Cell Cycle





Cell Cycle 3813
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The cell cycle is the ordered series of events required for the faithful duplication of one eukaryotic cells into two genetically identical daughter cells. In a cell cycle, precise replication of deoxyribonucleic acid (DNA) duplicates each chromosome . Subsequently, the duplicated chromosomes separate away from each other by mitosis , followed by division of the cytoplasm , called cytokinesis.

These monumental transformations in the chromosomes are accompanied by general cell growth, which provides enough material of all sorts (membranes, organelles , cytosol , nucleoplasm) required for the resultant doubling of cell number. This cycle continues indefinitely in specialized cells called stem cells, found in skin or bone marrow, causing constant replenishment of cells discarded by natural physiological processes.

Repetition of the cell cycle may produce a clone of identical cells, such as a colony of baker's yeast on a petri dish, or it may be accompanied by intricate changes that led to differentiation into distinctive cell types, or ultimately to the development of a complex organism. In all cases, the DNA sequence of each cell's genome remains unchanged, but the resultant cellular forms and functions may be quite varied.

Stages of the Cell Cycle

From the viewpoint of chromosomes, four distinct, ordered stages constitute a cell cycle. DNA synthesis (S) and mitosis (M) alternate with one another, separated by two "gap" phases (G 2 and G 1 ) of preparation and growth. Though a generic cell cycle possesses no definitive starting stage, the term "start" of the cell cycle has nonetheless been given to the initiation of chromosomal DNA replication or synthesis. During S phase, every chromosome replicates to yield two identical sister chromosomes (called chromatids ) that remain attached at their kinetochores. G 2 , a period of apparent chromosomal inactivity, follows S phase. In G 2 , cells prepare for the dynamic chromosomal movements of mitosis. In mitosis, the duplicated chromosomes separate into two equal groups through a series of highly coordinated events. First, condensed sister chromatids attach to the mitotic spindle at the center of the cell. The mitotic spindle, a fanlike array of microtubules, mediates the separation of all sister chromatid pairs as the chromatids, now called chromosomes, synchronously move to opposite poles of the cell.

Cytokinesis follows, in which the cytoplasm pinches apart and two new intact daughter cells are formed, each with the correct complement of chromosomes. G 1 , a phase of cellular growth and preparation for DNA synthesis, occurs next. Thus a cell cycle proceeds from S to G 2 to M to G 1 , and the two new cells' cycles continue to S and onward through the same series of stages. Cells that no longer undergo mitosis are said to be in G 0 . Such cells include most neurons and mature muscle cells.

Checkpoints

Both internal and external inputs trigger molecular events that regulate normal progress through the stages of the cell cycle. The precisely choreographed movements of chromosomes during mitosis provide one example

Transition between stages is triggered by cyclin-dependent kinases (CDK).
Transition between stages is triggered by cyclin-dependent kinases (CDK).
of this intrinsically faithful, careful regulation. The apparent simplicity of the particular alignment, division, and locomotion of chromosomes in each normal cell division belies the many levels of regulation that guarantee such precision. For example, without complete and proper DNA replication, the events of mitosis are not initiated. This control of cell-cycle order is maintained through an intracellular "checkpoint" that monitors the integrity and completion of DNA synthesis before authorizing the initiation of mitosis. This S-phase checkpoint responds to various forms of DNA damage, such as single-and double-strand breaks in the DNA backbone or incorporation of unusual nucleotides , and halts the progression of the cell cycle until effective repairs have occurred. The S-phase checkpoint also responds to stalled DNA replication forks, making the cell cycle pause until replication is completed. Ted Weinert and Lee Hartwell were the first to report experimental evidence of such a cell-cycle checkpoint in 1988. Since then, checkpoints have been discovered that regulate many aspects of cell-cycle progression in all organisms studied. Initiation of DNA synthesis, assembly and integrity of the mitotic spindle, and chromosome attachment to the mitotic spindle are all regulated by checkpoints. Mutations in checkpoint genes can lead to cancer, because of the resultant deregulation of cell division.

Regulation by CDK Proteins

Remarkably, the coordinated transitions between cell cycle stages depend on one family of evolutionarily conserved proteins , called cyclin-dependent kinases . Cyclin-dependent kinases (CDKs) act as oscillating driving forces to direct the progression of the cell cycle. Each CDK consists of two parts, an enzyme known as a kinase and a modifying protein called a cyclin. Kinases are regulatory enzymes that catalyze the addition of phosphate groups to protein substrates . Adding one or more phosphate groups to a substrate protein can change that substrate's ability to do its cellular job: One particular substrate may be inhibited by such a modification, while a different substrate may be activated by the same type of modification. Cyclins, so named because their activity cycles up and down during the cell cycle, restrict the action of their bound kinase to particular substrates. Together, the two integral parts of a CDK target specific cellular proteins for phosphorylation , thereby causing changes in cell-cycle progression.

Each CDK, consisting of a particular kinase bound by a particular cyclin, directs a critical transition in the cell cycle. For example, one CDK controls the initiation of DNA synthesis, while another CDK controls the onset of mitosis. Inactivation of the mitotic CDK is necessary for a subsequent cell-cycle transition, when cells exit mitosis and proceed to G 1 . CDKs are also the ultimate targets of most cell-cycle checkpoint activity. So that all cell-cycle events occur at the proper time during each cell cycle, CDK activity itself is tightly controlled by regulating the activity of every cyclin. Each cyclin is active only periodically during the cell cycle, with its peak of activity limited to the period during which it is needed. Regulated transcription of cyclin genes and regulated degradation of cyclin proteins provides this oversight.

Extrinsic Controls

In addition to intrinsic controls exerted by CDKs and checkpoints, many external controls affect cell division. Both normal and abnormal cell cycles can be triggered by such extrinsic controls. For example, the hormone estrogen affects the development of a wide variety of cell types in women. Estrogen exerts its effects on a receptive cell by binding to a specific receptor protein on the cell's nuclear membrane. By binding to an estrogen receptor, estrogen initiates a cascade of biochemical reactions that lead to changes in the cell-cycle program. Normally, estrogen moves cells out of a resting stage into an active cell cycle.

In a different context, however, even normal levels of estrogen encourage the growth of some forms of breast cancer. In these cases, estrogen increases the speed with which the cancerous cells complete their cell cycles, leading to more rapid growth of the tumor. The most effective current drug therapies for such breast cancers block the estrogen receptor's estrogenbinding ability, making cells unresponsive to estrogen's proliferation signal. Thus, while estrogen itself does not cause breast cancer, it plays an important role in stimulating the growth of some cancers once they initiate by other mechanisms, such as by an unregulated CDK or a defect in a cell-cycle checkpoint.

SEE ALSO Control Mechanisms ; Genetic Control of Development ; Hormones ; Oncogenes and Cancer Cells ; Signaling and Signal Transduction

Wendy E. Raymond

Bibliography

Hartwell, Leland H., et al. Genetics: From Genes to Genomes. New York: McGraw-Hill, 2000.

Hartwell, Leland H., and T. A. Weinert. "Checkpoints: Controls That Ensure the Order of Cell Cycle Events." Science 246 (1989): 629–634.

Murray, Andrew, and Tim Hunt. The Cell Cycle: An Introduction. New York: W. H. Freeman and Company, 1993.



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