the cell cycle, a series of sequential cellular events in preparation for cell division, is composed of inter- phase, when the cell becomes larger and duplicates its genetic material, and mitosis, a process that results in the formation of two identical daughter cells. the cell cycle is usually described as beginning at the end of cell division when the cell is entering interphase (Fig. 3.8).
• certain cells that are highly differentiated (e.g., muscle cells and neurons) cease to continue to go through mitosis and remain in a resting stage G0 (G zero) phase.
• other cells, such as peripheral lymphocytes, enter the G0 phase temporarily and at a later time they may again enter the cell cycle.
events such as mechanical forces, ischemia, or death of cells in a particular cell line may induce sig- naling cells to release growth factors that induce the expression of proto-oncogenes, which prompt the proliferative pathways of the cell. this process acti- vates the release of a cascade of cytoplasmic protein kinases triggering a series of nuclear transcription factors regulating the expression of proto-oncogenes that result in cell division. Many cancers are the result of mutations in the proto-oncogenes that permit the uncontrolled proliferation of the mutated cell.
A group of proteins known as cyclins, by complex- ing with specific cyclin-dependent kinases (CDKs), not only activate them, but also guide them to target proteins and, in that fashion, control the entry and advance of the cell through the cell cycle. there are three principal checkpoints where the control system can prevent the cell from entering or continuing the cell cycle. At each checkpoint, the cell may commit to finish the cell cycle, pause temporarily, or withdraw completely. these checkpoints are the:
• Start/restriction point in gap 1, which permits chromosome duplication and the entry into gap 2;
• G2/M checkpoint, which initiates the
condensation of chromosomes and other events necessary to permit the beginning of mitosis; and
• Metaphase/anaphase checkpoint, which permits the separation of sister chromatids, the comple- tion of the M phase, and the process of cytokinesis.
the four classes of cyclins and the cDKs with which they complex are as follows:
• G1 cyclins: cyclin D, early in the g1 phase, binds to cDK4 and to cDK6.
• G1/S cyclins: cyclin e is synthesized late in the g1 phase and binds to cDK2. these three complexes, along with other intermediaries, permit the cell to enter and progress through the s phase.
• S cyclins: cyclin A binds to cDK2 and cDK1 forming complexes that permit the cell to leave the s phase and enter the g2 phase and induce the formation of cyclin B.
• M cyclins: cyclin B binds to cDK1, and this complex allows the cell to leave the g2 phase and enter the M phase.
When the functions of the cyclins have been com- pleted, they are degraded to prevent their interfer- ence with the proper sequence of events.
INTERPHASE
interphase is subdivided into three phases: G1 (gap) phase, when the cell prepares to synthesize DnA; S (synthetic) phase, when DnA is replicated; and G2
phase, when the cell prepares for the mitotic event (see Fig. 3.8).
• G1 phase: At the conclusion of mitosis, the newly formed daughter cells enter the g1 phase of the cell cycle, a stage characterized by the synthesis of the regulatory proteins necessary for DnA replication, the restoration of the nucleoli and of the original cell volume of the daughter cell, and the initiation of centriole duplication.
• S phase: the s phase is the synthetic phase where the genome is duplicated. At this point, the cell’s normal complement of DnA has doubled from the normal (2n) to (4n) in preparation for the mitotic event.
• G2 phase: the interval between the end of DnA synthesis and the beginning of mitosis is known as the gap 2 phase; during this phase, the RnA, tubulin, and additional proteins required for cell division are synthesized. Additionally, adenosine triphosphate (AtP) reserves are increased, and the newly synthesized DnA is checked for possible errors and, if present, corrected.
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cLINIcAL coNSIDERATIoNS
Cancer chemotherapy has been enhanced by a more complete understanding of the cell cycle and mitosis. Certain drugs can be employed at specific times to arrest cell proliferation by disrupting certain stages of the cell cycle.
Vincristine disrupts the mitotic spindle
arresting the cell in mitosis. colchicine, a plant alkaloid, is used to produce the same effect and is used for individual chromosome studies and for karyotyping. Methotrexate, a drug that inhibits purine synthesis, and 5-fluorouracil, a drug that inhibits pyrimidine synthesis, act during the S phase of the cell cycle, preventing cell division, and are used in chemotherapy treatment.
Figure 3.8 the cell cycle in an actively dividing cell. nondividing cells such as neurons exit the cell cycle to enter the g0 phase (resting phase). other cells such as lymphocytes may return to the cell cycle. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 61.)
Mitosis
I II III IV V VI
G2
S
G1
G0
Division
Interphase
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36 MIToSIS
Mitosis is the component of the cell cycle that follows the g2 phase and results in the formation of two smaller but identical daughter cells from a single cell.
the first event in this process is called karyokinesis, the division of the nuclear material, and is followed by cytokinesis, cytoplasmic division. Although the process of mitosis is a continuous one, for conve- nience of the student it is divided into five stages:
prophase, prometaphase, metaphase, anaphase, and telophase (Fig. 3.9).
• the first phase of mitosis, prophase, is
characterized by condensing chromosomes, the disappearance of the nucleolus, the beginning of the disruption of the nucleus, and the division of the centrosome into two halves migrating away from each other toward the opposite poles of the cell. each half of the centrosome has a centriole and a microtubule organizing center (MOC). As the chromosomes, each composed of two sister chromatids held together at the centromere by cohesin (a chromatin binding protein), continue to condense, another Moc, the kinetochore, develops, and the formation of the mitotic spindle apparatus is initiated. this mitotic spindle apparatus is responsible for directing the sister chromatids in their migration to the opposing poles of the nucleus.
• During prometaphase, the nuclear envelope disappears secondary to the phosphorylation of the nuclear lamins. the chromosomes continue to condense and are randomly oriented within the cytoplasm. the mitotic spindle apparatus becomes defined by microtubules attached to the kinetochores, known as mitotic spindle microtubules, and polar microtubules that extend between the two centrosomes, known as polar microtubules. the former function in directing the chromosomes to their proper orientation, and the latter are believed to maintain the correct space between the two centrosomes.
• At metaphase, the maximally condensed chromosomes become aligned on the equatorial
plate (metaphase plate) of the mitotic spindle in such a fashion that each chromatid lies parallel to the cell’s equator.
• Anaphase begins when the cohesion proteins that attach the sister chromatids to each other at the centromere disappear, and the sister chromatids (chromosomes) start to be pulled apart. the chromosomes seem to play a passive role in the process of migration to the opposite poles of the cell. the depolymerization of the mitotic spindle microtubules in association with dynein is the responsible agent in the chromosome migration.
During the latter part of anaphase, a cleavage furrow develops indicating that the plasmalemma is beginning to anticipate cytokinesis.
• By telophase, the chromosomes have reached the opposite poles of the cell, and the nuclear envelope is reformed because of the
dephosphorylation of the nuclear lamins. the chromosomes begin to uncoil, and the nucleolar organizing regions of five pairs of chromosomes are unfolded.
• Although cytokinesis (the division of the cytoplasm into two halves, forming two daughter cells) began during anaphase, it is completed in telophase.
• As the cleavage furrow deepens in 360 degrees around the periphery of the cell, the cell resembles a dumbbell where the two spheres are very close to each other.
• eventually, only the midbody, the polar microtubules surrounded by a very thin rim of cytoplasm, connects the cytoplasm of the two daughter cells to each other.
• Within each daughter cell, a contractile ring, composed of actin and myosin, is responsible for the constriction process, which is
completed when the midbody’s microtubules are depolymerized.
• When the two daughter cells are completely separated from each other, the spindle apparatus also becomes depolymerized and cytokinesis is completed.
• the two diploid (2n) daughter cells are identical to each other.
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cLINIcAL coNSIDERATIoNS
Observations of a karyotype may indicate aneuploidy—an abnormal number of
chromosomes. An example of this condition is in Down syndrome, in which the individual has an extra chromosome 21 (trisomy 21). Individuals with this condition exhibit stubby hands, mental retardation, a malformed heart, and many other congenital malformations. Klinefelter syndrome is an example of aneuploidy of the sex
chromosomes. These individuals are males but possess an extra X chromosome (XXY). They exhibit the male phenotype, but do not develop secondary sex characteristics and are usually sterile. Individuals possessing less than the normal number of chromosomes exhibit monosomy.
Turner syndrome (XO) is an example. These individuals are mentally retarded females exhibiting undeveloped ovaries and breasts and a small uterus.
oncogenes are mutated forms of normal genes called proto-oncogenes, which code for proteins
that control cell division. Proto-oncogenes exhibit four regulatory mechanisms of cell growth, including growth factors, growth factor receptors, signal transduction molecules, and nuclear transcription factors. Oncogenes may result from a viral infection or random genetic accidents.
When present in a cell, oncogenes dominate genes over the normal proto-oncogene alleles, causing unregulated cell division and proliferation.
Examples of cancer cells arising from oncogenes include bladder cancer and acute myelogenous leukemia. Burkitt’s lymphoma develops from a proto-oncogene located on chromosome 8 that gets transformed onto chromosome 14, causing it to be detached from its normal regulatory element. Burkitt’s lymphoma is endemic in some parts of Africa, affecting children and young adults; it affects the maxilla and mandible.
Burkitt’s lymphoma responds to chemotherapy.
Figure 3.9 stages of mitosis in a cell containing a diploid number of six chromosomes. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 64.)
Interphase
Cytokinesis Telophase Anaphase
Prophase Prometaphase Metaphase
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38 MEIoSIS
Meiosis is a special type of cell division in which a single diploid (2n) cell produces four haploid (1n) germ cells. in females, one of the four haploid cells is known as an ovum, and the other three haploid cells are polar bodies that disintegrate. in males, the four haploid cells are spermatozoa. Meiosis—
divided into two separate events, meiosis i and meiosis ii—reduces the genetic complement of the germ cells, ensures genetic recombination by redis- tribution of genes, and introduces variability to the gene pool.