21.1 Overview of the Cell Cycle and Its Control

21.2 Biochemical Studies with Oocytes, Eggs, and Early Embryos

21.3 Genetic Studies with S. pombe

21.4 Molecular Mechanisms for Regulating Mitotic Events

21.5 Genetic Studies with S. cerevisiae

21.6 Cell-Cycle Control in Mammalian Cells

21.7 Checkpoints in Cell-Cycle Regulation

21.8 Meiosis: A Special Type of Cell Division

Overview of the Cell Cycle and Its Control

We begin our discussion by reviewing the stages of the eukaryotic cell cycle, presenting a summary of the current model of how the cycle is regulated, and briefly describing key experimental systems that have provided revealing information about cell-cycle regulation.

The Cell Cycle Is an Ordered Series of Events Leading to Cell Replication

As illustrated in Figure 21-1, the cell cycle is divided into four major phases. In cycling (replicating) somatic cells, cells synthesize RNAs and proteins during the G1 phase, preparing for DNA synthesis and chromosome replication during the S (synthesis) phase. After progressing through the G2 phase, cells begin the complicated process of mitosis, also called the M (mitotic) phase, which is divided into several stages (see Figure 20-29).

In discussing mitosis, we commonly use the term chromosome for the replicated structures that condense and become visible in the light microscope during the prophase period of mitosis. Thus each chromosome is composed of the two daughter DNA molecules resulting from DNA replication plus the histones and other chromosomal proteins associated with them (see Figure 10-27). The identical daughter DNA molecules and associated chromosomal proteins that form one chromosome are referred to as sister chro-matids. Sister chromatids are attached to each other by protein cross-links along their lengths. In vertebrates, these become confined to a single region of association called the centromere as chromosome condensation progresses.

During interphase, the portion of the cell cycle between the end of one M phase and the beginning of the next, the outer nuclear membrane is continuous with the endoplasmic reticulum (see Figure 5-19). With the onset of mitosis in prophase, the nuclear envelope retracts into the endoplasmic reticulum in most cells from higher eukaryotes, and Golgi membranes break down into vesicles. As described in Chapter 20, cellular microtubules disassemble and reassemble into the mitotic apparatus consisting of a football-shaped bundle of microtubules (the spindle) with a star-shaped cluster of microtubules radiating from each end, or spindle pole. During the metaphase period of mitosis, a multiprotein complex, the kinetochore, assembles at each centromere. The kinetochores of sister chromatids then associate with micro-tubules coming from opposite spindle poles (see Figure 20-31). During the anaphase period of mitosis, sister chro-matids separate. They initially are pulled by motor proteins along the spindle microtubules toward the opposite poles and then are further separated as the mitotic spindle elongates (see Figure 20-40).

Once chromosome separation is complete, the mitotic spindle disassembles and chromosomes decondense during telophase. The nuclear envelope re-forms around the segregated

▲ FIGURE 21-1 Summary of major events in the eukaryotic cell cycle and the fate of a single parental chromosome.

In proliferating cells, Gt is the period between "birth" of a cell following mitosis and the initiation of DNA synthesis, which marks the beginning of the S phase. At the end of the S phase, a replicated chromosome consists of two daughter DNA molecules and associated chromosomal proteins. Each of the individual daughter DNA molecules and their associated chromosomal proteins (not shown) is called a sister chromatid. The end of G2 is marked by the onset of mitosis, during which the mitotic spindle (red lines) forms and pulls apart sister chromatids, followed by division of the cytoplasm (cytokinesis) to yield two daughter cells. The Gt, S, and G2 phases are collectively referred to as interphase, the period between one mitosis and the next. Most nonproliferating cells in vertebrates leave the cell cycle in Gt, entering the G0 state.

chromosomes as they decondense. The physical division of the cytoplasm, called cytokinesis, then yields two daughter cells as the Golgi complex re-forms in each daughter cell. Following mitosis, cycling cells enter the G1 phase, embarking on another turn of the cycle. In yeasts and other fungi, the nuclear envelope does not break down during mitosis. In these organisms, the mitotic spindle forms within the nuclear envelope, which then pinches off, forming two nuclei at the time of cytokinesis.

In vertebrates and diploid yeasts, cells in G1 have a diploid number of chromosomes (2n), one inherited from each parent. In haploid yeasts, cells in G1 have one of each chromosome (1n), the haploid number. Rapidly replicating human cells progress through the full cell cycle in about 24 hours: mitosis takes «30 minutes; G1, 9 hours; the S phase, 10 hours; and G2, 4.5 hours. In contrast, the full cycle takes only «90 minutes in rapidly growing yeast cells.

In multicellular organisms, most differentiated cells "exit" the cell cycle and survive for days, weeks, or in some cases (e.g., nerve cells and cells of the eye lens) even the lifetime of the organism without dividing again. Such postmitotic cells generally exit the cell cycle in G1, entering a phase called G0 (see Figure 21-1). Some G0 cells can return to the cell cycle and resume replicating; this reentry is regulated, thereby providing control of cell proliferation.

Regulated Protein Phosphorylation and Degradation Control Passage Through the Cell Cycle

The concentrations of the cyclins, the regulatory subunits of the heterodimeric protein kinases that control cell-cycle events, increase and decrease as cells progress through the cell cycle. The catalytic subunits of these kinases, called cyclin-dependent kinases (CDKs), have no kinase activity unless they are associated with a cyclin. Each CDK can associate with different cyclins, and the associated cyclin determines which proteins are phosphorylated by a particular cyclin-CDK complex.

Figure 21-2 outlines the role of the three major classes of cyclin-CDK complexes that control passage through the cell cycle: the G1, S-phase, and mitotic cyclin-CDK complexes. When cells are stimulated to replicate, G1 cyclin-CDK complexes are expressed first. These prepare the cell for the S phase by activating transcription factors that promote

APC-Cdh1/proteasome degrades mitotic cyclins

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