Conserved RB functions in development and tumor suppression

doi:10.1007/s13238-011-1117-z

Prot Cell

2011, Vol. 2

Issue (11) : 864-878 https://doi.org/10.1007/s13238-011-1117-z PMID: 22180086

REVIEW

Conserved RB functions in development and tumor suppression

Gabriel M. Gordon, Wei Du(

)

Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA

Download: PDF(304 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

Abstract

The variety of human cancers in which the retinoblastoma protein pRb is inactivated reflects both its broad importance for tumor suppression and its multitude of cellular functions. Accumulating evidence indicates that pRb contributes to a diversity of cellular functions, including cell proliferation, differentiation, cell death, and genome stability. pRb performs these diverse functions through the formation of large complexes that include E2F transcription factors and chromatin regulators. In this review we will discuss some of the recent advances made in understanding the structure and function of pRb as they relate to tumor suppression, and highlight research using Drosophila melanogaster that reveals important, evolutionarily conserved functions of the RB family.

Keywords RB E2F Drosophila Rbf cell cycle chromatin modification

Corresponding Author(s): Du Wei,Email:wei@uchicago.edu

Issue Date: 01 November 2011

Cite this article:

Gabriel M. Gordon,Wei Du. Conserved RB functions in development and tumor suppression[J]. Prot Cell, 2011, 2(11): 864-878.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-011-1117-z
https://academic.hep.com.cn/pac/EN/Y2011/V2/I11/864

Tab.1 A list of the RB and E2F family genes and their regulators in and mammals

Fig.1 pRb structure and function.
(A) The structure of pRb consists of conserved N-terminal and C-terminal domains. The small pocket contains a tandem of folds, termed A and B, that bind to E2F transactivation domains and LxCxE motifs that frequently occur in viral oncoproteins and chromatin regulators. The large pocket encompasses the small pocket and the C-terminal domain that also interacts with E2F-DP complexes. Several important cyclin-dependent kinase target residues are indicated by asterisks. (B) Members of the RB family regulate gene expression in part by recruiting DREAM complexes and promoting chromatin repression.

Fig.2 Dependence of RB-deficient cells on TORC1 regulation.
pRb/E2F participates in oxidative stress and unfolded protein responses by promoting expression of the ROS scavenger SOD2 and ER chaperone GRP78, respectively. Therefore cells harboring RB mutations are more sensitive to ROS- and ER stress-induced death. Because loss of TSC function causes deregulated TORC1 activity, which induces increased cellular stress and feedback inhibition of PI3K/AKT survival, RB-deficient cells are sensitive to the loss of either TSC1 or TSC2 and show synthetic lethality.

Fig.3 Control of photoreceptor differentiation by Rbf and Rno.
Rbf is required for the high level of Rhomboid expression in the morphogenetic furrow (MF), although reduced cytoplasmic epidermal growth factor receptor (EGFR) signaling is apparently sufficient to induce photoreceptor differentiation. Rno is required for the transcription of Pointed, an Ets-family transcription factor that is important for photoreceptor differentiation. However Pointed is also required for the expression of Argos, a negative regulator of EGFR signaling. Thus the impairment of EGFR signaling output in the nucleus due to Rno mutation is mitigated by reduced feedback inhibition of EGFR in the cytoplasm. Loss of both Rbf and Rno together affects both cytoplasmic and nuclear components of EGFR-Ras signaling, leading to defective photoreceptor differentiation.

1	Attwooll, C., Lazzerini Denchi, E., and Helin, K. (2004). The E2F family: specific functions and overlapping interests. Embo J 23, 4709–4716 .
2	Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.V., Kolettas, E., Niforou, K., Zoumpourlis, V.C., et al. (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 .
3	Bates, S., Phillips, A.C., Clark, P.A., Stott, F., Peters, G., Ludwig, R.L., and Vousden, K.H. (1998). p14ARF links the tumour suppressors RB and p53. Nature 395, 124–125 .
4	Benevolenskaya, E.V., Murray, H.L., Branton, P., Young, R.A., and Kaelin, W.G. Jr. (2005). Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol Cell 18, 623–635 pmid:15949438.
5	Bergmann, A., Agapite, J., McCall, K., and Steller, H. (1998). The Drosophila gene hid is a direct molecular target of Ras-dependent survival signaling. Cell 95, 331–341 pmid:9814704.
6	Bester, A.C., Roniger, M., Oren, Y.S., Im, M.M., Sarni, D., Chaoat, M., Bensimon, A., Zamir, G., Shewach, D.S., and Kerem, B. (2011). Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145, 435–446 pmid:21529715.
7	Bier, E. (2005). Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6, 9–23 pmid:15630418.
8	Binné, U.K., Classon, M.K., Dick, F.A., Wei, W., Rape, M., Kaelin, W.G. Jr, N??r, A.M., and Dyson, N.J. (2007). Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol 9, 225–232 pmid:17187060.
9	Bosco, E.E., Wang, Y., Xu, H., Zilfou, J.T., Knudsen, K.E., Aronow, B.J., Lowe, S.W., and Knudsen, E.S. (2007). The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer. J Clin Invest 117, 218–228 pmid:17160137.
10	Bourgo, R.J., Thangavel, C., Ertel, A., Bergseid, J., McClendon, A.K., Wilkens, L., Witkiewicz, A.K., Wang, J.Y., and Knudsen, E.S. (2011). RB restricts DNA damage-initiated tumorigenesis through an LXCXE-dependent mechanism of transcriptional control. Mol Cell 43, 663–672 pmid:21855804.
11	Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J.P., Sedivy, J.M., Kinzler, K.W., and Vogelstein, B. (1998). Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501 pmid:9822382.
12	Burke, J.R., Deshong, A.J., Pelton, J.G., and Rubin, S.M. (2010). Phosphorylation-induced conformational changes in the retinoblastoma protein inhibit E2F transactivation domain binding. J Biol Chem 285, 16286–16293 pmid:20223825.
13	Burkhart, D.L., and Sage, J. (2008). Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8, 671–682 pmid:18650841.
14	Buttitta, L.A., Katzaroff, A.J., Perez, C.L., de la Cruz, A., and Edgar, B.A. (2007). A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila. Dev Cell 12, 631–643 pmid:17419999.
15	Calo, E., Quintero-Estades, J.A., Danielian, P.S., Nedelcu, S., Berman, S.D., and Lees, J.A. (2010). Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 pmid:20686481.
16	Chauveinc, L., Mosseri, V., Quintana, E., Desjardins, L., Schlienger, P., Doz, F., and Dutrillaux, B. (2001). Osteosarcoma following retinoblastoma: age at onset and latency period. Ophthalmic Genet 22, 77–88 pmid:11449317.
17	Chen, D., Pacal, M., Wenzel, P., Knoepfler, P.S., Leone, G., and Bremner, R. (2009a). Division and apoptosis of E2f-deficient retinal progenitors. Nature 462, 925–929 pmid:20016601.
18	Chen, H.Z., Tsai, S.Y., and Leone, G. (2009b). Emerging roles of E2Fs in cancer: an exit from cell cycle control. Nat Rev Cancer 9, 785–797 pmid:19851314.
19	Chicas, A., Wang, X., Zhang, C., McCurrach, M., Zhao, Z., Mert, O., Dickins, R.A., Narita, M., Zhang, M., and Lowe, S.W. (2010). Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 17, 376–387 pmid:20385362.
20	Chin, L., Hahn, W.C., Getz, G., and Meyerson, M. (2011). Making sense of cancer genomic data. Genes Dev 25, 534–555 pmid:21406553.
21	Chong, J.L., Wenzel, P.L., Sáenz-Robles, M.T., Nair, V., Ferrey, A., Hagan, J.P., Gomez, Y.M., Sharma, N., Chen, H.Z., Ouseph, M., (2009). E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462, 930–934 pmid:20016602.
22	Christensen, J., Agger, K., Cloos, P.A., Pasini, D., Rose, S., Sennels, L., Rappsilber, J., Hansen, K.H., Salcini, A.E., and Helin, K. (2007). RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell 128, 1063–1076 pmid:17320161.
23	Claudio, P.P., Zamparelli, A., Garcia, F.U., Claudio, L., Ammirati, G., Farina, A., Bovicelli, A., Russo, G., Giordano, G.G., McGinnis, D.E., (2002). Expression of cell-cycle-regulated proteins pRb2/p130, p107, p27(kip1), p53, mdm-2, and Ki-67 (MIB-1) in prostatic gland adenocarcinoma. Clin Cancer Res 8, 1808–1815 pmid:12060621.
24	Coschi, C.H., Martens, A.L., Ritchie, K., Francis, S.M., Chakrabarti, S., Berube, N.G., and Dick, F.A. (2010). Mitotic chromosome condensation mediated by the retinoblastoma protein is tumor-suppressive. Genes Dev 24, 1351–1363 pmid:20551166.
25	Dannenberg, J.H., Schuijff, L., Dekker, M., van der Valk, M., and te Riele, H. (2004). Tissue-specific tumor suppressor activity of retinoblastoma gene homologs p107 and p130. Genes Dev 18, 2952–2962 pmid:15574596.
26	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 pmid:8980230.
27	Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garre’, M., Nuciforo, P.G., Bensimon, A., (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 pmid:17136094.
28	Dick, F.A., and Mymryk, J.S. (2011). Sweet DREAMs for Hippo. Genes Dev 25, 889–894 pmid:21536729.
29	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 pmid:12975318.
30	Du, W., and Dyson, N. (1999). The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis. EMBO J 18, 916–925 pmid:10022834.
31	Du, W., and Pogoriler, J. (2006). Retinoblastoma family genes. Oncogene 25, 5190–5200 pmid:16936737.
32	Dynlacht, B.D., Flores, O., Lees, J.A., and Harlow, E. (1994). Differential regulation of E2F transactivation by cyclin/cdk2 complexes. Genes Dev 8, 1772–1786 pmid:7958856.
33	el-Deiry, W.S., Tokino, T., Velculescu, V.E., Levy, D.B., Parsons, R., Trent, J.M., Lin, D., Mercer, W.E., Kinzler, K.W., and Vogelstein, B. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 pmid:8242752.
34	Ewen, M.E., Sluss, H.K., Sherr, C.J., Matsushime, H., Kato, J., and Livingston, D.M. (1993). Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell 73, 487–497 pmid:8343202.
35	Feinberg, A.P., and Tycko, B. (2004). The history of cancer epigenetics. Nat Rev Cancer 4, 143–153 pmid:14732866.
36	Ferbeyre, G., de Stanchina, E., Querido, E., Baptiste, N., Prives, C., and Lowe, S.W. (2000). PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14, 2015–2027 pmid:10950866.
37	Ferres-Marco, D., Gutierrez-Garcia, I., Vallejo, D.M., Bolivar, J., Gutierrez-Avi?o, F.J., and Dominguez, M. (2006). Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430–436 pmid:16437107.
38	Firth, L.C., and Baker, N.E. (2005). Extracellular signals responsible for spatially regulated proliferation in the differentiating Drosophila eye. Dev Cell 8, 541–551 pmid:15809036.
39	Foijer, F., Wolthuis, R.M., Doodeman, V., Medema, R.H., and te Riele, H. (2005). Mitogen requirement for cell cycle progression in the absence of pocket protein activity. Cancer Cell 8, 455–466 pmid:16338659.
40	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 pmid:2877398.
41	Giangrande, P.H., Zhu, W., Schlisio, S., Sun, X., Mori, S., Gaubatz, S., and Nevins, J.R. (2004). A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription. Genes Dev 18, 2941–2951 pmid:15574595.
42	Ginsberg, D. (2002). E2F1 pathways to apoptosis. FEBS Lett 529, 122–125 pmid:12354623.
43	Gonzalo, S., García-Cao, M., Fraga, M.F., Schotta, G., Peters, A.H., Cotter, S.E., Eguía, R., Dean, D.C., Esteller, M., Jenuwein, T., (2005). Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 7, 420–428 pmid:15750587.
44	Goodrich, D.W. (2003). How the other half lives, the amino-terminal domain of the retinoblastoma tumor suppressor protein. J Cell Physiol 197, 169–180 pmid:14502556.
45	Gordon, G.M., and Du, W. (2011). Targeting Rb inactivation in cancers by synthetic lethality. Am J Cancer Res 1, 773–786 pmid:21814623.
46	Hallstrom, T.C., Mori, S., and Nevins, J.R. (2008). An E2F1-dependent gene expression program that determines the balance between proliferation and cell death. Cancer Cell 13, 11–22 pmid:18167336.
47	Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K., and Elledge, S.J. (1993). The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805–816 pmid:8242751.
48	Harrington, L.S., Findlay, G.M., Gray, A., Tolkacheva, T., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N.R., Cheng, S., Shepherd, P.R., (2004). The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166, 213–223 pmid:15249583.
49	Hassler, M., Singh, S., Yue, W.W., Luczynski, M., Lakbir, R., Sanchez-Sanchez, F., Bader, T., Pearl, L.H., and Mittnacht, S. (2007). Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture. Mol Cell 28, 371–385 pmid:17996702.
50	Hernando, E., Nahlé, Z., Juan, G., Diaz-Rodriguez, E., Alaminos, M., Hemann, M., Michel, L., Mittal, V., Gerald, W., Benezra, R., (2004). Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430, 797–802 pmid:15306814.
51	Hiebert, S.W. (1993). Regions of the retinoblastoma gene product required for its interaction with the E2F transcription factor are necessary for E2 promoter repression and pRb-mediated growth suppression. Mol Cell Biol 13, 3384–3391 pmid:8497257.
52	Hinds, P.W., Mittnacht, S., Dulic, V., Arnold, A., Reed, S.I., and Weinberg, R.A. (1992). Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 70, 993–1006 pmid:1388095.
53	Hirschi, A., Cecchini, M., Steinhardt, R.C., Schamber, M.R., Dick, F.A., and Rubin, S.M. (2010). An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein. Nat Struct Mol Biol 17, 1051–1057 pmid:20694007.
54	Hsieh, T.C., Nicolay, B.N., Frolov, M.V., and Moon, N.S. (2010). Tuberous sclerosis complex 1 regulates dE2F1 expression during development and cooperates with RBF1 to control proliferation and survival. PLoS Genet 6, e1001071 pmid:20808898.
55	Hu, N., Gutsmann, A., Herbert, D.C., Bradley, A., Lee, W.H., and Lee, E.Y. (1994). Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9, 1021–1027 pmid:8134105.
56	Ianari, A., Natale, T., Calo, E., Ferretti, E., Alesse, E., Screpanti, I., Haigis, K., Gulino, A., and Lees, J.A. (2009). Proapoptotic function of the retinoblastoma tumor suppressor protein. Cancer Cell 15, 184–194 pmid:19249677.
57	Isaac, C.E., Francis, S.M., Martens, A.L., Julian, L.M., Seifried, L.A., Erdmann, N., Binné, U.K., Harrington, L., Sicinski, P., Bérubé, N.G., (2006). The retinoblastoma protein regulates pericentric heterochromatin. Mol Cell Biol 26, 3659–3671 pmid:16612004.
58	Ishida, S., Huang, E., Zuzan, H., Spang, R., Leone, G., West, M., and Nevins, J.R. (2001). Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol Cell Biol 21, 4684–4699 pmid:11416145.
59	Iwase, S., Lan, F., Bayliss, P., de la Torre-Ubieta, L., Huarte, M., Qi, H.H., Whetstine, J.R., Bonni, A., Roberts, T.M., and Shi, Y. (2007). The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128, 1077–1088 pmid:17320160.
60	Julien, L.A., Carriere, A., Moreau, J., and Roux, P.P. (2010). mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 30, 908–921 pmid:19995915.
61	Kaelin, W.G. Jr. (2005). The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5, 689–698 pmid:16110319.
62	Kamijo, T., Weber, J.D., Zambetti, G., Zindy, F., Roussel, M.F., and Sherr, C.J. (1998). Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci U S A 95, 8292–8297 pmid:9653180.
63	Kanber, D., Berulava, T., Ammerpohl, O., Mitter, D., Richter, J., Siebert, R., Horsthemke, B., Lohmann, D., and Buiting, K. (2009). The human retinoblastoma gene is imprinted. PLoS Genet 5, e1000790 pmid:20041224.
64	Kato, J., Matsushime, H., Hiebert, S.W., Ewen, M.E., and Sherr, C.J. (1993). Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 7, 331–342 pmid:8449399.
65	Kaye, F.J., and Harbour, J.W. (2004). For whom the bell tolls: susceptibility to common adult cancers in retinoblastoma survivors. J Natl Cancer Inst 96, 342–343 pmid:14996847.
66	Klose, R.J., Yan, Q., Tothova, Z., Yamane, K., Erdjument-Bromage, H., Tempst, P., Gilliland, D.G., Zhang, Y., and Kaelin, W.G. Jr. (2007). The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889–900 pmid:17320163.
67	Knudsen, E.S., and Wang, J.Y. (2010). Targeting the RB-pathway in cancer therapy. Clin Cancer Res 16, 1094–1099 pmid:20145169.
68	Knudson, A.G. Jr. (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68, 820–823 pmid:5279523.
69	Korenjak, M., Taylor-Harding, B., Binné, 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 pmid:15479636.
70	Lalande, M., Dryja, T.P., Schreck, R.R., Shipley, J., Flint, A., and Latt, S.A. (1984). Isolation of human chromosome 13-specific DNA sequences cloned from flow sorted chromosomes and potentially linked to the retinoblastoma locus. Cancer Genet Cytogenet 13, 283–295 pmid:6210139.
71	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 pmid:8980229.
72	Laurie, N.A., Donovan, S.L., Shih, C.S., Zhang, J., Mills, N., Fuller, C., Teunisse, A., Lam, S., Ramos, Y., Mohan, A., (2006). Inactivation of the p53 pathway in retinoblastoma. Nature 444, 61–66 pmid:17080083.
73	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 pmid:3823889.
74	Lewis, P.W., Beall, E.L., Fleischer, T.C., Georlette, D., Link, A.J., and Botchan, M.R. (2004). Identification of a Drosophila Myb-E2F2/RBF transcriptional repressor complex. Genes Dev 18, 2929–2940 pmid:15545624.
75	Li, B., Gordon, G.M., Du, C.H., Xu, J., and Du, W. (2010). Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17, 469–480 pmid:20478529.
76	Li, J., Ran, C., Li, E., Gordon, F., Comstock, G., Siddiqui, H., Cleghorn, W., Chen, H.Z., Kornacker, K., Liu, C.G., (2008). Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development. Dev Cell 14, 62–75 pmid:18194653.
77	Lin, W., Cao, J., Liu, J., Beshiri, M.L., Fujiwara, Y., Francis, J., Cherniack, A.D., Geisen, C., Blair, L.P., Zou, M.R., (2011). Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc Natl Acad Sci U S A 108, 13379–13386 pmid:21788502.
78	Litovchick, L., Florens, L.A., Swanson, S.K., Washburn, M.P., and DeCaprio, J.A. (2011). DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev 25, 801–813 pmid:21498570.
79	Litovchick, L., Sadasivam, S., Florens, L., Zhu, X., Swanson, S.K., Velmurugan, S., Chen, R., Washburn, M.P., Liu, X.S., and DeCaprio, J.A. (2007). Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell 26, 539–551 pmid:17531812.
80	Longworth, M.S., Herr, A., Ji, J.Y., and Dyson, N.J. (2008). RBF1 promotes chromatin condensation through a conserved interaction with the Condensin II protein dCAP-D3. Genes Dev 22, 1011–1024 pmid:18367646.
81	Lopez-Bigas, N., Kisiel, T.A., Dewaal, D.C., Holmes, K.B., Volkert, T.L., Gupta, S., Love, J., Murray, H.L., Young, R.A., and Benevolenskaya, E.V. (2008). Genome-wide analysis of the H3K4 histone demethylase RBP2 reveals a transcriptional program controlling differentiation. Mol Cell 31, 520–530 pmid:18722178.
82	Ludlow, J.W., Glendening, C.L., Livingston, D.M., and DeCarprio, J.A. (1993). Specific enzymatic dephosphorylation of the retinoblastoma protein. Mol Cell Biol 13, 367–372 pmid:8380224.
83	Lukas, J., Parry, D., Aagaard, L., Mann, D.J., Bartkova, J., Strauss, M., Peters, G., and Bartek, J. (1995). Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375, 503–506 pmid:7777060.
84	Magnaghi-Jaulin, L., Groisman, R., Naguibneva, I., Robin, P., Lorain, S., Le Villain, J.P., Troalen, F., Trouche, D., and Harel-Bellan, A. (1998). Retinoblastoma protein represses transcription by recruiting a histone deacetylase. Nature 391, 601–605 pmid:9468140.
85	Manning, A.L., Longworth, M.S., and Dyson, N.J. (2010). Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev 24, 1364–1376 pmid:20551165.
86	Milet, C., Rincheval-Arnold, A., Mignotte, B., and Guénal, I. (2010). The Drosophila retinoblastoma protein induces apoptosis in proliferating but not in post-mitotic cells. Cell Cycle 9, 97–103 pmid:20016284.
87	Miller, C.W., Simon, K., Aslo, A., Kok, K., Yokota, J., Buys, C.H., Terada, M., and Koeffler, H.P. (1992). p53 mutations in human lung tumors. Cancer Res 52, 1695–1698 pmid:1312896.
88	Moon, N.S., Di Stefano, L., and Dyson, N. (2006). A gradient of epidermal growth factor receptor signaling determines the sensitivity of rbf1 mutant cells to E2F-dependent apoptosis. Mol Cell Biol 26, 7601–7615 pmid:16954388.
89	Moon, N.S., Frolov, M.V., Kwon, E.J., Di Stefano, L., Dimova, D.K., Morris, E.J., Taylor-Harding, B., White, K., and Dyson, N.J. (2005). Drosophila E2F1 has context-specific pro- and antiapoptotic properties during development. Dev Cell 9, 463–475 pmid:16198289.
90	Moroni, M.C., Hickman, E.S., Lazzerini Denchi, E., Caprara, G., Colli, E., Cecconi, F., Müller, H., and Helin, K. (2001). Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 3, 552–558 pmid:11389439.
91	Müller, 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 pmid:11159908.
92	Mulligan, G., and Jacks, T. (1998). The retinoblastoma gene family: cousins with overlapping interests. Trends Genet 14, 223–229 pmid:9635405.
93	Narita, M., N?nez, S., Heard, E., Narita, M., Lin, A.W., Hearn, S.A., Spector, D.L., Hannon, G.J., and Lowe, S.W. (2003). Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 pmid:12809602.
94	Nicolay, B.N., Bayarmagnai, B., Islam, A.B., Lopez-Bigas, N., and Frolov, M.V. (2011). Cooperation between dE2F1 and Yki/Sd defines a distinct transcriptional program necessary to bypass cell cycle exit. Genes Dev 25, 323–335 pmid:21325133.
95	Nicolay, B.N., Bayarmagnai, B., Moon, N.S., Benevolenskaya, E.V., and Frolov, M.V. (2010). Combined inactivation of pRB and hippo pathways induces dedifferentiation in the Drosophila retina. PLoS Genet 6, e1000918 pmid:20421993.
96	Nogueira, V., Park, Y., Chen, C.C., Xu, P.Z., Chen, M.L., Tonic, I., Unterman, T., and Hay, N. (2008). Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14, 458–470 pmid:19061837.
97	Ozcan, U., Ozcan, L., Yilmaz, E., Düvel, K., Sahin, M., Manning, B.D., and Hotamisligil, G.S. (2008). Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29, 541–551 pmid:18342602.
98	Pan, D. (2010). The hippo signaling pathway in development and cancer. Dev Cell 19, 491–505 pmid:20951342.
99	Pearson, M., Carbone, R., Sebastiani, C., Cioce, M., Fagioli, M., Saito, S., Higashimoto, Y., Appella, E., Minucci, S., Pandolfi, P.P., (2000). PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210 pmid:10910364.
100	Pickering, M.T., and Kowalik, T.F. (2006). Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation. Oncogene 25, 746–755 pmid:16186801.
101	Polyak, K., Lee, M.H., Erdjument-Bromage, H., Koff, A., Roberts, J.M., Tempst, P., and Massagué, J. (1994). Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78, 59–66 pmid:8033212.
102	Qin, X.Q., Chittenden, T., Livingston, D.M., and Kaelin, W.G. Jr. (1992). Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev 6, 953–964 pmid:1534305.
103	Racek, T., Buhlmann, S., Rüst, F., Knoll, S., Alla, V., and Pützer, B.M. (2008). Transcriptional repression of the prosurvival endoplasmic reticulum chaperone GRP78/BIP by E2F1. J Biol Chem 283, 34305–34314 pmid:18840615.
104	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 pmid:11799067.
105	Robertson, K.D., Ait-Si-Ali, S., Yokochi, T., Wade, P.A., Jones, P.L., and Wolffe, A.P. (2000). DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25, 338–342 pmid:10888886.
106	Rogoff, H.A., Pickering, M.T., Debatis, M.E., Jones, S., and Kowalik, T.F. (2002). E2F1 induces phosphorylation of p53 that is coincident with p53 accumulation and apoptosis. Mol Cell Biol 22, 5308–5318 pmid:12101227.
107	Rubin, S.M., Gall, A.L., Zheng, N., and Pavletich, N.P. (2005). Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release. Cell 123, 1093–1106 pmid:16360038.
108	Ruthenburg, A.J., Li, H., Patel, D.J., and Allis, C.D. (2007). Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8, 983–994 pmid:18037899.
109	Sage, J., Miller, A.L., Pérez-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 pmid:12853964.
110	Sarbassov, D.D., Guertin, D.A., Ali, S.M., and Sabatini, D.M. (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 pmid:15718470.
111	Schvartzman, J.M., Duijf, P.H., Sotillo, R., Coker, C., and Benezra, R. (2011). Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. Cancer Cell 19, 701–714 pmid:21665145.
112	Searle, J.S., Li, B., and Du, W. (2010). Targeting Rb mutant cancers by inactivating TSC2. Oncotarget 1, 228–232 pmid:20706560.
113	Serrano, M., Hannon, G.J., and Beach, D. (1993). A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 pmid:8259215.
114	Shah, O.J., Wang, Z., and Hunter, T. (2004). Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14, 1650–1656 pmid:15380067.
115	Sharma, A., Yeow, W.S., Ertel, A., Coleman, I., Clegg, N., Thangavel, C., Morrissey, C., Zhang, X., Comstock, C.E., Witkiewicz, A.K., (2010). The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest 120, 4478–4492 pmid:21099110.
116	Sherr, C.J., and McCormick, F. (2002). The RB and p53 pathways in cancer. Cancer Cell 2, 103–112 pmid:12204530.
117	Stanelle, J., Stiewe, T., Theseling, C.C., Peter, M., and Pützer, B.M. (2002). Gene expression changes in response to E2F1 activation. Nucleic Acids Res 30, 1859–1867 pmid:11937641.
118	Steele, L., Sukhanova, M.J., Xu, J., Gordon, G.M., Huang, Y., Yu, L., and Du, W. (2009). Retinoblastoma family protein promotes normal R8-photoreceptor differentiation in the absence of rhinoceros by inhibiting dE2F1 activity. Dev Biol 335, 228–236 pmid:19744473.
119	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 pmid:12234932.
120	Stirzaker, C., Millar, D.S., Paul, C.L., Warnecke, P.M., Harrison, J., Vincent, P.C., Frommer, M., and Clark, S.J. (1997). Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res 57, 2229–2237 pmid:9187126.
121	Stott, F.J., Bates, S., James, M.C., McConnell, B.B., Starborg, M., Brookes, S., Palmero, I., Ryan, K., Hara, E., Vousden, K.H., (1998). The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J 17, 5001–5014 pmid:9724636.
122	Sukhanova, M.J., Steele, L.J., Zhang, T., Gordon, G.M., and Du, W.. RBF and Rno promote photoreceptor differentiation onset through modulating EGFR signaling in the Drosophila developing eye. Dev Biol . Sep 2, 2011. [Epub ahead of print].
123	Takahashi, Y., Rayman, J.B., and Dynlacht, B.D. (2000). Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev 14, 804–816 pmid:10766737.
124	Talluri, S., Isaac, C.E., Ahmad, M., Henley, S.A., Francis, S.M., Martens, A.L., Bremner, R., and Dick, F.A. (2010). A G1 checkpoint mediated by the retinoblastoma protein that is dispensable in terminal differentiation but essential for senescence. Mol Cell Biol 30, 948–960 pmid:20008551.
125	Tanaka, H., Matsumura, I., Ezoe, S., Satoh, Y., Sakamaki, T., Albanese, C., Machii, T., Pestell, R.G., and Kanakura, Y. (2002). E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell 9, 1017–1029 pmid:12049738.
126	Tanaka-Matakatsu, M., Xu, J., Cheng, L., and Du, W. (2009). Regulation of apoptosis of rbf mutant cells during Drosophila development. Dev Biol 326, 347–356 pmid:19100727.
127	Taubert, S., Gorrini, C., Frank, S.R., Parisi, T., Fuchs, M., Chan, H.M., Livingston, D.M., and Amati, B. (2004). E2F-dependent histone acetylation and recruitment of the Tip60 acetyltransferase complex to chromatin in late G1. Mol Cell Biol 24, 4546–4556 pmid:15121871.
128	Taylor, B.S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B.S., Arora, V.K., Kaushik, P., Cerami, E., Reva, B., (2010). Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 pmid:20579941.
129	Thomas, D.M., Carty, S.A., Piscopo, D.M., Lee, J.S., Wang, W.F., Forrester, W.C., and Hinds, P.W. (2001). The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol Cell 8, 303–316 pmid:11545733.
130	Toyoshima, H., and Hunter, T. (1994). p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67–74 pmid:8033213.
131	Treins, C., Warne, P.H., Magnuson, M.A., Pende, M., and Downward, J. (2010). Rictor is a novel target of p70 S6 kinase-1. Oncogene 29, 1003–1016 pmid:19935711.
132	Tsai, K.Y., Hu, Y., Macleod, K.F., Crowley, D., Yamasaki, L., and Jacks, T. (1998). Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol Cell 2, 293–304 pmid:9774968.
133	Tsch?p, K., Conery, A.R., Litovchick, L., Decaprio, J.A., Settleman, J., Harlow, E., and Dyson, N. (2011). A kinase shRNA screen links LATS2 and the pRB tumor suppressor. Genes Dev 25, 814–830 pmid:21498571.
134	van den Heuvel, S., and Dyson, N.J. (2008). Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol 9, 713–724 pmid:18719710.
135	van Harn, T., Foijer, F., van Vugt, M., Banerjee, R., Yang, F., Oostra, A., Joenje, H., and te Riele, H. (2010). Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling. Genes Dev 24, 1377–1388 pmid:20551164.
136	Vernier, M., Bourdeau, V., Gaumont-Leclerc, M.F., Moiseeva, O., Bégin, V., Saad, F., Mes-Masson, A.M., and Ferbeyre, G. (2011). Regulation of E2Fs and senescence by PML nuclear bodies. Genes Dev 25, 41–50 pmid:21205865.
137	Voas, M.G., and Rebay, I. (2003). The novel plant homeodomain protein rhinoceros antagonizes Ras signaling in the Drosophila eye. Genetics 165, 1993–2006 pmid:14704181.
138	Wang, H., Bauzon, F., Ji, P., Xu, X., Sun, D., Locker, J., Sellers, R.S., Nakayama, K., Nakayama, K.I., Cobrinik, D., (2010). Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice. Nat Genet 42, 83–88 pmid:19966802.
139	Wei, W., Ayad, N.G., Wan, Y., Zhang, G.J., Kirschner, M.W., and Kaelin, W.G. Jr. (2004). Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428, 194–198 pmid:15014503.
140	Wikenheiser-Brokamp, K.A. (2004). Rb family proteins differentially regulate distinct cell lineages during epithelial development. Development 131, 4299–4310 pmid:15294860.
141	Wikenheiser-Brokamp, K.A. (2006a). Retinoblastoma family proteins: insights gained through genetic manipulation of mice. Cell Mol Life Sci 63, 767–780 pmid:16465443.
142	Wikenheiser-Brokamp, K.A. (2006b). Retinoblastoma regulatory pathway in lung cancer. Curr Mol Med 6, 783–793 pmid:17100603.
143	Williams, B.O., Remington, L., Albert, D.M., Mukai, S., Bronson, R.T., and Jacks, T. (1994). Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet 7, 480–484 pmid:7951317.
144	Wirt, S.E., Adler, A.S., Gebala, V., Weimann, J.M., Schaffer, B.E., Saddic, L.A., Viatour, P., Vogel, H., Chang, H.Y., Meissner, A., (2010). G1 arrest and differentiation can occur independently of Rb family function. J Cell Biol 191, 809–825 pmid:21059851.
145	Xie, W., Jiang, P., Miao, L., Zhao, Y., Zhimin, Z., Qing, L., Zhu, W.G., and Wu, M. (2006). Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1. Nucleic Acids Res 34, 2046–2055 pmid:16617145.
146	Yamasaki, L., Bronson, R., Williams, B.O., Dyson, N.J., Harlow, E., and Jacks, T. (1998). Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-) mice. Nat Genet 18, 360–364 pmid:9537419.
147	Yamasaki, L., Jacks, T., Bronson, R., Goillot, E., Harlow, E., and Dyson, N.J. (1996). Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85, 537–548 pmid:8653789.
148	Young, A.P., and Longmore, G.D. (2004). Ras protects Rb family null fibroblasts from cell death: a role for AP-1. J Biol Chem 279, 10931–10938 pmid:14688262.
149	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 pmid:10778858.
150	Zhang, Y., Xiong, Y., and Yarbrough, W.G. (1998). ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92, 725–734 pmid:9529249.
151	Zhu, L., Harlow, E., and Dynlacht, B.D. (1995). p107 uses a p21CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F. Genes Dev 9, 1740–1752 pmid:7622038.

[1]	Jing Liu, Xu Kong, Mengkai Zhang, Xiao Yang, Xiuqin Xu. RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy[J]. Protein Cell, 2019, 10(6): 405-416.
[2]	Zhanping Shi, Yanan Geng, Jiping Liu, Huina Zhang, Liqiang Zhou, Quan Lin, Juehua Yu, Kunshan Zhang, Jie Liu, Xinpei Gao, Chunxue Zhang, Yinan Yao, Chong Zhang, Yi E. Sun. Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations[J]. Protein Cell, 2018, 9(4): 351-364.
[3]	Jihong Lian, Randal Nelson, Richard Lehner. Carboxylesterases in lipid metabolism: from mouse to human[J]. Protein Cell, 2018, 9(2): 178-195.
[4]	Huang Cao, Kaitao Zhao, Yongxuan Yao, Jing Guo, Xiaoxiao Gao, Qi Yang, Min Guo, Wandi Zhu, Yun Wang, Chunchen Wu, Jizheng Chen, Yuan Zhou, Xue Hu, Mengji Lu, Xinwen Chen, Rongjuan Pei. RNA binding protein 24 regulates the translation and replication of hepatitis C virus[J]. Protein Cell, 2018, 9(11): 930-944.
[5]	Xuyuan Zhang, Pan Yang, Nan Wang, Jialong Zhang, Jingyun Li, Hao Guo, Xiangyun Yin, Zihe Rao, Xiangxi Wang, Liguo Zhang. The binding of a monoclonal antibody to the apical region of SCARB2 blocks EV71 infection[J]. Protein Cell, 2017, 8(8): 590-600.
[6]	Yingli Shang,Sinead Smith,Xiaoyu Hu. Role of Notch signaling in regulating innate immunity and inflammation in health and disease[J]. Protein Cell, 2016, 07(03): 159-174.
[7]	Julia Foldi,Yingli Shang,Baohong Zhao,Lionel B. Ivashkiv,Xiaoyu Hu. RBP-J is required for M2 macrophage polarization in response to chitin and mediates expression of a subset of M2 genes[J]. Protein Cell, 2016, 07(03): 201-209.
[8]	Ping Wang,Chang Sun,Tingting Zhu,Yanhui Xu. Structural insight into mechanisms for dynamic regulation of PKM2[J]. Protein Cell, 2015, 6(4): 275-287.
[9]	Caiguo Zhang,Fan Zhang. Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities[J]. Protein Cell, 2015, 6(2): 88-100.
[10]	Minghao Dang,Xiangxi Wang,Quan Wang,Yaxin Wang,Jianping Lin,Yuna Sun,Xuemei Li,Liguo Zhang,Zhiyong Lou,Junzhi Wang,Zihe Rao. Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71[J]. Protein Cell, 2014, 5(9): 692-703.
[11]	Zhen Cai,Guoxia Liu,Junli Zhang,Yin Li. Development of an activity-directed selection system enabled significant improvement of the carboxylation efficiency of Rubisco[J]. Protein Cell, 2014, 5(7): 552-562.
[12]	Zhixiu Yang,Qiang Guo,Simon Goto,Yuling Chen,Ningning Li,Kaige Yan,Yixiao Zhang,Akira Muto,Haiteng Deng,Hyouta Himeno,Jianlin Lei,Ning Gao. *Structural insights into the assembly of the 30S ribosomal subunit in vivo: functional role of S5 and location of the 17S rRNA precursor sequence*[J]. Protein Cell, 2014, 5(5): 394-407.
[13]	Dengwen Li,Xiaodong Sun,Linlin Zhang,Bing Yan,Songbo Xie,Ruming Liu,Min Liu,Jun Zhou. Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells[J]. Protein Cell, 2014, 5(3): 214-223.
[14]	Changhui Sun,Dan Chen,Jun Fang,Pingrong Wang,Xiaojian Deng,Chengcai Chu. Understanding the genetic and epigenetic architecture in complex network of rice flowering pathways[J]. Protein Cell, 2014, 5(12): 889-898.
[15]	Caiguo Zhang. Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control[J]. Protein Cell, 2014, 5(10): 750-760.

Viewed

Full text

Abstract

Cited

Shared

Discussed