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Cell Growth and Development

Retinoblastoma Protein Contains a C-terminal Motif That Targets It for Phosphorylation by Cyclin-cdk Complexes

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Pages 1068-1080 | Received 30 Jun 1998, Accepted 04 Nov 1998, Published online: 28 Mar 2023

REFERENCES

  • Adams, P. D., and J. Kaelin 1995. Transcriptional control by E2F. Semin. Cancer Biol. 6:99–108.
  • Adams, P. D., W. R. Sellers, S. K. Sharma, A. D. Wu, C. M. Nalin, and J. Kaelin 1996. Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cdk inhibitors. Mol. Cell. Biol. 16:6623–6633.
  • Bartkova, J., J. Lukas, H. Muller, D. Lutzhoft, M. Strauss, and J. Bartek 1994. Cyclin D1 protein expression and function in human breast cancer. Int. J. Cancer 57:353–361.
  • Botz, J., K. Zerfass-Thome, D. Spitzovsky, H. Delius, B. Vogt, M. Eilers, A. Hatzigeorgiou, and J. Jansen-Durr 1996. Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter. Mol. Cell. Biol. 16:3401–3409.
  • Cantley, L. C., K. R. Auger, C. Carpenter, B. Duckworth, A. Graziani, R. Kapeller, and J. Soltoff 1991. Oncogenes and signal transduction. Cell 64:281–302.
  • Chen, C., and J. Okayama 1987. High-efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 7:2745–2752.
  • Chen, J., P. Saha, S. Kornbluth, B. D. Dynlacht, and J. Dutta 1996. Cyclin binding motifs are essential for the function of p21cip1. Mol. Cell. Biol. 16:4673–4682.
  • Cobrinik, D., P. Whyte, D. S. Peeper, T. Jacks, and J. Weinberg 1993. Cell cycle-specific association of E2F with the p130 E1A-binding protein. Genes Dev. 7:2392–2404.
  • Connell-Crowley, L., J. W. Harper, and J. Goodrich 1997. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol. Biol. Cell 8:287–301.
  • DeCaprio, J. A., Y. Furukawa, F. Ajchenbaum, J. Griffen, and J. Livingston 1992. The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression. Proc. Natl. Acad. Sci. USA 89:1795–1798.
  • DeGregori, J., G. Leone, K. Ohtani, A. Miron, and J. Nevins 1995. E2F1 accumulation bypasses a G1 arrest resulting from the inhibition of G1 cyclin-dependent kinase activity. Genes Dev. 9:2873–2887.
  • Dowdy, S. F., P. W. Hinds, K. Louie, S. I. Reed, A. Arnold, and J. Weinberg 1993. Physical interaction of the retinoblastoma protein with human D cyclins. Cell 73:499–511.
  • Duronio, R. J., A. Brook, N. Dyson, and J. O’Farrell 1996. E2F induced S phase requires cyclin E. Genes Dev. 10:2505–2513.
  • Duronio, R. J., and J. O’Farrell 1995. Developmental control of the G1 to S transition in Drosophila: cyclin E is a limiting downstream target of E2F. Genes Dev. 9:1456–1468.
  • Dynlacht, B., D. Flores, O. Lees, and J. Harlow, E 1994. Differential regulation of E2F transactivation by cyclin/cdk complexes. Genes Dev. 8:1772–1786.
  • Dynlacht, B. D., K. Moberg, J. A. Lees, E. Harlow, and J. Zhu 1997. Specific Regulation of E2F family members by cyclin-dependent kinases. Mol. Cell. Biol. 17:3867–3875.
  • Ewen, M. E., B. Faha, E. Harlow, and J. Livingston 1992. Interaction of p107 with cyclin A independent of complex formation with viral oncoproteins. Science 255:85–87.
  • Ewen, M. E., H. K. Sluss, C. J. Sherr, H. Matsushime, J.-Y. Kato, and J. Livingston 1993. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell 73:487–497.
  • Ezhevsky, S., H. Nagahara, A. Vocero-Akbani, D. Gius, M. Wei, and J. Dowdy 1997. Hypo-phosphorylation protein (pRb) by cyclin D:Cdk/6 complexes results in active pRb. Proc. Natl. Acad. Sci. USA 94:10699–10704.
  • Fagan, R., K. J. Flint, and J. Jones 1994. Phosphorylation of E2F1 modulates its interaction with the retinoblastoma gene product and the adenoviral E4 19kD protein. Cell 78:799–811.
  • Faha, B., M. Ewen, L. Tsai, D. M. Livingston, and J. Harlow 1992. Interaction between human cyclin A and adenovirus E1A-associated p107 protein. Science 255:87–90.
  • Frangioni, J., and J. Neel 1993. Solubilisation and purification of enzymatically active glutathione S-transferase (pGEX) fusion proteins. Anal. Biochem. 210:179–187.
  • Geng, Y., E. N. Eaton, M. Picon, J. M. Roberts, A. S. Lundberg, A. Gifford, C. Sardet, and J. Weinberg 1996. Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene 12:1173–1180.
  • Gu, Y., C. W. Turek, and J. Morgan 1993. Inhibition of cdk2 activity in vivo by an associated 20K regulatory subunit. Nature 366:707–710.
  • Guan, K.-L., C. W. Jenkins, Y. Li, M. A. Nichols, X. Wu, C. L. O’Keefe, A. G. Matera, and J. Xiong 1994. Growth suppression by p18, a p16 INK4/MTS1 and p14 INK4B/MTS1-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev. 8:2939–2952.
  • Gupta, S., T. Barrett, A. J. Whitmarsh, J. Cavanagh, H. K. Sluss, B. Derijard, and J. Davis 1996. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 15:2760–2770.
  • Hall, M., and J. Peters 1996. Genetic alterations of cyclins, cyclin dependent kinases, and Ddk inhibitors in human cancer. Adv. Cancer Res. 68:67–108.
  • Hamel, P. A., B. L. Cohen, L. M. Sorce, B. L. Gallie, and J. Phillips 1990. Hyperphosphorylation of the retinoblastoma gene product is determined by domains outside the simian virus 40 large-T-antigen-binding regions. Mol. Cell. Biol. 10:6586–6595.
  • Hamel, P. A., R. M. Gill, R. A. Phillips, and J. Gallie 1992. Regions controlling hyperphosphorylation and conformation of the retinoblastoma gene product are independent of domains required for transcriptional repression. Oncogene 7:693–701.
  • Harper, J. W., G. R. Adami, N. Wei, K. Keyomarsi, and J. Elledge 1993. The p21 cdk-interacting protein CIP1 is a potent inhibitor of G1 Cyclin-dependent kinases. Cell 75:805–816.
  • Hatakeyama, M., J. Brill, G. Fink, and J. Weinberg 1994. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev. 8:1759–1771.
  • Herrera, R. E., V. P. Sah, B. O. Williams, T. P. Makela, R. A. Weinberg, and J. Jacks 1996. Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts. Mol. Cell. Biol. 16:2402–2407.
  • 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.
  • Hinds, P. W., S. Mittnacht, V. Dulic, A. Arnold, S. I. Reed, and J. Weinberg 1992. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 70:993–1006.
  • Hoang, A., B. Lutterbach, B. C. Lewis, T. Yano, T. Y. Chou, J. F. Barrett, M. Raffeld, S. R. Hann, and J. Dang 1995. A link between increased transforming activity of lymphoma derived MYC mutant alleles, their defective regulation by p107, and altered phosphorylation of the c-myc transactivation domain. Mol. Cell. Biol. 15:4031–4042.
  • Holmes, J. K., and J. Solomon 1996. A predictive scale for evaluating cyclin-dependent kinase substrates. J. Biol. Chem. 41:25240–25246.
  • Horton, L. E., Y. Qian, and J. Templeton 1995. G1 cyclins control the retinoblastoma gene product growth regulation activity via upstream mechanisms. Cell Growth Differ. 6:395–407.
  • Hunter, T., and J. Pines 1991. Cyclins and cancer. Cell 66:1071–1074.
  • Hunter, T., and J. Pines 1994. Cyclins and cancer II: cyclin D and CDK inhibitors come of age. Cell 79:573–582.
  • Hurford, R. K., D. Cobrinik, M.-H. Lee, and J. Dyson 1997. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev. 11:1447–1463.
  • Kaelin, W. G. 1997. Recent insights into the functions of the retinoblastoma gene product. Cancer Investig. 15:243–254.
  • Kallunki, T., T. Deng, M. Hibi, and J. Karin 1996. c-jun can recruit JNK to phosphorylate dimerisation partners via specific docking interactions. Cell 87:929–39.
  • Kato, J.-Y., H. Matsushime, S. W. Hiebert, M. E. Ewen, and J. Sherr 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.
  • Kaye, F. J., R. A. Kratzke, J. L. Gerster, and J. Horowitz 1990. A single amino acid substitution results in a retinoblastoma protein defective in phosphorylation and oncoprotein binding. Proc. Natl. Acad. Sci. USA 87:6922–6926.
  • Kelly, B., K. Wolfe, and J. Roberts 1998. Identification of a substrate-targeting domain in cyclin E necessary for phosphorylation of the retinoblastoma protein. Proc. Natl. Acad. Sci. USA 95:2535–2540.
  • Kitagawa, M., H. Higashi, H.-K. Jung, I. Suzuki-Takahashi, M. Ikeda, K. Tamai, J. Kato, K. Seqawa, E. Yoshida, S. Nishimura, and J. Taya 1996. The consensus motif for phosphorylation by cyclin D1-cdk4 is different from that for phosphorylation by cyclin A/E-cdk2. EMBO J. 15:7060–7069.
  • Knudsen, E. S., C. Buckmaster, T.-T. Chen, J. R. Feramisco, and J. Wang 1998. Inhibition of DNA synthesis by RB: effects on G1/S transition and S-phase progression. Genes Dev. 12:2278–2821.
  • Knudsen, E. S., and J. Wang 1996. Differential regulation of retinoblastoma function by specific cdk phosphorylation sites. J. Biol. Chem. 271:8313–20.
  • Knudsen, E. S., and J. Wang 1997. Dual mechanisms for the inhibition of E2F binding to RB by cyclin-dependent kinase-mediated RB phosphorylation. Mol. Cell. Biol. 17:5771–5783.
  • Koh, J., G. Enders, B. Dynlacht, and J. Harlow 1995. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature 375:506–510.
  • Krek, W., M. Ewen, S. Shirodkar, Z. Arany, W. G. Kaelin, and J. Livingston 1994. Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 78:1–20.
  • LaBaer, J., M. D. Garrett, L. F. Stevenson, J. M. Slingerland, C. Sandhu, H. S. Chou, A. Fattaey, and J. Harlow 1997. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11:847–862.
  • Lees, E., B. Faha, V. Dulic, S. I. Reed, and J. Harlow 1992. Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Genes Dev. 6:1874–1885.
  • Lees, J. A., K. J. Buchkovich, D. R. Marshak, C. W. Anderson, and J. Harlow 1991. The retinoblastoma protein is phosphorylated on multiple sites by human cdc2. EMBO J. 10:4279–4290.
  • Leng, X., L. Connell-Crowley, D. Goodrich, and J. Harper 1997. S-phase entry upon ectopic production of G1 cyclin-dependent kinases in the absence of retinoblastoma phosphorylation. Curr. Biol. 7:709–712.
  • Leone, G., J. DeGregori, R. Sears, L. Jakoi, and J. Nevins 1997. Myc and Ras collaborate in inducing accumulation of active cyclin E/cdk2 and E2F. Nature 387:422–426.
  • Li, Y., C. Graham, S. Lacy, A. M. V. Duncan, and J. Whyte 1993. The adenovirus E1A-associated 130-kd protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Dev. 7:2366–2377.
  • Lin, B. T.-Y., S. Gruenwald, A. O. Moria, W.-H. Lee, and J. Wang 1991. Retinoblastoma cancer suppressor gene product is a substrate of the cell cycle regulator cdc2 kinase. EMBO J. 10:857–864.
  • Lisztwan, J., A. Marti, H. Sutterluty, M. Gstaiger, C. Wirbelauer, and J. Krek 1998. Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway. EMBO 17:368–383.
  • Lukas, J., T. Herzinger, K. Hansen, M. C. Moroni, D. Resnitzky, I. Helin, S. I. Reed, and J. Bartek 1997. Cyclin E induced S phase without activation of the Rb/E2F pathway. Genes Dev. 11:1479–1492.
  • Lukas, J., D. Parry, L. Aargaard, D. J. Mann, J. Bartkova, M. Strauss, G. Peters, and J. Bartek 1995. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumor suppressor p16. Nature 375:503–506.
  • Lukas, J. B., J. Rohde, M. Strauss, and J. Bartek 1995. Cyclin D1 is dispensable for G1 control in retinoblastoma gene deficient cells independently of cdk4 activity. Mol. Cell. Biol. 15:2600–2611.
  • Lundberg, A., and J. Weinberg 1998. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol. Cell. Biol. 18:743–761.
  • Marsilio, E., S. H. Cheng, B. Schaffhausen, E. Paucha, and J. Livingston 1991. The T/t common region of simian virus 40 large T antigen contains a distinct transformation-governing sequence. J. Virol. 65:5647–5652.
  • Mitchison, T. J. 1989. Mitosis: basic concepts. Curr. Opin. Cell Biol. 1:67–74.
  • Mittnacht, S. 1998. Control of pRB phosphorylation. Curr. Opin. Genet. Dev. 8:21–27.
  • Moreno, S., and J. Nurse 1990. Substrates for p34cdc2: in vivo veritas. Cell 61:549–551.
  • Muller, H., J. Lukas, A. Schneider, P. Warthoe, J. Bartek, M. Eilers, and J. Strauss 1994. Cyclin D1 expression is regulated by the retinoblastoma protein. Proc. Natl. Acad. Sci. USA 91:2945–2949.
  • Nevins, J. R. 1992. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science 258:424–429.
  • Nigg, E. 1991. The substrates of the cdc2 kinase. Semin. Cell. Biol. 2:261–270.
  • Norbury, C., and J. Nurse 1992. Animal cell cycles and their control. Annu. Rev. Biochem. 61:441–470.
  • Ohtani, K., J. DeGregori, and J. Nevins 1995. Regulation of the cyclin E gene by transcription factor E2F1. Proc. Natl. Acad. Sci. USA 92:12146–12150.
  • Ohtsubo, M. T., A. M. Schumacher, J. Roberts, and J. Pagano 1995. Human cyclin E, a nuclear protein essential for the G1/S phase transition. Mol. Cell. Biol. 15:2612–2624.
  • Pan, W., T. Sun, R. Hoess, and J. Grafstrom 1998. Defining the minimal portion of the retinoblastoma protein that serves as an efficient substrate for cdk4 kinase/cyclin D1 complex. Carcinogenesis 19:765–769.
  • Peeper, D. S., P. Keblusek, K. Helin, M. Toebes, A. J. van der Eb, and J. Zantema 1995. Phosphorylation of a specific site in E2F1 affects its electrophoretic mobility and promotes pRB binding in vitro. Oncogene 10:39–48.
  • Peeper, D. S., L. L. Parker, M. E. Ewen, M. Toebes, F. L. Frederick, M. Xu, A. Zantema, A. J. van der Eb, and H. Piwnica-Worms. A- and B- type cyclins differentially modulate substrate specificity of cyclin-CDK complexes. EMBO J., in press.
  • Polyak, K., M. Lee, H. Erdjument-Bromage, A. Koff, J. Roberts, P. Tempst, and J. Massague 1994. Cloning of p27kip1, a cyclin dependent kinase inhibitor and a potential mediator of extracellular mitogenic signals. Cell 78:59–66.
  • Qin, X.-Q., T. Chittenden, D. M. Livingston, and J. Kaelin 1992. Identification of a growth suppression domain within the retinoblastoma gene product. Genes Dev. 6:953–964.
  • Russo, A. A., P. D. Jeffrey, A. K. Patten, J. Massague, and J. Pavletich 1996. Crystal structure of the p27kip1 cyclin dependent kinase inhibitor bound to the cyclin A-cdk2 complex. Nature 382:325–331.
  • Schulman, B., D. Lindstrom, and J. Harlow 1998. Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin A. Proc. Natl. Acad. Sci. USA 95:10453–10458.
  • Sellers, W. R., B. G. Novitch, S. Miyake, A. Heith, G. A. Otterson, F. J. Kaye, A. Lassar, and J. Kaelin 1998. 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.
  • Sherr, C. 1993. Mammalian G1 cyclins. Cell 73:1059–1065.
  • Songyang, Z., S. Blechner, N. Hoagland, M. F. Hoekstra, H. Piwnica-Worms, and J. Cantley 1994. Use of an orientated peptide library to determine the optimal substrates of protein kinases. Curr. Biol. 4:973–982.
  • Soucek, T., O. Pusch, E. Hengstschlager-Ottnad, P. D. Adams, and J. Hengstschlager 1997. Deregulated Expression of E2F1 induces cyclin A- and E-associated kinase activities independently from cell cycle position. Oncogene 14:2251–2257.
  • Srinivasan, J., M. Koszelak, M. Mendelow, Y.-G. Kwon, and J. Lawrence 1995. The design of peptide based substrates for the cdc2 protein kinase. Biochem. J. 309:927–931.
  • Taya, Y. Unpublished data.
  • Templeton, D. J., S. H. Park, L. Lanier, and J. Weinberg 1991. Nonfunctional mutants of the retinoblastoma protein are characterized by defects in phosphorylation, viral oncoprotein association, and nuclear tethering. Proc. Natl. Acad. Sci. USA 88:3033–3037.
  • Toyoshima, H., and J. Hunter 1994. p27, a novel inhibitor of G1 cyclin/cdk protein kinase activity is related to p21. Cell 78:67–74.
  • van den Heuvel, S., and J. Harlow 1993. Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262:2050–2053.
  • Weinberg, R. A. 1995. The retinoblastoma protein and cell cycle control. Cell 81:323–330.
  • Williams, R. T., D. A. Carbonaro-Hall, and J. Hall 1992. Co-purification of p34 cdc2/p58cyclin A proline-directed protein kinase and the retinoblastoma tumor susceptibility gene product: interaction of an oncogenic serine-threonine protein kinase with a tumor-suppressor protein. Oncogene 7:423–432.
  • Wilson, I. A., D. H. Haft, E. D. Getzoff, J. A. Tainer, R. A. Lerner, and J. Brenner 1985. Identical short peptide sequences in unrelated proteins can have different confirmations: a testing ground for theories of immune recognition. Proc. Natl. Acad. Sci. USA 82:5255–5259.
  • Xiong, Y., H. Zhang, and J. Beach 1993. Subunit rearrangement of the cyclin dependent kinases is associated with cellular transformation. Genes Dev. 7:1572–1583.
  • Xiong, Y., G. Hannon, H. Zhang, D. Casso, R. Kobayashi, and J. Beach 1993. p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704.
  • Xu, M., K. A. Sheppard, C.-Y. Peng, A. S. Yee, and J. Piwnica-Worms 1994. Cyclin A/cdk2 binds directly to E2F1 and inhibits the DNA-binding activity of E2F1/DP1 by phosphorylation. Mol. Cell. Biol. 14:8420–8431.
  • Zarkowska, T., and J. Mittnacht 1997. Differential phosphorylation of the retinoblastoma protein by G1/S cyclin-dependent kinases. J. Biol. Chem. 272:12738–12746.
  • Zhang, H., G. J. Hannon, and J. Beach 1994. p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 8:1750–1758.
  • Zhang, J., R. J. Sanchez, S. Wang, C. Guarnaccia, A. Tossi, S. Zahariev, and J. Pongor 1994. Substrate specificity of cdc2 kinase from human HeLa cells as determined with synthetic peptides and molecular modelling. Arch. Biochem. Biophys. 315:415–424.
  • Zhao, Y., C. Bjorbaek, and J. Moller 1996. Regulation and Interaction of pp90(rsk) isoforms with mitogen-activated protein kinases. J. Biol. Chem. 271:29773–29779.
  • Zhu, L., E. Harlow, and J. Dynlacht 1995. p107 uses a p21/CIP1-related domain to bind cyclin/cdk2 and regulate interactions with E2F. Genes Dev. 9:1740–1752.

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