UNSW Embryology

Molecular Development- Signaling- Cell Cycle

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Other pages: Molecular Development | Notes- Week 1 Cell Division | Mitosis | Meiosis
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Introduction

The cell cycle is regulated by a complex series of cascading internal signals. In some cases the arrest of cell cycle or synchronous division of a population of cells will be a signal to alter that cell's fate. There are probably external signals derived from surrounding cells and endocrine (hormonal) signals that can also impact on this form of developmental signaling.

To see more detail on the 2 types of cell division see Week 1 Mitosis (in all cells) and Meiosis (in gametes).

These notes still under development.

References- Cell Cycle

  • Pumin Zhang The cell cycle and development: redundant roles of cell cycle regulators Current Opinion in Cell Biology 1999, 11:655-662.
    • excellent recent review on liver development. (source for references cited below)
  • Weinberg RA:
    The retinoblastoma protein and cell cycle control.
    Cell 1995, 81: 323&endash;330.
  • Harper JW, Elledge SJ:
    Cdk inhibitors in development and cancer.
    Curr Opin Genet Dev 1996, 6: 56&endash;64.
  • Geng Y, Eaton EN, Picon M, Roberts JM, Lundberg AS, Gifford A, Sardet C, Weinberg RA:
    Regulation of cyclin E transcription by E2Fs and retinoblastoma protein.
    Oncogene 1996, 12: 1173&endash;1180.
  • Botz J, Zerfass-Thome K, Spitkovsky D, Delius H, Vogt B, Eilers M, Hatzigeorgiou A, Jansen-Durr P:
    Cell cycle regulation of the murine cyclin E gene depends on an E2F binding site in the promoter.
    Mol Cell Biol 1996, 16: 3401&endash;3409.
  • Ohtani K, DeGregori J, Nevins JR:
    Regulation of the cyclin E gene by transcription factor E2F1.
    Proc Natl Acad Sci USA 1995, 92: 12146&endash;12150.
  • Dyson N:
    The regulation of E2F by pRb-family proteins.
    Genes Dev 1998, 12: 2245&endash;2262.
  • Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T:
    Retinoblastoma protein recruits histone deacetylase to repress transcription.
    Nature 1998, 391: 597&endash;601.
  • Luo RX, Postigo AA, Dean DC:
    Rb interacts with histone deacetylase to repress transcription.
    Cell 1998, 92: 463&endash;473.
  • Magnaghi-Jaulin L, Groisman R, Naguibneva I, Robin P, Lorain S, Le Villain JP, Troalen F, Trouche D, Harel-Bellan A:
    Retinoblastoma protein represses transcription by recruiting a histone deacetylase.
    Nature 1998, 391: 601&endash;605.
  • Grunstein M:
    Histone acetylation in chromatin structure and transcription.
    Nature 1997, 389: 349&endash;352.
  • Gu W, Schneider JW, Condorelli G, Kaushal S, Mahdavi V, Nadal-Ginard B:
    Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation.
    Cell 1993, 72: 309&endash;324.
  • Novitch BG, Mulligan GJ, Jacks T, Lassar AB:
    Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle.
    J Cell Biol 1996, 135: 441&endash;456.
  • Nead MA, Baglia LA, Antinore MJ, Ludlow JW, McCance DJ:
    Rb binds c-Jun and activates transcription.
    EMBO J 1998, 17: 2342&endash;2352.
  • Chen PL, Riley DJ, Chen Y, Lee WH:
    Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs.
    Genes Dev 1996, 10: 2794&endash;2804.
  • Sellers WR, Novitch BG, Miyake S, Heith A, Otterson GA, Kaye FJ, Lassar AB, Kaelin WG Jr:
    Stable binding to E2F is not required for the retinoblastoma protein to activate transcription, promote differentiation, and suppress tumor cell growth.
    Genes Dev 1998, 12: 95&endash;106.
  • Dunaief JL, Strober BE, Guha S, Khavari PA, Alin K, Luban J, Begemann M, Crabtree GR, Goff SP:
    The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest.
    Cell 1994, 79: 119&endash;130.
  • Strober BE, Dunaief JL, Guha , Goff SP:
    Functional interactions between the hBRM/hBRG1 transcriptional activators and the pRB family of proteins.
    Mol Cell Biol 1996, 16: 1576&endash;1583.
  • Singh P, Coe J, Hong W:
    A role for retinoblastoma protein in potentiating transcriptional activation by the glucocorticoid receptor.
    Nature 1995, 374: 562&endash;565.
  • Shao Z, Ruppert S, Robbins PD:
    The retinoblastoma-susceptibility gene product binds directly to the human TATA-binding protein-associated factor TAFII250.
    Proc Natl Acad Sci USA 1995, 92: 3115&endash;3119.
  • Ruppert S, Wang EH, Tjian R:
    Cloning and expression of human TAFII250: a TBP-associated factor implicated in cell-cycle regulation.
    Nature 1993, 362: 175&endash;179.
  • Mizzen CA, Yang XJ, Kokubo T, Brownell JE, Bannister AJ, Owen-Hughes T, Workman J, Wang L, Berger SL, Kouzarides T et al.:
    The TAF(II) 250 subunit of TFIID has histone acetyltransferase activity.
    Cell 1996, 87: 1261&endash;1270.
  • Cobrinik D, Lee M-H, Hannon G, Mulligan G, Bronson RT, Dyson N, Harlow E, Beach D, Weinberg RA, Jacks T:
    Shared role of the pRB-related p130 and p107 proteins in limb development.
    Genes Dev 1996, 10: 1633&endash;1644.
  • Lee M-H, Williams BO, Mulligan G, Mukai S, Bronson RT, Dyson N, Harlow E, Jacks T:
    Targeted disruption of p107: functional overlap between p107 and Rb.
    Genes Dev 1996, 10: 1621&endash;1632.
  • Clarke AR, Maandag ER, van Roon M, van der Lugt NM, van der Valk M, Hooper ML, Berns A, te Riele H:
    Requirement for a functional Rb-1 gene in murine development.
    Nature 1992, 359: 328&endash;330.
  • Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA:
    Effects of an Rb mutation in the mouse.
    Nature 1992, 359: 295&endash;300.
  • Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH, Bradley A:
    Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis.
    Nature 1992, 359: 288&endash;294.
  • Zacksenhaus E, Jiang Z, Chung D, Marth JD, Phillips RA, Gallie BL:
    pRb controls proliferation, differentiation, and death of skeletal muscle cells and other lineages during embryogenesis.
    Genes Dev 1996, 10: 3051&endash;3064.
  • Tsai KY, Hu Y, Macleod KF, Crowley D, Yamasaki L, Jacks T:
    Mutation of E2F-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos.
    Mol Cell 1998, 2: 293&endash;304.
  • Novitch BG, Spicer DB, Kim PS, Cheung WL, Lassar AB:
    pRb is required for MEF2-dependent gene expression as well as cell-cycle arrest during skeletal muscle differentiation.
    Curr Biol 1999, 9: 449&endash;459.
  • Molkentin JD, Black BL, Martin JF, Olson EN:
    Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins.
    Cell 1995, 83: 1125&endash;1136.
  • Parker SB, Eichele G, Zhang P, Rawls A, Sands AT, Bradley A, Olson EN, Harper JW, Elledge SJ:
    p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells.
    Science 1995, 267: 1024&endash;1027.
  • Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D, Lassar AB:
    Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD.
    Science 1995, 267: 1018&endash;1021.
  • Guo K, Wang J, Andres V, Smith RC, Walsh K:
    MyoD-induced expression of p21 inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation.
    Mol Cell Biol 1995, 15: 3823&endash;3829.
  • Deng C, Zhang P, Harper JW, Elledge SJ, Leder P:
    Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control.
    Cell 1995, 82: 675&endash;684.
  • Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ:
    Radiation-induced cell cycle arrest compromised by p21 deficiency.
    Nature 1995, 377: 552&endash;557.
  • Zhang P, Wong C, Liu D, Finegold M, Harper JW, Elledge SJ:
    p21CIP1 and p57KIP2 control muscle differentiation at the myogenin step.
    Genes Dev 1999, 13: 213&endash;224.
  • Matsuoka S, Edwards MC, Bai C, Parker S, Zhang P, Baldini A, Harper JW, Elledge SJ:
    p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene.
    Genes Dev 1995, 9: 650&endash;662.
  • Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, DePinho RA, Elledge SJ:
    Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith&endash;Wiedemann syndrome.
    Nature 1997, 387: 151&endash;158.
  • Yan Y, Frisen J, Lee MH, Massague J, Barbacid M:
    Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development.
    Genes Dev 1997, 11: 973&endash;983.
  • Venuti JM, Morris JH, Vivian JL, Olson EN, Klein WH:
    Myogenin is required for late but not early aspects of myogenesis during mouse development.
    J Cell Biol 1995, 128: 563&endash;576.
  • Schneider JW, Gu W, Zhu L, Mahdavi V, Nadal-Ginard B:
    Reversal of terminal differentiation mediated by p107 in Rb-/- muscle cells.
    Science 1994, 264: 1467&endash;1471.
  • Di Cunto F, Topley G, Calautti E, Hsiao J, Ong L, Seth PK, Dotto GP:
    Inhibitory function of p21Cip1/WAF1 in differentiation of primary mouse keratinocytes independent of cell cycle control.
    Science 1998, 280: 1069&endash;1072.
  • Zhang JM, Wei Q, Zhao X, Paterson BM:
    Coupling of the cell cycle and myogenesis through the cyclin D1- dependent interaction of MyoD with Cdk4.
    EMBO J 1999, 18: 926&endash;933.
  • Morgenbesser SD, Williams BO, Jacks T, DePinho RA:
    p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens.
    Nature 1994, 371: 72&endash;74.
  • Piatigorsky J:
    Lens differentiation in vertebrates. A review of cellular and molecular features.
    Differentiation 1981, 19: 134&endash;153.
  • McAvoy JW:
    Induction of the eye lens.
    Differentiation 1980, 17: 137&endash;149.
  • DeGregori J, Leone G, Miron A, Jakoi L, Nevins J:
    Distinct roles for E2F proteins in cell growth control and apoptosis.
    Proc Natl Acad Sci USA 94: 7245&endash;7250.
  • Quelle DE, Zindy F, Ashmun RA, Sherr CJ:
    Alternative reading frames of the INK4A tumour supressor gene encode two unrelated proteins capable of inducing cell cycle arrest.
    Cell 1995, 83: 993&endash;1000.
  • Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA:
    The Ink4a tumour suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53.
    Cell 1998, 92: 713&endash;723.
  • Zhang Y, Xiong Y, Yarbrough WG:
    ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumour suppression pathways.
    Cell 1992, 92: 725&endash;734.
  • Zhang P, Wong C, DePinho RA, Harper JW, Elledge SJ:
    Cooperation between the Cdk inhibitors p27KIP1 and p57KIP2 in the control of tissue growth and development.
    Genes Dev 1998, 12: 3162&endash;3167.
  • Fero ML, Rivkin M, Tasch M, Porter P, Carow CE, Firpo E, Polyak K, Tsai LH, Broudy V, Perlmutter RM et al.:
    A syndrome of multiorgan hyperplasia with features of gigantism, tumorigenesis, and female sterility in p27Kip1-deficient mice.
    Cell 1996, 85: 733&endash;744.
  • Kiyokawa H, Kineman RD, Manova-Todorova KO, Soares VC, Hoffman ES, Ono M, Khanam D, Hayday AC, Frohman LA, Koff A:
    Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27Kip1.
    Cell 1996, 85: 721&endash;732.
  • Nakayama K, Ishida N, Shirane M, Inomata A, Inoue T, Shishido N, Horii I, Loh DY:
    Mice lacking p27Kip1 display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors.
    Cell 1996, 85: 707&endash;720.
  • Franklin DS, Godfrey VL, Lee H, Kovalev GI, Schoonhoven R, Chen Kiang S, Su L, Xiong Y:
    CDK inhibitors p18INK4c and p27Kip1 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis.
    Genes Dev 1998, 12: 2899&endash;2911.
  • Sherr CJ:
    Cancer cell cycles.
    Science 1996, 274: 1672&endash;1677.
  • Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M:
    Human cyclin E, a nuclear protein essential for the G1-to-S phase transition.
    Mol Cell Biol 1995, 15: 2612&endash;2624.
  • Lacey KR, Jackson PK, Stearns T:
    Cyclin-dependent kinase control of centrosome duplication.
    Proc Natl Acad Sci USA 1999, 96: 2817&endash;2822.
  • Matsumoto Y, Hayashi K, Nishida E:
    Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells.
    Curr Biol 1999, 9: 429&endash;432.
  • Hinchcliffe EH, Li C, Thompson EA, Maller JL, Sluder G:
    Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts.
    Science 1999, 283: 851&endash;854.
  • Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, Haslam SZ, Bronson RT, Elledge SJ, Weinberg RA:
    Cyclin D1 provides a link between development and oncogenesis in the retina and breast.
    Cell 1995, 82: 621&endash;630.
  • Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li T, Weinberg RA, Sicinski P:
    Rescue of cyclin D1 deficiency by knockin cyclin E.
    Cell 1999, 97: 767&endash;777.
  • Draetta GF:
    Mammalian G1 cyclins.
    Curr Opin Cell Biol 1994, 6: 842&endash;846. Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M:
    Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia.
    Nat Genet 1999, 22: 44&endash;52.
    • Sicinski P, Donaher JL, Geng Y, Parker SB, Gardner H, Park MY, Robker RL, Richards JS, McGinnis LK, Biggers JD et al.:
      Cyclin D2 is an FSH-responsive gene involved in gonadal cell proliferation and oncogenesis.
      Nature 1996, 384: 470&endash;474.

Some signaling examples

  • cell cycle
    • metaphase 2 arrest of the egg,
    • rapid proliferation of the neural cell population in the 3 layer embryo.
    • neurons upon differentiation become post-mitotic and cease dividing.

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About Notes

  • Notes from the Embryology Program compiled and written by Dr Mark Hill. This updated section of notes is still being developed Mar2000 and is not yet complete.
  • Note that reference lists are only relevant to the date of the original search.

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Date Last Modified: 8/6/2000
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