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13.1Overview of the Cell Cycle

Fig. 13-1 The cell cycle is the process for cell growth

When cell division is observed under a microscope, a series of changes, ranging from chromosome condensation to chromosome alignment and segregation, take place within just 1 hour in human cells. Such dramatic changes, however, are not frequently repeated. More than 20 hours are necessary for the next dynamic change to occur. What kind of work and preparation do cells carry out during this period between cell divisions?

When cells multiply, the process in which the structural components of the cell, such as chromosomes, are doubled and segregated into two cells is repeated. This process is called the cell cycle (Figure 13-1). During the cell cycle, the phase in which cells divide is called the mitosis phase (M phase), whereas the phase in which DNA is replicated is called the synthesis phase (S phase). Between the M and S phases is the gap 1 phase (G1 phase), and between the S and M phases is the gap 2 phase (G2 phase) (Figure 13-2). Ass uming the G1 and G2 phases are the preparative phases for DNA synthesis and cell division, respectively, the cell cycle can be described as a repeated series of events in which cell division and replication alternate in the following order: M phase, G1 phase, S phase, and G2 phase (and back to the next M phase). Multicellular organisms including human beings have countless cells in the gap 0 phase (G0 phase), which are cells in their quiescent state (a state in which cells stop multiplying even though they have proliferating potency). The cell cycle for human cells to multiply takes about 1 day, during which the S phase lasts for 6–8 hours and the M phase, for approximately 1 hour.

The following paragraphs look closer at the features of each phase of the cell cycle.

Fig. 13-2 Phases of the cell cycle

A) The cell cycle can be divided into four phases: the S phase for DNA synthesis, the M phase for the division of the nucleus and cytoplasm, and two gap phases (G1 and G2) between the M and S phases. The G1 phase is between the M and S phases, and the G2 phase is between the S and M phases. Many cells stop the cell cycle in the G1 phase and enter a state of quiescence referred as G0 phase. The combined phases of G1, S, and G2 are called the interphase.

B) DNA doubling and chromosomal segregation during the cell cycle. DNA is not observed in the interphase but can be observed after condensation as chromosomes during mitosis.

C) Changes in the quantity of DNA per cell

D) DNA quantification of asynchronous cells by FACS*2

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13.1.1

M phase

When observing a proliferating cell under a microscope, the most dynamic changes can be observed during the M phase. This phase consists of 5 stages: prophase, prometaphase, metaphase, anaphase, and telophase. In the prophase stage, the chromosomes of a parent cell start condensing inside the nucleus, whereas outside the nucleus, the 2 centrosomes*1 —one at each end of the cell (see Chapter 11)—separate. In the prometaphase, the nuclear membrane starts breaking down, and the kinetochores of the chromosomes attach to spindle microtubules (see Chapter 18). During the metaphase, the chromosomes align along the equatorial plane, which is between the spindle poles. In the subsequent anaphase, the sister chromatids of each chromosome separate to form 2 sets of daughter chromosomes and move to the opposite spindle poles of the cell (Figure 13-3). Subsequently, in animal cells, the cell membrane begins to pinch into the cytoplasm forming a cleavage furrow and eventually splits into two daughter cells, whereas in plant cells, a cell wall is formed between the two daughter cells and separates them.

Figure 13-3 Stages of mitosis

A) Stages of M-phase

B) Fluorescence micrograph of spindle

*1 A type of organelle in animal cells from which microtubules grow. Plant cells do not have centrosomes, but have numerous polar centers dispersed inside cells instead.

*2 Device that measures cell suspensions flowing at a high speed, analyzes the fluorescence intensity of each cell, and separates cells based on fluorescence intensity. The fluorescence labeling of cells allows the measurement of fluorescence intensity and types, thereby identifying cells and analyzing the abundance ratio of different groups of cells. In addition, the fluorescence labeling of DNA also allows the analysis of the abundance of DNA inside cells.

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13.1.2

G1 phase

The G1 phase plays an important role in the regulation of cell proliferation, although no conspicuous changes are observed from the outside. It is during this phase that cells decide whether or not to divide. Mammalian cells detect signals from the extracellular environment, such as nutrients, just before they pass the restriction point (R point) and decide whether to progress through to the S-phase. During this G1 phase, cells not only decide whether to enter the G0 phase or not, but at the same time, they also determine whether to progress to meiosis, differentiation, senescence, or apoptosis based on external environment factors. For instance, budding yeast is one of the microorganisms for which studies on cell cycle are progressing. When different mating-type cells of the budding yeast come in contact with each other, they sense the other party’s mating pheromone, which acts to arrest cell division. If the mating pheromone is absent, the cell cycle arrest is not induced, allowing the yeast cells to proliferate. However, this is not the only condition required for cell proliferation. In order to initiate the cell cycle, pro-proliferative signals need to be delivered to these cells through the presence of nutrients, such as carbon and nitrogen.

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13.1.3

S phase

Figure 13-4 Cell fusion experiment demonstrating the existence of cell-cycle regulators

DNA replication, a process in which genetic information is precisely doubled (see Chapter 7 for details) occurs once in one cell cycle and only during the S phase. If DNA replication occurs randomly or more than once, daughter cells with different amounts of genetic information will be created every time a cell divides. To ensure that DNA replication occurs only once in a cell cycle, cells have a mechanism that differentiates replicated DNA from those before replication. Cell fusion experiments have demonstrated that the fusion of S-phase cells with G1-phase cells encourages the latter cells to start DNA replication. However, the fusion of S-phase cells with G2-phase cells does not initiate additional DNA replication (Figure 13-4), suggesting that G2-phase cells do not start DNA replication unless they undergo some kind of a change.

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The cell cycle repeatedly stops and starts

Column Figure 13-1 Cells of neonatal mouse cerebral cortex

At the cortical surface (top), neurons that have completed differentiation (red) are arranged in layers. Inside the cortex (bottom), cells are proliferating actively (white). As the nucleus of cells in the G1-phase is labeled in red and that of cells in the S/G2/M phase as white, the color of the nucleus is seen to be changing with the progression of the cell cycle.

The fertilized ovum of human beings, who are mammals, continues cell division (from fertilization to birth) inside the mother’s body for 9 months. Assuming that a baby has approximately 2–3 trillion cells, cell division must be carried out 41 times to produce this number of cells (241 = 2.2 × 1012). If the cell cycle for human cells to multiply is completed in approximately 1 day, and cell division is constantly repeated, the required number of cells will be created in 41 days. However, it actually takes as long as 9 months (265 days) until birth because the cell cycle occurs slowly by repeatedly starting and stopping as the fetus grows.

In Column Figure 13-1, the cerebral cortex of a neonatal mouse is shown with probes emitting fluorescence light in different colors to represent the phases of the cell cycle. Cells that have stopped dividing and differentiated are seen at the cortical surface, whereas those currently dividing are seen within the cortex.

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13.1.4

G2 phase

Cells in the G1, S, and G2 phases do not show conspicuous changes when observed under a microscope; hence, these are collectively called interphase. The G2 phase, following the S phase, is a phase where the preparation for cell division takes place. Specifically, it serves as a checkpoint to determine whether DNA replication has been completed, DNA damage has occurred, and whether it is safe to transition to the M phase.

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Cytokinesis

Cytokinesis is the process in which the cytoplasm is divided into two, following chromosome segregation during the M phase (Column Figure 13-2). The process is not only important for cell proliferation, but its appropriate execution is also important for the maintenance of genomic stability. Cytokinesis is a complex process consisting of numerous steps represented by ingenious interactions between the actin cytoskeleton on the cell surface, microtubules of the cytoplasm, and intracellular vesicular transport. In typical animal cells, the bundle structure of microtubules, called the central spindle, is formed first in the anaphase of cell division, while at the same time, the astral microtubules*2 extend from the spindle poles.
Soon, the position of the division plane is determined, in which a contractile ring composed of actin and myosin filaments is formed. The contraction of the ring causes constriction on the cell membrane to form a cleavage furrow. For the cleavage furrow ingression to continue, the presence of the central spindles is important. Once the furrow reaches the center of the cell, the cell surface comes into contact with the central spindle to form a structure called the mid-body, which plays an important role in the eventual separation of the cell into two daughter cells with independent cellular membranes. Intracellular vesicular transport is known to be actively involved in this process. During cytokinesis, regulation by Rho GTPase (see Chapter 14) is thought to play an important role along with phosphorylation by several mitotic kinases.

*2 Astral structure observed when microtubules have extended from the centrosome.

Column Figure 13-2 Steps of cytokinesis

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