Chapter 17 The Cell Cycle
The Eukaryotic Cell Cycle
Phases of the cell cycle: Eukaryotic cell cycles are divided into four discrete phases: M, G1, S, and G2. M phase consists of mitosis, which is usually followed by cytokinesis. S phase is the period of DNA replication.
See Animations 17.1, 17.2, and Video 17.1.
Regulation of the cell cycle by cell growth and extracellular signals: Extracellular signals and cell size regulate progression through specific control points in the cell cycle.
See Video 17.2.
Cell cycle checkpoints: Checkpoints and feedback controls coordinate the events that take place during different phases of the cell cycle and arrest cell cycle progression if DNA is damaged.
See Animation 17.3.
Regulators of Cell Cycle Progression
Protein kinases and cell cycle regulation: MPF is the key molecule responsible for regulating the G2 to M transition in all eukaryotes. MPF is a dimer of the Cdk1 protein kinase and cyclin B.
See Animation 17.4.
Families of cyclins and cyclin-dependent kinases: Distinct pairs of cyclins and Cdk1-related protein kinases regulate progression through different stages of the cell cycle. The activity of Cdk’s is regulated by association with cyclins, activating and inhibitory phosphorylations, and the binding of Cdk inhibitors.
Growth factors and the regulation of G1 Cdk’s: Growth factors stimulate animal cell proliferation by inducing synthesis of the D-type cyclins. Cdk4, 6/cyclin D complexes then act to drive cells through the restriction point in G1. A key substrate of Cdk4, 6/cyclin D complexes is the tumor suppressor protein Rb, which regulates transcription of genes required for cell cycle progression, including cyclin E. Activation of Cdk2/cyclin E complexes is then responsible for entry into S phase.
S phase and regulation of DNA replication: Cdk2/cyclin E, together with the DDK protein kinase, initiates DNA replication by activating the MCM helicase at origins of replication. Once MCM has been activated, reinitiation of replication is prevented by high Cdk activity until the cell has passed through mitosis.
DNA damage checkpoints: DNA damage or incompletely replicated DNA arrest cell cycle progression in G1, S, and G2. Cell cycle arrest is mediated by protein kinases that are activated by DNA damage and inhibit Cdc25 phosphatases, which are required for Cdk activation. In mammalian cells, arrest at the G1 checkpoint is also mediated by p53, which induces synthesis of the Cdk inhibitor p21.
The Events of M Phase
Stages of mitosis: Mitosis is conventionally divided into four stages: prophase, metaphase, anaphase, and telophase. The basic events of mitosis include chromosome condensation, formation of the mitotic spindle, nuclear envelope breakdown, and attachment of spindle microtubules to chromosomes at the kinetochore. Sister chromatids then separate and move to opposite poles of the spindle. Finally, nuclei re-form, the chromosomes decondense, and cytokinesis divides the cell in half.
See Animation 17.5, and Videos 17.3,17.4.
Entry into mitosis: M phase is initiated by activation of Cdk1/cyclin B, Aurora, and Polo-like kinases, which are responsible for chromatin condensation, nuclear envelope breakdown, fragmentation of the Golgi apparatus, and reorganization of microtubules to form the mitotic spindle. The attachment of spindle microtubules to the kinetochores of sister chromatids then leads to their alignment on the metaphase plate.
The spindle assembly checkpoint and progression to anaphase: Activation of the APC/C ubiquitin ligase leads to degradation of key regulatory proteins at the metaphase to anaphase transition. The activity of APC/C is inhibited until the cell passes the spindle assembly checkpoint and all chromosomes are properly aligned on the spindle. Ubiquitin-mediated proteolysis initiated by the APC/C then leads to the degradation of cohesin, breaking the link between sister chromatids at the onset of anaphase. The APC/C also ubiquitylates cyclin B, leading to inactivation of Cdk1 and exit from mitosis.
See Videos 17.5 and 17.6.
Cytokinesis: Inactivation of Cdk1/cyclin B also triggers cytokinesis. In yeast and animal cells, cytokinesis results from contraction of a ring of actin and myosin filaments. In higher plant cells, cytokinesis results from the formation of a new cell wall and plasma membrane inside the cell.
See Animation 17.6.
Meiosis and Fertilization
The process of meiosis: Meiosis is a specialized cell cycle that gives rise to haploid daughter cells. A single round of DNA synthesis is followed by two sequential cell divisions. During meiosis I, homologous chromosomes first form pairs and then segregate to different daughter cells. Meiosis II then resembles a normal mitosis in which sister chromatids separate.
See Animations 17.7, 17.8, and 17.9.
Regulation of oocyte meiosis: Meiosis of vertebrate oocytes is regulated at two unique points in the cell cycle: the diplotene stage of meiosis I and metaphase of meiosis II. Metaphase II arrest results from inhibition of the APC/C by a protein kinase expressed in oocytes.
See Animation 17.10.
Fertilization: Fertilization triggers the resumption of oocyte meiosis by Ca2+-dependent activation of the APC/C. The fertilized egg then contains two haploid nuclei, which form a new diploid genome and initiate embryonic cell divisions.