Cell Cycle Control: Molecular Interaction Map

Kurt W Kohn, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
Mirit I Aladjem, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
Stefania Pasa, University of Genoa, Genoa, Italy
Silvio Parodi, University of Genoa and National Institute for Cancer Research, Genoa, Italy
Yves Pommier, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Published online: January 2006

DOI: 10.1038/npg.els.0005993

Complex network of molecular interactions that control the mammalian cell division cycle can be organized in the form of a map with associated annotations. The map utilizes a specifically designed notation and is in four parts, each with a different focus: control of E2F-dependent genes, control of and by c-Myc, checkpoint control responses to DNA damage and control of replication origins.

Keywords: molecular interaction maps; cell division cycle; cell cycle checkpoints; DNA damage response pathways; replication origins

Figure 1. Symbol definitions. For further details, see Kohn 1999, (2001).
Figure 2. Concise representation of alternative binding modes. The labeled nodes represent the following: a: cyclin E:Cdk2 heterodimer; b: Cdk2 bound to cyclin E or cyclin A; c: cyclin A:Cdk2 heterodimer; d: cyclin A bound to Cdk2 or Cdk1; e: cyclin A:Cdk1 heterodimer; f: Cdk1 bound to cyclin A or cyclin B; g: cyclin B:Cdk1 heterodimer. This convention greatly simplifies the representation of multiple related interactions in molecular interaction maps, such as those in Figures 4–7.
Figure 3. Contingencies and effects of pRb phosphorylations (an example). Protein modification arrows 1 and 2 represent two sets of phosphorylation sites, P(D) and P(E), induced by cyclin D:Cdk4 (3) and cyclin E:Cdk2 (4) respectively. The P(D) sites must be phosphorylated before P(E) phosphorylations can be added (5); reaction 5 points to a state-combination node representing the combination of P(D) and P(E) phosphorylations. The combination of P(D) and P(E) phosphorylations makes pRb unable to bind E2F1:DP1 (6).
Figure 4. Map A: Molecular interaction map of the control of S phase genes by E2F:DP and other transcription factors, showing controls by networks centered on cyclin:Cdk and pRb family proteins. The color coding is as follows: black represents binding interactions; blue represents protein modifications; green represents enzymatic or other stimulatory processes; red represents inhibitions or other negative effects; and purple represents transcription/translation processes.
Figure 5. Map B: An abbreviated map of the cell cycle control network centered on Myc. The color coding is as follows: black represents binding interactions; blue represents protein modifications; green represents enzymatic or other stimulatory processes; red represents inhibitions or other negative effects; and purple represents transcription/translation processes.
Figure 6. Map C: Molecular interaction map of cell cycle checkpoint controls responsive to deoxyribonucleic acid (DNA) damage. The color coding is as follows: black represents binding interactions; blue represents protein modifications; green represents enzymatic or other stimulatory processes; red represents inhibitions or other negative effects; and purple represents transcription/translation processes.
Figure 7. Map D: An abbreviated map of the control of initiation of deoxyribonucleic acid (DNA) replication at replication origins during S phase. The color coding is as follows: black represents binding interactions; blue represents protein modifications; green represents enzymatic or other stimulatory processes; red represents inhibitions or other negative effects; and purple represents transcription/translation processes. A more detailed version of this map is in preparation.
close
 References
    Bartek J, Falck J and Lukas J (2001) Chk2 kinase: a busy messenger. Nature Reviews Molecular Cell Biology 2: 877–886.
    Berns K, Martins C, Dannenberg JH, et al. (2000) p27KIP1-independent cell cycle regulation by MYC. Oncogene 19: 4822–4827.
    Chen CR, Kang Y, Siegel PM and Massague J (2002) E2F4/5 and p107 as Smad cofactors linking the TGF receptor to c-Myc repression. Cell 110: 19–32.
    Cheng SW, Davies KP, Yung E, et al. (1999) c-Myc interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function. Nature Genetics 22: 102–105.
    Dang CV (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Molecular and Cellular Biology 19: 1–11.
    Daniels DL, Spink KE and Weis WI (2001) -Catenin: molecular plasticity and drug design. Trends in Biochemical Sciences 26: 672–678.
    DeGregori J (2002) The genetics of the E2F family of transcription factors: shared functions and unique roles. Biochimica et Biophysica Acta 1602(2): 131–150.
    Del Sal G, Ruaro ME, Philipson L and Schneider C (1992) The growth arrest-specific gene, gas1, is involved in growth suppression. Cell 70: 595–607.
    Dyson N (1998) The regulation of E2F by pRB-family proteins. Genes and Development 12: 2245–2262.
    Eberhardy SR and Farnham PJ (2001) c-Myc mediates activation of the cad promoter via a post-RNA polymerase II recruitment mechanism. Journal of Biological Chemistry 276: 48562–48571.
    Foray N, Marot D, Randrianarison V, et al. (2002) Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. Molecular and Cellular Biology 22: 4020–4032.
    Galaktionov K, Chen X and Beach D (1996) Cdc25 cell-cycle phosphatase as a target of c-Myc. Nature 382: 511–517.
    Grandori C, Cowley SM, James LP and Eisenman RN (2000) The Myc/Max/Mad network and the transcriptional control of cell behavior. Annual Review of Cell and Developmental Biology 16: 653–699.
    Hall C, Nelson DM, Ye X, et al. (2001) HIRA, the human homologue of yeast Hir1p and Hir2p, is a novel cyclin-cdk2 substrate whose expression blocks S-phase progression. Molecular and Cellular Biology 21: 1854–1865.
    Henriksson M and Luscher B (1996) Proteins of the Myc network: essential regulators of cell growth and differentiation. Cancer Research 68: 109–182.
    Huelsken J and Behrens J (2002) The Wnt signalling pathway. Journal of Cell Science 275: 3977–3978.
    Jin S, Antinore MJ, Lung FD, et al. (2000) The GADD45 inhibition of Cdc2 kinase correlates with GADD45-mediated growth suppression. Journal of Biological Chemistry 275: 16602–16608.
    Kelly TJ and Brown GW (2000) Regulation of chromosome replication. Annual Review of Biochemistry 69: 829–880.
    Kitaura H, Shinshi M, Uchikoshi Y, et al. (2000) Reciprocal regulation via protein interaction between c-Myc and p21cip1/waf1/sdi1 in DNA replication and transcription. Journal of Biological Chemistry 275: 10477–10483.
    Kohn KW (1998) Functional capabilities of molecular network components controlling the mammalian G1–S cell cycle phase transition. Oncogene 16: 1065–1075.
    Kohn KW (1999) Molecular interaction map of the mammalian cell cycle control and DNA repair systems. Molecular Biology of the Cell 10: 2703–2734.
    Kohn KW (2001) Molecular interaction maps as information organizers and simulation guides. Chaos 1: 1–14.
    La Thangue NB (2002) Chromatin control: a place for E2F and Myc to meet. Science 296: 1034–1035.
    proceedings Lee TC, Li L, Philipson L and Ziff EB (1997) Myc represses transcription of the growth arrest gene gas1. Proceedings of the National Academy of Sciences of the United States of America 94: 12886–12891.
    Lee TC, Li L, Philipson L and Ziff EB (2001) Function and regulation of the transcription factors of the Myc/Max/Mad network. Gene 277: 1–14.
    Lei M and Tye BK (2001) Initiating DNA synthesis: from recruiting to activating the MCM complex. Journal of Cell Science 114: 1447–1454.
    Leone G, Sears R, Huang E, et al. (2001) Myc requires distinct E2F activities to induce S phase and apoptosis. Molecular Cell 8: 105–113.
    Li CJ and DePamphilis ML (2002) Mammalian Orc1 protein is selectively released from chromatin and ubiquitinated during the S-to-M transition in the cell division cycle. Molecular and Cellular Biology 22: 105–116.
    Lukas J, Herzinger T, Hansen K, et al. (1997) Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes and Development 11: 1479–1492.
    Luscher B (2001) Function and regulation of the transcription factors of the Myc/Max/Mad network. Gene 277: 1–14.
    Maiorano D, Moreau J and Mechali M (2000) XCDT1 is required for the assembly of prereplicative complexes in Xenopus laevis. Nature 404: 622–625.
    McMahon SB, Wood MA and Cole MD (2000) The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Molecular and Cellular Biology 20: 556–562.
    Mendez J, Zou-Yang XH, Kim SY, et al. (2002) Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication. Molecular Cell 9: 481–491.
    Nelson DM, Ye X, Hall C, et al. (2002) Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity. Molecular and Cellular Biology 22: 7459–7472.
    Nevins JR (1998) Toward an understanding of the functional complexity of the E2F and retinoblastoma families. Cell Growth and Differentiation 9: 585–593.
    O'Hagan RC, Ohh M, David G, et al. (2000) Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes and Development 14: 2185–2191.
    Ogawa H, Ishiguro K, Gaubatz S, Livingston DM and Nakatani Y (2002) A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296: 1132–1136.
    Öster SK, Ho CS, Soucie EL and Penn LZ (2002) The Myc oncogene: MarvelouslY complex. Advances in Cancer Research 84: 81–154.
    Okamoto K, Li H, Jensen MR, et al. (2002) Cyclin G recruits PP2A to dephosphorylate Mdm2. Molecular Cell 9: 761–771.
    Sears R, Nuckolls F, Haura E, et al. (2000) Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes and Development 14: 2501–2514.
    Sheaff RJ, Groundine M, Gordon M, Roberts JM and Clurman BE (1997) Cyclin E-CDK2 is a regulator of p27KIP1. Genes and Development 11: 1464–1478.
    Sherr CJ and Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes and Development 13: 1501–1512.
    Tada S, Li A, Maiorano D, Mechali M and Blow JJ (2001) Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by geminin. Nature Cell Biology 3: 107–113.
    proceedings Trimarchi JM, Fairchild B, Wen J and Lees JA (2001) The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex. Proceedings of the National Academy of Sciences of the United States of America 98: 1519–1524.
    Trimarchi JM and Lees JA (2002) Sibling rivalry in the E2F family. Nature Reviews Molecular Cell Biology 3: 11–20.
    Walter J and Newport J (2000) Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase . Molecular Cell 5: 617–627.
    Watanabe G, Albanese C, Lee RJ, et al. (1998) Inhibition of cyclin D1 kinase activity is associated with E2F-mediated inhibition of cyclin D1 promoter activity through E2F and Sp1. Molecular and Cellular Biology 18: 3212–3222.
    Watson JD, Öster SK, Shago M, Khosravi F and Penn LZ (2002) Identifying genes regulated in a Myc-dependent manner. Journal of Biological Chemistry 277: 36921–36930.

Related Sub-Topics:

Cell Cycle | Replication and Recombination | DNA Structure and Function | DNA Damage and Repair
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Cell Cycle Control: Molecular Interaction Map
 
How to Cite close
Kohn, Kurt W, Aladjem, Mirit I, Pasa, Stefania, Parodi, Silvio, and Pommier, Yves(Jan 2006) Cell Cycle Control: Molecular Interaction Map. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005993]