. M., Li, X., Makuuchi, M., Takayama, T. & Kubota, K. Over-expression and lack of retinoblastoma protein are associated with tumor progression and metastasis in hepatocellular carcinoma. Int. J. Cancer 84, 604–608 (1999). source

In the paper

“One recent example supports this model: loss of function of the Von Hippel Lindau (VHL) tumour suppressor creates an oncogenic stress that triggers a senescence response both in vitro and in vivo.”

What the sources say

• Not checked yetcites [128] Young, A. P. et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nature Cell Biol. 10, 361–369 (2008). source

In the paper

“the role of RB in maintaining chromosomal stability might be crucial to the prevention of cancer progression.”

In the paper

“Furthermore, the RB family controls the length of telomeres and mediates the cellular signals to induce senescence in cells with shortened telomeres125–127.”

What the sources say

• Not checked yetcites [125] Garcia-Cao, M., Gonzalo, S., Dean, D. & Blasco, M. A. A role for the Rb family of proteins in controlling telomere length. Nature Genet. 32, 415–419 (2002). source
• Not checked yetcites [126] Kong, L. J., Meloni, A. R. & Nevins, J. R. The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1. Mol. Cell 22, 63–71 (2006). source
• Not checked yetcites [127] Wei, W., Herbig, U., Wei, S., Dutriaux, A. & Sedivy, J. M. Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts. EMBO Rep. 4, 1061–1066 (2003). 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

“Targeted alterations in upstream components of the RB pathway can result in the inactivation of all of the Rb family genes, but because the RB pathway is not strictly linear, these experiments might not directly inform us about the mechanisms of RB tumour suppressive action4,7,150–153.”

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 [150] Dannenberg, J. H., Schuijff, L., Dekker, M., van der Valk, M. & te Riele, H. Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev. 18, 2952–2962 (2004). source
• Not checked yetcites [151] Sotillo, R. et al. Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J. 20, 6637–6647 (2001). source
• Not checked yetcites [152] Rane, S. G., Cosenza, S. C., Mettus, R. V. & Reddy, E. P. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol. Cell. Biol. 22, 644–656 (2002). source
• Not checked yetcites [153] Ortega, S., Malumbres, M. & Barbacid, M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 1602, 73–87 (2002).

In the paper

“In conclusion, however, although RB inactivation is clearly an initiating event in many cancers, much work remains to be done and new systems need to be developed to better understand how loss of RB function can promote cancer initiation in vivo.”

In the paper

“In addition, the analysis of mice expressing T121 in the prostate indicates that loss of Rb family function in epithelial cells triggers signals to surrounding stromal cells, underscoring that not all the mechanisms of cancer initiation are cell autonomous159.”

What the sources say

• 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

In the paper

“However, alterations in upstream members of the RB pathway also impinge upon the activities of p107 and p130, as well as other cellular proteins165,166.”

What the sources say

• Not checked yetcites [165] Zwijsen, R. M. CDK-independent activation of estrogen receptor by cyclin D1. Cell 88, 405–415 (1997). source
• Not checked yetcites [166] Liu, F. Smad3 phosphorylation by cyclin-dependent kinases. Cytokine Growth Factor Rev. 17, 9–17 (2006). source

In the paper

“Targeted alterations in upstream components of the RB pathway can result in the inactivation of all of the Rb family genes, but because the RB pathway is not strictly linear, these experiments might not directly inform us about the mechanisms of RB tumour suppressive action4,7,150–153.”

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 [150] Dannenberg, J. H., Schuijff, L., Dekker, M., van der Valk, M. & te Riele, H. Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev. 18, 2952–2962 (2004). source
• Not checked yetcites [151] Sotillo, R. et al. Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J. 20, 6637–6647 (2001). source
• Not checked yetcites [152] Rane, S. G., Cosenza, S. C., Mettus, R. V. & Reddy, E. P. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol. Cell. Biol. 22, 644–656 (2002). source
• Not checked yetcites [153] Ortega, S., Malumbres, M. & Barbacid, M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 1602, 73–87 (2002).

In the paper

“The correlation between loss of RB and an increase in COX2 expression might reflect a potential mechanism through which RB can prevent metastasis in a tissue-specific manner.”

In the paper

“These experiments illustrate the point that different cell types respond differently to loss of Rb family members, which could dictate the requirement for specific mutations during tumour progression161.”

What the sources say

• Not checked yetcites [161] Simin, K. et al. Deciphering cancer complexities in genetically engineered mice. Cold Spring Harb. Symp. Quant. Biol. 70, 283–290 (2005). References 154–161 illustrate the efforts from the Van Dyke group to study the role of the entire Rb family in preventing cancer initiation in different cell types in mice. source

In the paper

“In addition, the analysis of mice expressing T121 in the prostate indicates that loss of Rb family function in epithelial cells triggers signals to surrounding stromal cells, underscoring that not all the mechanisms of cancer initiation are cell autonomous159.”

What the sources say

• 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

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

“Because loss of Rb in mouse models is not sufficient to initiate retinoblastoma, osteosarcoma or SCLC, we do not know if the phenotypes of Rb-deficient cells in these organs truly reflect the mechanisms of cancer initiation in the corresponding human cells.”

What the sources say

• 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

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

“Additionally, E2F1 over-expression has been shown to increase the invasiveness of human tumour cell lines145.”

What the sources say

• Not checked yetcites [145] Zhang, S. Y., Liu, S. C., Johnson, D. G. & Klein-Szanto, A. J. E2F-1 gene transfer enhances invasiveness of human head and neck carcinoma cell lines. Cancer Res. 60, 5972–5976 (2000).

In the paper

“When loss of Trp53 and Rb are combined, more tumours develop in mutant mice24,147–149 but it becomes difficult to dissect the respective roles of these two potent tumour suppressors.”

What the sources say

• Not checked yetcites [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 yetcites [147] Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004. (2000). source
• Not checked yetcites [148] Zhou, Z., Flesken-Nikitin, A. & Nikitin, A. Y. Prostate cancer associated with p53 and Rb deficiency arises from the stem/progenitor cell-enriched proximal region of prostatic ducts. Cancer Res. 67, 5683–5690 (2007). source
• Not checked yetcites [149] Flesken-Nikitin, A., Choi, K. C., Eng., J. P., Shmidt, E. N. & Nikitin, A. Y. Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium. Cancer Res. 63, 3459–3463 (2003).

In the paper

“Similarly, because ectopic expression of RB in cells in culture can produce nonspecific effects, a detailed structure–function analysis of RB in vivo will be key to our understanding of RB tumour suppressor functions78.”

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

“However, E2F3 inactivation has also been found to enhance the metastatic potential of RB-deficient thyroid carcinomas in vivo142.”

What the sources say

• Not checked yetcites [142] Ziebold, U., Lee, E. Y., Bronson, R. T. & Lees, J. A. E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. Mol. Cell. Biol. 23, 6542–6552 (2003). source