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Gene Review

Rb1  -  retinoblastoma 1

Mus musculus

Synonyms: Rb, Rb-1, Retinoblastoma-associated protein, pRb, pp105
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Disease relevance of Rb1

  • In contrast, retinoblastomas do not develop in Rb+/- mice [1].
  • Thus, pRb functions as a direct transcriptional coactivator promoting osteoblast differentiation, which may contribute to the targeting of pRb in osteosarcoma [2].
  • This cell cycle block was reversed by inactivation of Rb proteins with viral oncoproteins such as polyoma large T (PyLT) antigen and Adenovirus E1A [3].
  • The retinoblastoma (RB) protein is present at low levels in early mouse embryos and in pluripotent P19 embryonal carcinoma cells; however, the levels of RB rise dramatically in neuroectoderm formed both in embryos and in differentiating cultures of P19 cells [4].
  • E2F3 loss suppresses the development of the pituitary tumors that normally account for the death of Rb(+/-) mice [5].
  • Under a high-fat diet, pRb-deficient (pRb(ad-/-)) mice failed to gain weight because of increased energy expenditure [6].

Psychiatry related information on Rb1

  • Thus, in spite of long latency periods during which secondary alterations can accumulate, the initial loss of Rb function remains essential for tumor progression in multiple types of neuroendocrine cells [7].
  • This suggests that the metabolism of the brain neurosteroids is linked to psychological stress, and Rb1 attenuates the stress-induced increase in neurosteroids [8].
  • The avoidance learning of the mice in all RB-exposed A and B groups was significantly poorer than that of controls [9].

High impact information on Rb1

  • Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation [10].
  • Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor [10].
  • By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras [10].
  • We demonstrate that this indeed occurs in a mouse model of prostate cancer where epithelial cell cycle disruption via cell-specific inhibition of pRb function induces a paracrine p53 response that suppresses fibroblast proliferation in associated stroma [11].
  • Combined with data from studies of conditional inactivation of Rb1 using a combination of Cre transgenic mouse lines, these results show that Rb is required in a cell-autonomous manner for appropriate exit from the cell cycle of retinal progenitor cells and for rod development [12].

Chemical compound and disease context of Rb1


Biological context of Rb1


Anatomical context of Rb1

  • To determine whether E2F-1 deregulation--as a result of loss of pRB--promotes proliferation in vivo, we have tested whether loss of E2f1 interferes with the pituitary and thyroid tumorigenesis that occurs in Rb1(+/-) mice [23].
  • We did observe increased transcriptional expression of Lap2alpha and delayed expression of Rb1, which may regulate alternative transcriptional pathways in the Lmna null myoblasts [19].
  • Immunohistochemical analysis revealed the Rb1cc1 and Rb1 proteins are co-localized in the cell nuclei of NIH3T3-3 cell and various mouse tissues [24].
  • We have generated an isogenic set of embryonic stem (ES) cell lines carrying single or compound loss-of-function mutations in the Rb gene family, including a cell line completely devoid of all three pocket proteins [25].
  • The redundancy of the retinoblastoma proteins in vivo is reflected by the behavior of Rb-family-defective mouse embryonic fibroblasts in vitro [26].

Associations of Rb1 with chemical compounds


Physical interactions of Rb1

  • Various assays have demonstrated a tight correlation between the functional capacity of Rb as a growth suppressor and its ability to bind to E2F [32].
  • Cyclin D mutants defective in binding to the retinoblastoma protein were impaired in rescuing mitogenic signaling [33].
  • The present data demonstrate that JMJ interacts with the retinoblastoma protein (Rb), one of the master regulatory genes of cell cycle [34].
  • The inhibition of MyoD family function by HBP1 required binding to RB and/or p130 [29].
  • We conclude that inactivation of ARF acts more broadly than that of p53 in connecting abrogation of the Rb pathway to tumorigenesis [35].

Enzymatic interactions of Rb1


Regulatory relationships of Rb1


Other interactions of Rb1

  • In addition, the tumor-suppressor pathway Cdkn2a/Rb1 has also been implicated as a barrier to immortalization [18].
  • Here we show that the E2f3 mutation completely suppresses both the inappropriate proliferation and the p53-dependent apoptosis arising in the Rb mutant embryos [46].
  • E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos [46].
  • Hypoxia-induced arrest is accompanied by dephosphorylation of pRb and inhibition of cyclin-dependent kinase 2, which results in part from inhibitory phosphorylation [47].
  • Combined mutations of p27(-)(/)(-) and Men1(+/)(-), in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth [48].

Analytical, diagnostic and therapeutic context of Rb1


  1. Cell type-specific effects of Rb deletion in the murine retina. MacPherson, D., Sage, J., Kim, T., Ho, D., McLaughlin, M.E., Jacks, T. Genes Dev. (2004) [Pubmed]
  2. The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Thomas, D.M., Carty, S.A., Piscopo, D.M., Lee, J.S., Wang, W.F., Forrester, W.C., Hinds, P.W. Mol. Cell (2001) [Pubmed]
  3. FGF signaling targets the pRb-related p107 and p130 proteins to induce chondrocyte growth arrest. Laplantine, E., Rossi, F., Sahni, M., Basilico, C., Cobrinik, D. J. Cell Biol. (2002) [Pubmed]
  4. Cells differentiating into neuroectoderm undergo apoptosis in the absence of functional retinoblastoma family proteins. Slack, R.S., Skerjanc, I.S., Lach, B., Craig, J., Jardine, K., McBurney, M.W. J. Cell Biol. (1995) [Pubmed]
  5. E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. Ziebold, U., Lee, E.Y., Bronson, R.T., Lees, J.A. Mol. Cell. Biol. (2003) [Pubmed]
  6. Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure. Dali-Youcef, N., Mataki, C., Coste, A., Messaddeq, N., Giroud, S., Blanc, S., Koehl, C., Champy, M.F., Chambon, P., Fajas, L., Metzger, D., Schoonjans, K., Auwerx, J. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  7. RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb+/- mice. Nikitin, A.Y., Juárez-Pérez, M.I., Li, S., Huang, L., Lee, W.H. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  8. Influence of ginsenoside Rb1 on brain neurosteroid during acute immobilization stress. Lee, S.H., Jung, B.H., Choi, S.Y., Kim, S.Y., Lee, E.H., Chung, B.C. Arch. Pharm. Res. (2006) [Pubmed]
  9. Effects of prenatal rubratoxin-B exposure on behaviors of mouse offspring. Kihara, T., Surjono, T.W., Sakamoto, M., Matsuo, T., Yasuda, Y., Tanimura, T. Toxicol. Sci. (2001) [Pubmed]
  10. Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor. Takahashi, C., Contreras, B., Iwanaga, T., Takegami, Y., Bakker, A., Bronson, R.T., Noda, M., Loda, M., Hunt, J.L., Ewen, M.E. Nat. Genet. (2006) [Pubmed]
  11. Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Hill, R., Song, Y., Cardiff, R.D., Van Dyke, T. Cell (2005) [Pubmed]
  12. Rb regulates proliferation and rod photoreceptor development in the mouse retina. Zhang, J., Gray, J., Wu, L., Leone, G., Rowan, S., Cepko, C.L., Zhu, X., Craft, C.M., Dyer, M.A. Nat. Genet. (2004) [Pubmed]
  13. Suppression of cyclin-dependent kinase 4 during induced differentiation of erythroleukemia cells. Kiyokawa, H., Richon, V.M., Rifkind, R.A., Marks, P.A. Mol. Cell. Biol. (1994) [Pubmed]
  14. Mutation analysis of the pRb pathway in 2',3'-dideoxycytidine- and 1, 3-butadiene-induced mouse lymphomas. Zhuang, S.M., Wiseman, R.W., Söderkvist, P. Cancer Lett. (2000) [Pubmed]
  15. Cytosine methylation transforms an E2F site in the retinoblastoma gene promoter into a binding site for the general repressor methylcytosine-binding protein 2 (MeCP2). Di Fiore, B., Palena, A., Felsani, A., Palitti, F., Caruso, M., Lavia, P. Nucleic Acids Res. (1999) [Pubmed]
  16. Effect of repeated convulsive seizures on brain gamma-aminobutyric acid metabolism in three sublines of mice differing by their response to acoustic stimulations. Ciesielski, L., Simler, S., Clement, J., Mandel, P. J. Neurochem. (1987) [Pubmed]
  17. Hexamethylenebisacetamide-induced erythroleukemia cell differentiation involves modulation of events required for cell cycle progression through G1. Kiyokawa, H., Richon, V.M., Venta-Perez, G., Rifkind, R.A., Marks, P.A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  18. A role for the Rb family of proteins in controlling telomere length. García-Cao, M., Gonzalo, S., Dean, D., Blasco, M.A. Nat. Genet. (2002) [Pubmed]
  19. Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Melcon, G., Kozlov, S., Cutler, D.A., Sullivan, T., Hernandez, L., Zhao, P., Mitchell, S., Nader, G., Bakay, M., Rottman, J.N., Hoffman, E.P., Stewart, C.L. Hum. Mol. Genet. (2006) [Pubmed]
  20. An E2F binding-deficient Rb1 protein partially rescues developmental defects associated with Rb1 nullizygosity. Sun, H., Chang, Y., Schweers, B., Dyer, M.A., Zhang, X., Hayward, S.W., Goodrich, D.W. Mol. Cell. Biol. (2006) [Pubmed]
  21. Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype. Ouyang, H., Mou, L.j., Luk, C., Liu, N., Karaskova, J., Squire, J., Tsao, M.S. Am. J. Pathol. (2000) [Pubmed]
  22. The E2F1-3 transcription factors are essential for cellular proliferation. Wu, L., Timmers, C., Maiti, B., Saavedra, H.I., Sang, L., Chong, G.T., Nuckolls, F., Giangrande, P., Wright, F.A., Field, S.J., Greenberg, M.E., Orkin, S., Nevins, J.R., Robinson, M.L., Leone, G. Nature (2001) [Pubmed]
  23. Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-)mice. Yamasaki, L., Bronson, R., Williams, B.O., Dyson, N.J., Harlow, E., Jacks, T. Nat. Genet. (1998) [Pubmed]
  24. Isolation, characterization and mapping of the mouse and human RB1CC1 genes. Chano, T., Ikegawa, S., Saito-Ohara, F., Inazawa, J., Mabuchi, A., Saeki, Y., Okabe, H. Gene (2002) [Pubmed]
  25. Ablation of the retinoblastoma gene family deregulates G(1) control causing immortalization and increased cell turnover under growth-restricting conditions. Dannenberg, J.H., van Rossum, A., Schuijff, L., te Riele, H. Genes Dev. (2000) [Pubmed]
  26. Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Dannenberg, J.H., Schuijff, L., Dekker, M., van der Valk, M., te Riele, H. Genes Dev. (2004) [Pubmed]
  27. The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. Wen, S.T., Jackson, P.K., Van Etten, R.A. EMBO J. (1996) [Pubmed]
  28. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Almasan, A., Yin, Y., Kelly, R.E., Lee, E.Y., Bradley, A., Li, W., Bertino, J.R., Wahl, G.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  29. Regulation of differentiation by HBP1, a target of the retinoblastoma protein. Shih, H.H., Tevosian, S.G., Yee, A.S. Mol. Cell. Biol. (1998) [Pubmed]
  30. Balance between acetylation and methylation of histone H3 lysine 9 on the E2F-responsive dihydrofolate reductase promoter. Nicolas, E., Roumillac, C., Trouche, D. Mol. Cell. Biol. (2003) [Pubmed]
  31. Cyclin-dependent kinase 2-associating protein 1 commits murine embryonic stem cell differentiation through retinoblastoma protein regulation. Kim, Y., Deshpande, A., Dai, Y., Kim, J.J., Lindgren, A., Conway, A., Clark, A.T., Wong, D.T. J. Biol. Chem. (2009) [Pubmed]
  32. Interactions of the p107 and Rb proteins with E2F during the cell proliferation response. Schwarz, J.K., Devoto, S.H., Smith, E.J., Chellappan, S.P., Jakoi, L., Nevins, J.R. EMBO J. (1993) [Pubmed]
  33. Rescue of defective mitogenic signaling by D-type cyclins. Roussel, M.F., Theodoras, A.M., Pagano, M., Sherr, C.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  34. Jumonji regulates cardiomyocyte proliferation via interaction with retinoblastoma protein. Jung, J., Kim, T.G., Lyons, G.E., Kim, H.R., Lee, Y. J. Biol. Chem. (2005) [Pubmed]
  35. ARF mutation accelerates pituitary tumor development in Rb+/- mice. Tsai, K.Y., MacPherson, D., Rubinson, D.A., Nikitin, A.Y., Bronson, R., Mercer, K.L., Crowley, D., Jacks, T. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  36. Role of cyclin D1 cytoplasmic sequestration in the survival of postmitotic neurons. Sumrejkanchanakij, P., Tamamori-Adachi, M., Matsunaga, Y., Eto, K., Ikeda, M.A. Oncogene (2003) [Pubmed]
  37. Tumor promotion by caspase-resistant retinoblastoma protein. Borges, H.L., Bird, J., Wasson, K., Cardiff, R.D., Varki, N., Eckmann, L., Wang, J.Y. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  38. Changes in motility, gene expression and actin dynamics: Cdk6-induced cytoskeletal changes associated with differentiation in mouse astrocytes. Slomiany, P., Baker, T., Elliott, E.R., Grossel, M.J. J. Cell. Biochem. (2006) [Pubmed]
  39. The Cdk inhibitor p21 is required for necrosis, but it inhibits apoptosis following toxin-induced liver injury. Kwon, Y.H., Jovanovic, A., Serfas, M.S., Tyner, A.L. J. Biol. Chem. (2003) [Pubmed]
  40. Cdk2 knockout mice are viable. Berthet, C., Aleem, E., Coppola, V., Tessarollo, L., Kaldis, P. Curr. Biol. (2003) [Pubmed]
  41. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Diehl, J.A., Zindy, F., Sherr, C.J. Genes Dev. (1997) [Pubmed]
  42. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. Macleod, K.F., Hu, Y., Jacks, T. EMBO J. (1996) [Pubmed]
  43. Accumulation of p16INK4a in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status. Palmero, I., McConnell, B., Parry, D., Brookes, S., Hara, E., Bates, S., Jat, P., Peters, G. Oncogene (1997) [Pubmed]
  44. Inhibition of retinoblastoma protein phosphorylation by myogenesis-induced changes in the subunit composition of the cyclin-dependent kinase 4 complex. Wang, J., Walsh, K. Cell Growth Differ. (1996) [Pubmed]
  45. Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis. Guo, Z., Yikang, S., Yoshida, H., Mak, T.W., Zacksenhaus, E. Cancer Res. (2001) [Pubmed]
  46. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Ziebold, U., Reza, T., Caron, A., Lees, J.A. Genes Dev. (2001) [Pubmed]
  47. p21(Cip1) and p27(Kip1) regulate cell cycle reentry after hypoxic stress but are not necessary for hypoxia-induced arrest. Green, S.L., Freiberg, R.A., Giaccia, A.J. Mol. Cell. Biol. (2001) [Pubmed]
  48. p18Ink4c, but Not p27Kip1, Collaborates with Men1 To Suppress Neuroendocrine Organ Tumors. Bai, F., Pei, X.H., Nishikawa, T., Smith, M.D., Xiong, Y. Mol. Cell. Biol. (2007) [Pubmed]
  49. Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4. Soni, R., O'Reilly, T., Furet, P., Muller, L., Stephan, C., Zumstein-Mecker, S., Fretz, H., Fabbro, D., Chaudhuri, B. J. Natl. Cancer Inst. (2001) [Pubmed]
  50. Visualizing dynamic E2F-mediated repression in vivo. Agromayor, M., Wloga, E., Naglieri, B., Abrashkin, J., Verma, K., Yamasaki, L. Mol. Cell. Biol. (2006) [Pubmed]
  51. Distinct gene expression phenotypes of cells lacking Rb and Rb family members. Black, E.P., Huang, E., Dressman, H., Rempel, R., Laakso, N., Asa, S.L., Ishida, S., West, M., Nevins, J.R. Cancer Res. (2003) [Pubmed]
  52. Mutations in the retinoblastoma-related gene RB2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. Claudio, P.P., Howard, C.M., Pacilio, C., Cinti, C., Romano, G., Minimo, C., Maraldi, N.M., Minna, J.D., Gelbert, L., Leoncini, L., Tosi, G.M., Hicheli, P., Caputi, M., Giordano, G.G., Giordano, A. Cancer Res. (2000) [Pubmed]
  53. Molecular cloning and developmental expression of mouse p130, a member of the retinoblastoma gene family. Chen, G., Guy, C.T., Chen, H.W., Hu, N., Lee, E.Y., Lee, W.H. J. Biol. Chem. (1996) [Pubmed]
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