Abstract
The Retinoblastoma gene Rb was the first tumor suppressor gene cloned, and it is well known as a negative cell cycle regulator. A simplified model for Rb function is that it blocks cell cycle progression by binding to the E2F transcription factors and recruiting co-repressor complexes to repress the expression of E2F target genes. Both E2F and Rb have multiple family members, with specific members of the Rb family capable of binding only to a specific subset of the E2F family. In addition, different E2F proteins exhibit distinct capacities to regulate natural E2F targets due to their different ability to interact with other transcription factors which are also required for the activation of particular E2F target genes. Although Rb and E2F are best known for their cell cycle roles, recent genome wide analysis of E2F targets has suggested that E2F and Rb control not only genes important in the cell cycle but also genes involved in apoptosis, differentiation, and development. Consistent with these observations, analysis of mice and Drosophila with mutations in the Rb and E2F genes has revealed important roles of E2F and Rb proteins in all these areas.
This is a preview of subscription content, log in via an institution to check access.
Preview
Unable to display preview. Download preview PDF.
References
Attwooll, C., Denchi, E. L., and Helin, K. (2004a). The E2F family: specific functions and overlapping interests. Embo J 23, 4709–4716.
Attwooll, C., Oddi, S., Cartwright, P., Prosperini, E., Agger, K., Steensgaard, P., Wagener, C., Sardet, C., Moroni, M. C., and Helin, K. (2004b). A novel repressive E2F6 complex containing the polycomb group protein, EPC1, that interacts with EZH2 in a proliferation-specific manner. J Biol Chem.
Bagchi, S., Raychaudhuri, P., and Nevins, J. R. (1990). Adenovirus E1A proteins can dissociate heteromeric complexes involving the E2F transcription factor: a novel mechanism for E1A trans-activation. Cell 62, 659–669.
Bagchi, S., Weinmann, R., and Raychaudhuri, P. (1991). The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F. Cell 65, 1063–1072.
Bracken, A. P., Ciro, M., Cocito, A., and Helin, K. (2004). E2F target genes: unraveling the biology. Trends Biochem Sci 29, 409–417.
Brehm, A., Miska, E. A., McCance, D. J., Reid, J. L., Bannister, A. J., and Kouzarides, T. (1998). Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391, 597–601.
Chellappan, S. P., Hiebert, S., Mudryj, M., Horowitz, J. M., and Nevins, J. R. (1991). The E2F transcription factor is a cellular target for the RB protein. Cell 65, 1053–1061.
Chen, C. R., Kang, Y., Siegel, P. M., and Massague, J. (2002). E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 110, 19–32.
Classon, M., and Harlow, E. (2002). The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2, 910–917.
Cloud, J. E., Rogers, C., Reza, T. L., Ziebold, U., Stone, J. R., Picard, M. H., Caron, A. M., Bronson, R. T., and Lees, J. A. (2002). Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo. Mol Cell Biol 22, 2663–2672.
Cobrinik, D., Lee, M. H., Hannon, G., Mulligan, G., Bronson, R. T., Dyson, N., Harlow, E., Beach, D., Weinberg, R. A., and Jacks, T. (1996). Shared role of the pRB-related p130 and p107 proteins in limb development. Genes Dev 10, 1633–1644.
de Bruin, A., Maiti, B., Jakoi, L., Timmers, C., Buerki, R., and Leone, G. (2003). Identification and characterization of E2F7, a novel mammalian E2F family member capable of blocking cellular proliferation. J Biol Chem 278, 42041–42049.
de Nooij, J. C., Letendre, M. A., and Hariharan, I. K. (1996). A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell 87, 1237–1247.
Di Stefano, L., Jensen, M. R., and Helin, K. (2003). E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes. Embo J 22, 6289–6298.
Dimova, D. K., Stevaux, O., Frolov, M. V., and Dyson, N. J. (2003). Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev 17, 2308–2320.
Du, W. (2000). Suppression of the rbf null mutants by a de2f1 allele that lacks transactivation domain. Development 127, 367–379.
Du, W., and Dyson, N. (1999). The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis. Embo J 18, 916–925.
Du, W., Vidal, M., Xie, J. E., and Dyson, N. (1996a). RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. Genes Dev 10, 1206–1218.
Du, W., Xie, J. E., and Dyson, N. (1996b). Ectopic expression of dE2F and dDP induces cell proliferation and death in the Drosophila eye. Embo J 15, 3684–3692.
Dunaief, J. L., Strober, B. E., Guha, S., Khavari, P. A., Alin, K., Luban, J., Begemann, M., Crabtree, G. R., and Goff, S. P. (1994). The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 79, 119–130.
Dunn, J. M., Phillips, R. A., Becker, A. J., and Gallie, B. L. (1988). Identification of germline and somatic mutations affecting the retinoblastoma gene. Science 241, 1797–1800.
Duronio, R. J., and O’Farrell, P. H. (1994). Developmental control of a G1-S transcriptional program in Drosophila. Development 120, 1503–1515.
Duronio, R. J., O’Farrell, P. H., Xie, J. E., Brook, A., and Dyson, N. (1995). The transcription factor E2F is required for S phase during Drosophila embryogenesis. Genes Dev 9, 1445–1455.
Dynlacht, B. D., Brook, A., Dembski, M., Yenush, L., and Dyson, N. (1994). DNA-binding and trans-activation properties of Drosophila E2F and DP proteins. Proc Natl Acad Sci USA 91, 6359–6363.
Dyson, N. (1998). The regulation of E2F by pRB-family proteins. Genes Dev 12, 2245–2262.
Field, S. J., Tsai, F. Y., Kuo, F., Zubiaga, A. M., Kaelin, W. G., Jr., Livingston, D. M., Orkin, S. H., and Greenberg, M. E. (1996). E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561.
Friend, S. H., Bernards, R., Rogelj, S., Weinberg, R. A., Rapaport, J. M., Albert, D. M., and Dryja, T. P. (1986). A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323, 643–646.
Frolov, M. V., and Dyson, N. J. (2004). Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J Cell Sci 117, 2173–2181.
Frolov, M. V., Huen, D. S., Stevaux, O., Dimova, D., Balczarek-Strang, K., Elsdon, M., and Dyson, N. J. (2001). Functional antagonism between E2F family members. Genes Dev 15, 2146–2160.
Giangrande, P. H., Hallstrom, T. C., Tunyaplin, C., Calame, K., and Nevins, J. R. (2003). Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription factor. Mol Cell Biol 23, 3707–3720.
Giangrande, P. H., Zhu, W., Rempel, R. E., Laakso, N., and Nevins, J. R. (2004). Combinatorial gene control involving E2F and E Box family members. Embo J 23, 1336–1347.
Hallstrom, T. C., and Nevins, J. R. (2003). Specificity in the activation and control of transcription factor E2F-dependent apoptosis. Proc Natl Acad Sci USA 100, 10848–10853.
Jacks, T., Fazeli, A., Schmitt, E. M., Bronson, R. T., Goodell, M. A., and Weinberg, R. A. (1992). Effects of an Rb mutation in the mouse. Nature 359, 295–300.
Jost, C. A., Ginsberg, D., and Kaelin, W. G., Jr. (1996). A conserved region of unknown function participates in the recognition of E2F family members by the adenovirus E4 ORF 6/7 protein. Virology 220, 78–90.
Kang, H., Cui, K., and Zhao, K. (2004). BRG1 controls the activity of the retinoblastoma protein via regulation of p21CIP1/WAF1/SDI. Mol Cell Biol 24, 1188–1199.
Knudson, A. G., Jr. (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68, 820–823.
Korenjak, M., Taylor-Harding, B., Binne, U. K., Satterlee, J. S., Stevaux, O., Aasland, R., White-Cooper, H., Dyson, N., and Brehm, A. (2004). Native E2F/RBF complexes contain Myb-interacting proteins and repress transcription of developmentally controlled E2F target genes. Cell 119, 181–193.
Krek, W., Ewen, M. E., Shirodkar, S., Arany, Z., Kaelin, W. G., Jr., and Livingston, D. M. (1994). Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 78, 161–172.
Landsberg, R. L., Sero, J. E., Danielian, P. S., Yuan, T. L., Lee, E. Y., and Lees, J. A. (2003). The role of E2F4 in adipogenesis is independent of its cell cycle regulatory activity. Proc Natl Acad Sci USA 100, 2456–2461.
Lane, M. E., Sauer, K., Wallace, K., Jan, Y. N., Lehner, C. F., and Vaessin, H. (1996). Dacapo, a cyclin-dependent kinase inhibitor, stops cell proliferation during Drosophila development. Cell 87, 1225–1235.
Lee, W. H., Bookstein, R., Hong, F., Young, L. J., Shew, J. Y., and Lee, E. Y. (1987). Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235, 1394–1399.
Lin, W. C., Lin, F. T., and Nevins, J. R. (2001). Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev 15, 1833–1844.
Liu, H., Dibling, B., Spike, B., Dirlam, A., and Macleod, K. (2004). New roles for the RB tumor suppressor protein. Curr Opin Genet Dev 14, 55–64.
Martinez-Balbas, M. A., Bauer, U. M., Nielsen, S. J., Brehm, A., and Kouzarides, T. (2000). Regulation of E2F1 activity by acetylation. Embo J 19, 662–671.
Morris, E. J., and Dyson, N. J. (2001). Retinoblastoma protein partners. Adv Cancer Res 82, 1–54.
Muller, H., Bracken, A. P., Vernell, R., Moroni, M. C., Christians, F., Grassilli, E., Prosperini, E., Vigo, E., Oliner, J. D., and Helin, K. (2001). E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev 15, 267–285.
Muller, H., Moroni, M. C., Vigo, E., Petersen, B. O., Bartek, J., and Helin, K. (1997). Induction of S-phase entry by E2F transcription factors depends on their nuclear localization. Mol Cell Biol 17, 5508–5520.
Mundle, S. D., and Saberwal, G. (2003). Evolving intricacies and implications of E2F1 regulation. Faseb J 17, 569–574.
Munger, K. (2002). The role of human papillomaviruses in human cancers. Front Biosci 7, d641–649.
Nielsen, S. J., Schneider, R., Bauer, U. M., Bannister, A. J., Morrison, A., O’Carroll, D., Firestein, R., Cleary, M., Jenuwein, T., Herrera, R. E., and Kouzarides, T. (2001). Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565.
Ohtani, K., and Nevins, J. R. (1994). Functional properties of a Drosophila homolog of the E2F1 gene. Mol Cell Biol 14, 1603–1612.
Polager, S., Kalma, Y., Berkovich, E., and Ginsberg, D. (2002). E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Oncogene 21, 437–446.
Ren, B., Cam, H., Takahashi, Y., Volkert, T., Terragni, J., Young, R. A., and Dynlacht, B. D. (2002). E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev 16, 245–256.
Royzman, I., Whittaker, A. J., and Orr-Weaver, T. L. (1997). Mutations in Drosophila DP and E2F distinguish G1-S progression from an associated transcriptional program. Genes Dev 11, 1999–2011.
Sage, J., Miller, A. L., Perez-Mancera, P. A., Wysocki, J. M., and Jacks, T. (2003). Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228.
Sawado, T., Yamaguchi, M., Nishimoto, Y., Ohno, K., Sakaguchi, K., and Matsukage, A. (1998). dE2F2, a novel E2F-family transcription factor in Drosophila melanogaster. Biochem Biophys Res Commun 251, 409–415.
Spike, B. T., Dirlam, A., Dibling, B. C., Marvin, J., Williams, B. O., Jacks, T., and Macleod, K. F. (2004). The Rb tumor suppressor is required for stress erythropoiesis. Embo J 23, 4319–4329.
Stevaux, O., Dimova, D., Frolov, M. V., Taylor-Harding, B., Morris, E., and Dyson, N. (2002). Distinct mechanisms of E2F regulation by Drosophila RBF1 and RBF2. Embo J 21, 4927–4937.
Trimarchi, J. M., Fairchild, B., Verona, R., Moberg, K., Andon, N., and Lees, J. A. (1998). E2F-6, a member of the E2F family that can behave as a transcriptional repressor. Proc Natl Acad Sci USA 95, 2850–2855.
Trimarchi, J. M., Fairchild, B., Wen, J., and Lees, J. A. (2001). The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex. Proc Natl Acad Sci USA 98, 1519–1524.
Verona, R., Moberg, K., Estes, S., Starz, M., Vernon, J. P., and Lees, J. A. (1997). E2F activity is regulated by cell cycle-dependent changes in subcellular localization. Mol Cell Biol 17, 7268–7282.
Weintraub, S. J., Chow, K. N., Luo, R. X., Zhang, S. H., He, S., and Dean, D. C. (1995). Mechanism of active transcriptional repression by the retinoblastoma protein. Nature 375, 812–815.
Weintraub, S. J., Prater, C. A., and Dean, D. C. (1992). Retinoblastoma protein switches the E2F site from positive to negative element. Nature 358, 259–261.
Wells, J., Yan, P. S., Cechvala, M., Huang, T., and Farnham, P. J. (2003). Identification of novel pRb binding sites using CpG microarrays suggests that E2F recruits pRb to specific genomic sites during S phase. Oncogene 22, 1445–1460.
Whyte, P., Buchkovich, K. J., Horowitz, J. M., Friend, S. H., Raybuck, M., Weinberg, R. A., and Harlow, E. (1988). Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 334, 124–129.
Whyte, P., Williamson, N. M., and Harlow, E. (1989). Cellular targets for transformation by the adenovirus E1A proteins. Cell 56, 67–75.
Wu, L., de Bruin, A., Saavedra, H. I., Starovic, M., Trimboli, A., Yang, Y., Opavska, J., Wilson, P., Thompson, J. C., Ostrowski, M. C., et al. (2003). Extra-embryonic function of Rb is essential for embryonic development and viability. Nature 421, 942–947.
Wu, L., Timmers, C., Maiti, B., Saavedra, H. I., Sang, L., Chong, G. T., Nuckolls, F., Giangrande, P., Wright, F. A., Field, S. J., et al. (2001). The E2F1-3 transcription factors are essential for cellular proliferation. Nature 414, 457–462.
Xin, S., Weng, L., Xu, J., and Du, W. (2002). The role of RBF in developmentally regulated cell proliferation in the eye disc and in Cyclin D/Cdk4 induced cellular growth. Development 129, 1345–1356.
Zhang, H. S., Gavin, M., Dahiya, A., Postigo, A. A., Ma, D., Luo, R. X., Harbour, J. W., and Dean, D. C. (2000). Exit from G1 and S phase of the cell cycle is regulated by repressor complexes containing HDAC-Rb-hSWI/SNF and Rb-hSWI/SNF. Cell 101, 79–89.
Zheng, N., Fraenkel, E., Pabo, C. O., and Pavletich, N. P. (1999). Structural basis of DNA recognition by the heterodimeric cell cycle transcription factor E2F-DP. Genes Dev 13, 666–674.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Higher Education Press
About this chapter
Cite this chapter
Du, W., Pogoriler, J. (2006). The Rb and E2F Families of Proteins. In: Ma, J. (eds) Gene Expression and Regulation. Springer, New York, NY. https://doi.org/10.1007/978-0-387-40049-5_12
Download citation
DOI: https://doi.org/10.1007/978-0-387-40049-5_12
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-33208-6
Online ISBN: 978-0-387-40049-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)