The Cell Cycle

Mitosis is the visible manifestation of cell division, but other processes, not so easily observed with the light microscope, play a fundamental role in cell multiplication. Principal among these is the phase in which DNA replicates. This process can be analyzed by introducing labeled radioactive DNA precursors (eg, [³H]thymidine) into the cell and tracing them by means of biochemical and autoradiographic methods. DNA replication has been shown to occur during interphase, when no visible phenomena of cell division can be seen with the microscope. This alternation between mitosis and interphase, known as the cell cycle, occurs in all tissues with cell turnover. A careful study of the cell cycle reveals that it can be divided into two stages: mitosis, consisting of the four phases already described (prophase, metaphase, anaphase, and telophase), and interphase (Figures 3-20 and 3-21).

Figure 3-20

Phases of the cell cycle in bone tissue. The G₁ phase (presynthesis) varies in duration, which depends on many factors, including the rate of cell division in the tissue. In bone tissue, G₁ lasts 25 h. The S phase (DNA synthesis) lasts about 8 h. The G₂-plus-mitosis phase lasts 2.5-3 h. (The times indicated are courtesy of RW Young.)

Figure 3-21

The four phases of the cell cycle. In G₁ the cell either continues the cycle or enters a quiescent phase called G₀. From this phase, most cells can return to the cycle, but some stay in G₀ for a long time or even for their entire lifetime. The checking or restriction point (R) in G₁ stops the cycle under conditions unfavorable to the cell. When the cell passes this restriction point, it continues the cycle through the synthetic phase (S) and the G₂ phase, originating two daughter cells in mitosis (M) except when interrupted by another restriction point (not shown) in G₂.

Interphase is itself divided into three phases: G₁ (presynthesis), S (DNA synthesis), and G₂ (post-DNA duplication). The sequence of these phases and the approximate times involved are illustrated in Figures 3-20 and 3-21. The S phase is characterized by the synthesis of DNA and the beginning of the duplications of the centrosomes with their centrioles. During the G₁ phase, there is an intense synthesis of RNA and proteins, including proteins that control the cell cycle, and the cell volume, previously reduced to one-half by mitosis, is restored to its normal size. In cells that are not continuously dividing, the activities of the cell cycle may be temporarily or permanently suspended. Cells in such a state (eg, muscle, nerve) are referred to as being in the G₀ phase.

Regulation of the mammalian cell cycle is complex. It is known that cultured cells deprived of serum stop proliferating and arrest in G₀. The essential components provided by serum are highly specific proteins called growth factors, which are required only in very low concentrations.

Medical Application

Some growth factors are being used in medicine. One example is erythropoietin, which stimulates proliferation, differentiation, and survival of red blood cell precursors in the bone marrow.

The cell cycle is also regulated by a variety of signals that inhibit progression through the cycle. DNA damage arrests the cell cycle not only in G₂ but also at a checkpoint in G₁ (Figure 3-21). G₁ arrest may permit the damage to be repaired before the cell enters S phase, where the damaged DNA would be replicated. In mammalian cells, arrest at the G1 checkpoint is mediated by the action of a protein known as p53. The gene encoding p53 is often mutated in human cancers, thus reducing the cell's ability to repair damaged DNA. Inheritance of damaged DNA by daughter cells results in an increased frequency of mutations and general instability of the genome, which may contribute to the development of cancer.

Processes that occur during the G₂ phase include the accumulation of energy to be used during mitosis, the synthesis of tubulin to be assembled in mitotic microtubules, and the synthesis of chromosomal nonhistone proteins. In G₂ there is also a checkpoint at which the cell remains until all DNA synthesized with defects is corrected. In G₂ there is an accumulation of the protein complex maturation promoting factor (MPF) that induces the beginning of mitosis, the condensation of the chromosomes, the rupture of the nuclear envelope, and other events related to mitosis.

Medical Application

Rapidly growing tissues (eg, intestinal epithelium) frequently contain cells in mitosis, whereas slowly growing tissues do not. The increased number of mitotic figures and abnormal mitoses in tumors is an important characteristic that distinguishes malignant from benign tumors. The organism has elaborate regulatory systems that control cell reproduction by either stimulating or inhibiting mitosis. Normal cell proliferation and differentiation are controlled by a group of genes called protooncogenes; altering the structure or expression of these genes promotes the production of tumors. Altered protooncogenes are present in tumor-producing viruses and are probably derived from cells. Altered oncogene activity can be induced by a change in the DNA sequence (mutation), an increase in the number of genes (gene amplification), or gene rearrangement, in which genes are relocated near an active promoter site. Altered oncogenes have been associated with several tumors and hematological neoplasia. Proteins that stimulate mitotic activity in various cell types include nerve growth factor, epithelial growth factor, fibroblast growth factor, and precursors of erythrocyte growth factor (erythropoietin); there is an extensive and rapidly growing list of these proteins (see Chapter 13: Hematopoiesis).

Cell proliferation is usually regulated by precise mechanisms that can, when necessary, stimulate or retard mitosis according to the needs of the organism. Several factors (eg, chemical substances, certain types of radiation, viral infections) can induce DNA damage, mutation, and abnormal cell proliferation that bypass normal regulatory mechanisms for controlled growth and result in the formation of tumors.

The term tumor, initially used to denote any localized swelling in the body caused by inflammation or abnormal cell proliferation, is now usually used as a synonym for neoplasm (Gr. neos, new, + plasma, thing formed). Neoplasm can be defined as an abnormal mass of tissue formed by uncoordinated cell proliferation. Neoplasms are either benign or malignant according to their characteristics of slow growth and no invasiveness (benign) or rapid growth and great capacity to invade other tissues and organs (malignant). Cancer is the common term for all malignant tumors (Figures 3-22 and 3-23).

Figure 3-22

Section of a malignant epithelial skin tumor (squamous cell carcinoma). An increase in the number of cells in mitosis and diversity of nuclear morphology are signs of malignancy. PT stain. Medium magnification.

Figure 3-23

Section of a fast-growing malignant epithelial skin tumor showing an increased number of cells in mitosis and great diversity of nuclear morphology. H&E stain. Medium magnification.

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