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cell cycle

 
Dictionary: cell cycle
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n.
The series of events involving the growth, replication, and division of a eukaryotic cell.


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Sci-Tech Encyclopedia: Cell cycle
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The succession of events that culminates in the asexual reproduction of a cell; also known as cell division cycle. In a typical cell cycle, the parent cell doubles its volume, mass, and complement of chromosomes, then sorts its doubled contents to opposite sides of the cell, and finally divides in half to yield two genetically identical offspring. Implicit in the term “cycle” is the idea that division brings the double-sized parent cell back to its original size and chromosome number, and ready to begin another cell cycle. This idea fits well with the behavior of many unicellular organisms, but for multicellular organisms the daughter cells may differ from their parent cell and from each other in terms of size, shape, and differentiation state.

The time required for completion of a eukaryotic cell cycle varies enormously from cell to cell. Embryonic cells that do not need to grow between divisions can complete a cell cycle in as little as 8 min, whereas cycling times of 10–24 h are typical of the most rapidly dividing somatic cells. Many somatic cells divide much less frequently; liver cells divide about once a year, and mature neurons never divide. Such cells may be thought of as temporarily or permanently withdrawing from the cell cycle.

Eukaryotic phases

The cell cycle is divided into two main parts: interphase and mitosis (see illustration). During interphase, the cell grows and replicates its chromosomes. Interphase accounts for all but an hour or two of a 24-h cell cycle, and is subdivided into three phases: gap phase 1 (G1), synthesis (S), and gap phase 2 (G2). Interphase is followed by mitosis (nuclear division) and cytokinesis (cell division). This relatively brief part of the cell cycle includes some of the most dramatic events in cell biology.

Phases of the eukaryotic cell cycle.
Phases of the eukaryotic cell cycle.

G1 phase

Gap phase 1 begins at the completion of mitosis and cytokinesis and lasts until the beginning of S phase. This phase is generally the longest of the four cell cycle phases and is quite variable in length. During this phase, the cell chooses either to replicate its deoxyribonucleic acid (DNA) or to exit the cell cycle and enter a quiescent state (the G0 phase).

S phase

Replication of the chromosomes is restricted to one specific portion of interphase, called S phase (DNA synthesis phase), which typically lasts about 6 h. In mammalian cells, the start of S phase—the actual initiation of DNA synthesis—takes place several hours after the cell has committed to carrying out DNA synthesis. During S phase, each chromosome replicates exactly once to form a pair of physically linked sister chromatids. In animal cells, a pair of centrioles is also duplicated during S phase. See also Chromosome; Genetics.

G2 phase

The portion of interphase that follows S phase is called gap phase 2. Some cells can exit the cell cycle from G2 phase, just as they can from G1 phase.

M phase

M phase includes the overlapping processes of mitosis and cytokinesis. Mitosis is divided into five stages: prophase, prometaphase, metaphase, anaphase, and telophase. Cytokinesis usually begins during anaphase and ends at a point after the completion of mitosis. At the end of cytokinesis, the parent cell has formed its two G1 phase progeny and the cell is ready to repeat the cycle. See also Cytokinesis; Mitosis.

Control of cell cycle

The network of proteins that regulate DNA synthesis (G1/S), mitotic entry (G1/M), and mitotic exit (the transition from mitotic metaphase to anaphase and then out of mitosis) appears to be well conserved throughout eukaryotic evolution. At the heart of these cell cycle transtions is the periodic activation and inactivation of cyclin-dependent protein kinases. In addition, in multicellular eukaryotes, pathways regulating entry into and exit from the cell cycle entrain these central cyclin-dependent kinases to extrinsic signals.

Dental Dictionary: cell cycle
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n

The sequence of events that occur during the growth and division of tissue cells.

Genetics Encyclopedia: Cell Cycle
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The cell cycle is the process by which a cell grows, duplicates its DNA, and divides into identical daughter cells. Cell cycle duration varies according to cell type and organism. In mammals, cell division occurs over a period of approximately twenty-four hours.

In multicellular organisms, only a subset of cells go through the cycle continuously. Those cells include the stem cells of the hematopoietic system, the basal cells of the skin, and the cells in the bottom of the colon crypts. Other cells, such as those that make up the endocrine glands, as well as liver cells, certain renal (kidney) tubular cells, and cells that belong to connective tissue, exist in a nonreplicating state but can enter the cell cycle after receiving signals from external stimuli. Finally, postmitotic cells are incapable of cell division even after maximal stimulation, and include most neurons, striated muscle cells, and heart muscle cells.

The cell cycle is functionally divided into discrete phases. During the DNA synthesis (S) phase, the cell replicates its chromosomes. During the mitosis (M) phase, the duplicated chromosomes are segregated, migrating to opposite poles of the cell. The cell then divides into two daughter cells, each having the same genetic components as the parental cell. Mammalian cells undergo two gap, or growth, phases (G1 and G2). G1 occurs prior to the S phase, and G2 occurs before the M phase.

Control of the Cycle

During the G1 and G2 phases, cells grow and make sure that conditions are proper for DNA replication and cell division. During the G1 phase, cells monitor their environment and determine if conditions, including the availability of nutrients, growth factors and hormones, justify DNA replication. The decision to initiate replication is made at a specific "checkpoint" in G1 called the "restriction point."

The processes of DNA replication and mitosis, and intervening events during the cell cycle, occur in a highly ordered and specific manner. A complex network of proteins ensures that these events occur at the proper times. Intracellular and extracellular signals block cell-cycle progression at checkpoints if certain events have not yet been completed. After the restriction point, the cell is committed to replicating its genome and dividing, completing one round of the cell cycle. If, prior to the restriction point, cells sense inadequate growth conditions or receive inhibitory signals from other cells, they enter G0 (G-zero) phase, also called quiescence. In the G0 phase, they are maintained for prolonged periods in a nondividing state. If cells sense such conditions after the restriction point, they complete the current round of the cell cycle and exit to G0 during the subsequent G1 phase. The G2 phase is shorter than G1, but it, too, consists of important mechanisms that control the completion and fidelity of DNA replication and that prepare the cell for entry into mitosis. Whereas some conditions cause cells to enter the G0 phase, others trigger apoptosis. One such signal that may trigger apoptosis is if a cell's DNA has undergone significant damage.

After the restriction point, at the transition from the G2 to the M phase, another checkpoint occurs. Mitosis is prevented if DNA damage has occurred or if genomic replication is not complete. The final key checkpoint occurs at the end of mitosis, when the cycle stops if chromosomes are not properly attached to the mitotic spindle.

Proteins That Regulate the Cycle

The mammalian cell cycle control system is regulated by a group of protein kinases called cyclin-dependent kinases (CDKs). These proteins catalyze the attachment of phosphate groups to specific serine or threonine amino acids in a target protein. The phosphate groups alter the target protein's properties, such as its interaction with other proteins. (The alteration of protein activity by the attachment of phosphate groups occurs frequently in cells.)

CDKs are called "cyclin-dependent" because their activity requires their association with activating subunits called cyclins. While the number of CDKs in a cell remains constant during the cell cycle, the levels of cyclins oscillate. There are G1 cyclins, S-phase cyclins, and G2/M cyclins, each of which interact differently with CDK subunits to regulate the various phases of the cell cycle. CDKs can also associate with inhibitory subunits called CDK inhibitors (CKIs). In response to signals that work against proliferation, such as growth factor deprivation, DNA damage, cell-cell contact inhibition and lack of cell adhesion, CKIs cause the cell cycle to halt.

By the end of 2001, many structurally related cyclins (A1, A2, B1, B2, B3, B4, B5, C, D1, D2, D3, E1, E2, F, G1, G2, H, I, L, and T) and nine CDKs (CDK1 to CDK9) were identified in mammalian cells. Complexes of cyclin D and CDK4, as well as complexes of cyclin D and CDK6, operate during the G1 phase. Complexes of cyclin A and CDK2, as well as complexes of cyclin E and CDK2, act during the transition from the G1 to the S phase. Complexes of cyclin A and CDK1, as well as cyclin B and CDK1, function during the transition from the G2 to the M phase.

Active complexes of cyclins and CDKs exert their biological effects by phosphorylating proteins. During the G1 phase, a major target of cyclin/CDK complexes is the retinoblastoma protein (pRb). pRb is a growth-suppressing protein whose activity is controlled by whether or not it is phosphorylated.

When pRb is in the dephosphorylated form, during the G0 phase and early in the G1 phase, it is active. pRb exerts its growth-suppressing effects by binding to many cellular proteins, including the transcription factors of the E2F family (Figure 1). E2F transcription factors regulate the expression of numerous genes that are expressed during G1, or at the transition from the G1 to the S phase, to initiate DNA replication.

pRb that is bound to an E2F transcription factor inhibits the transcription factor's activity. Following phosphorylation by cyclin/CDK complexes, pRb dissociates from E2F, allowing the transcription factor to bind DNA sequences and activate the expression of genes necessary for the cell to enter the S phase. Cyclin D1/CDK4 complexes phosphorylation of pRb during the middle of the G1 phase. They allow for subsequent phosphorylation of pRb by additional cyclin/CDK complexes that act later in the cell cycle.

Two families of CKIs have been identified, based on their amino acid sequence similarity and the specificity of their interactions with CDKs. One of the families of CKIs, the INK family, includes four proteins (p15, p16 p18 and p20). These CKIs exclusively bind complexes of cyclin D and CDK4, as well as complexes of cyclin D and CDK6, to block cells that are in the G1 phase of the cell cycle. The other family of CKIs, the Cip/Kip family, consists of three proteins (p21, p27, and p57). These inhibitors bind to all complexes of cyclins and CDKs that function during the G1 phase and during the transition from the G1 to the S phase. They act preferentially, however, to block the activity of complexes containing CDK2.

Deregulation and Cancer

Deregulation of cell cycle control proteins plays a key role in the development of cancer. Overactivation of proteins that favor cell cycle progression, namely cyclins and CDKs, and the inactivation of proteins that impede cell cycle progression, such as CKIs, can result in uncontrolled cell proliferation.

In human tumors, it is genes encoding the proteins that control the transition from the G1 to the S phase that are most commonly altered. These genes include those for cyclins, CKIs, and pRb. Such mutations overcome the inhibitory effects of pRb on the cell cycle, causing cells to have a growth advantage. In some cancers, this occurs after the direct mutation of the pRb gene, resulting in the protein's loss of function. In a larger set of cancers, pRb is indirectly inactivated by the hyper-activation of CDKs. This may result from over expression of cyclins, from an activating mutation in CDK4, or from inactivation of CKIs.

There is much evidence to suggest that cyclins can act as oncogenes to induce cells to become cancerous. In particular the G1 cyclins, cyclin D1, and cyclin E have been implicated in the development of cancer. Over-expression of the cyclin D1 protein is frequently detected in human breast cancer, and increasing evidence suggests that cyclin E overexpression plays an important role in the pathogenesis of breast cancer.

CKIs antagonize the function of cyclins, and considerable evidence suggests that these proteins function as tumor suppressors. CKI function is often altered in cancer cells. The gene encoding p16, a protein that belongs to the INK family of CKIs, is mutated, deleted, or inactivated in a large number of human malignancies and tumors. Such alterations prevent the inhibition of cyclin D/CDK4 and cyclin D/CDK6 complexes during G1.

Decreased expression of p21 and p27, proteins that belong to the Cip/Kip family of CKIs, also has been demonstrated in numerous human tumors. In contrast to the genetic mutations observed with p16, the decrease in p27 levels in tumors is due to enhanced degradation of the p27 protein. One of the proteins required for the degradation of p27, Skp2, has oncogenic properties. Skp2 over expression is observed in several human cancers and likely contributes to the uncontrolled progression of the cell cycle by increasing the degradation of p27. Understanding of the fine details of cell cycle regulation is likely to lead to specific cancer therapies targeting one or more of these important proteins.

Bibliography

Goldberg, Alfred L., Stephen J. Elledge, and J. Wade Harper. "The Cellular Chamber of Doom." Scientific American 284, no. 1 (2001): 68-73.

Gutkind, J. Silvio, ed. Signaling Networks and Cell Cycle Control. Totowa, NJ: Humana Press, 2000.

Murray, Andrew, and Tim Hunt. The Cell Cycle: An Introduction. Oxford, U.K.: Oxford University Press, 1993.

Pagano, Michele, ed. Cell Cycle Control. New York: Springer-Verlag, 1998.

Weinberg, Robert A. "How Cancer Arises." Scientific American 275, no. 3 (1996): 62-70.

—Joanna Bloom and Michele Pagano

Wikipedia: Cell cycle
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For the separation of chromosomes that occurs as part of the cell cycle, see mitosis.
Each turn of the cell cycle divides the chromosomes in a cell nucleus.

The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication (replication). In cells without a nucleus (prokaryotes), the cell cycle occurs via a process termed binary fission. In cells with a nucleus (eukaryotes), the cell cycle can be divided in two brief periods: interphase—during which the cell grows, accumulating nutrients needed for mitosis and duplicating its DNA—and the mitosis (M) phase, during which the cell splits itself into two distinct cells, often called "daughter cells". The cell-division cycle is a vital process by which a single-celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and some internal organs are renewed.

Contents

Phases

The cell cycle consists of four distinct phases: G1 phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis). M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm divides forming distinct cells. Activation of each phase is dependent on the proper progression and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.

Schematic of the cell cycle. outer ring: I = Interphase, M = Mitosis; inner ring: M = Mitosis, G1 = Gap 1, G2 = Gap 2, S = Synthesis; not in ring: G0 = Gap 0/Resting. The duration of mitosis in relation to the other phases has been exaggerated in this diagram.
State Phase Abbreviation Description
quiescent/
senescent		 Gap 0 G0 A resting phase where the cell has left the cycle and has stopped dividing.
Interphase Gap 1 G1 Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis.
Synthesis S DNA replication occurs during this phase.
Gap 2 G2 During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.
Cell division Mitosis M Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.

After cell division, each of the daughter cells begin the interphase of a new cycle. Although the various stages of interphase are not usually morphologically distinguishable, each phase of the cell cycle has a distinct set of specialized biochemical processes that prepare the cell for initiation of cell division.

Resting (G0 phase)

The term "post-mitotic" is sometimes used to refer to both quiescent and senescent cells. Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated. Cellular senescence is a state that occurs in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis.

Interphase

G1 phase

The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis is called G1 (G indicating gap). It is also called the growth phase. During this phase the biosynthetic activities of the cell, which had been considerably slowed down during M phase, resume at a high rate. This phase is marked by synthesis of various enzymes that are required in S phase, mainly those needed for DNA replication. Duration of G1 is highly variable, even among different cells of the same species.[1]

S phase

The ensuing S phase starts when DNA synthesis commences; when it is complete, all of the chromosomes have been replicated, i.e., each chromosome has two (sister) chromatids. Thus, during this phase, the amount of DNA in the cell has effectively doubled, though the ploidy of the cell remains the same. Rates of RNA transcription and protein synthesis are very low during this phase. An exception to this is histone production, most of which occurs during the S phase.[2][3][4]

G2 phase

The cell then enters the G2 phase, which lasts until the cell enters mitosis. Again, significant protein synthesis occurs during this phase, mainly involving the production of microtubules, which are required during the process of mitosis. Inhibition of protein synthesis during G2 phase prevents the cell from undergoing mitosis.

Mitosis (M Phase)

Main article: Mitosis

The relatively brief M phase consists of nuclear division (karyokinesis) and cytoplasmic division (cytokinesis). In plants and algae, cytokinesis is accompanied by the formation of a new cell wall. The M phase has been broken down into several distinct phases, sequentially known as prophase, prometaphase, metaphase, anaphase and telophase leading to cytokinesis.

Mitosis is the process in which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two daughter nuclei.[5] It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two daughter cells containing roughly equal shares of these cellular components. Mitosis and cytokinesis together define the mitotic (M) phase of the cell cycle - the division of the mother cell into two daughter cells, genetically identical to each other and to their parent cell.

Mitosis occurs exclusively in eukaryotic cells, but occurs in different ways in different species. For example, animals undergo an "open" mitosis, where the nuclear envelope breaks down before the chromosomes separate, while fungi such as Aspergillus nidulans and Saccharomyces cerevisiae (yeast) undergo a "closed" mitosis, where chromosomes divide within an intact cell nucleus.[6] Prokaryotic cells, which lack a nucleus, divide by a process called binary fission.

The process of mitosis is complex and highly regulated. The sequence of events is divided into phases, corresponding to the completion of one set of activities and the start of the next. These stages are prophase, prometaphase, metaphase, anaphase and telophase. During the process of mitosis the pairs of chromosomes condense and attach to fibers that pull the sister chromatids to opposite sides of the cell. The cell then divides in cytokinesis, to produce two identical daughter cells.[7]

Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "mitotic phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei. This occurs most notably among the fungi and slime moulds, but is found in various different groups. Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development.[8] Errors in mitosis can either kill a cell through apoptosis or cause mutations that may lead to cancer.

Regulation of eukaryotic cell cycle

Regulation of cell cycle: Schematic

Regulation of the cell cycle involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control the cell cycle are ordered and directional; that is, each process occurs in a sequential fashion and it is impossible to "reverse" the cycle.

Role of cyclins and CDKs

Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), determine a cell's progress through the cell cycle.[9] Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules.[10] Many of the genes encoding cyclins and CDKs are conserved among all eukaryotes, but in general more complex organisms have more elaborate cell cycle control systems that incorporate more individual components. Many of the relevant genes were first identified by studying yeast, especially Saccharomyces cerevisiae;[11] genetic nomenclature in yeast dubs many these genes cdc (for "cell division cycle") followed by an identifying number, e.g., cdc25.

Cyclins form the regulatory subunits and CDKs the catalytic subunits of an activated heterodimer; cyclins have no catalytic activity and CDKs are inactive in the absence of a partner cyclin. When activated by a bound cyclin, CDKs perform a common biochemical reaction called phosphorylation that activates or inactivates target proteins to orchestrate coordinated entry into the next phase of the cell cycle. Different cyclin-CDK combinations determine the downstream proteins targeted. CDKs are constitutively expressed in cells whereas cyclins are synthesised at specific stages of the cell cycle, in response to various molecular signals.[12]

General mechanism of cyclin-CDK interaction

Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome.

Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins. The phosphorylation serves two purposes: to activate each already-assembled pre-replication complex, and to prevent new complexes from forming. This ensures that every portion of the cell's genome will be replicated once and only once. The reason for prevention of gaps in replication is fairly clear, because daughter cells that are missing all or part of crucial genes will die. However, for reasons related to gene copy number effects, possession of extra copies of certain genes would also prove deleterious to the daughter cells.

Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.

Interphase: Interphase generally lasts at least 12 to 24 hours in mammalian tissue. During this period, the cell is constantly synthesizing RNA, producing protein and growing in size. By studying molecular events in cells, scientists have determined that interphase can be divided into 4 steps: Gap 0 (G0), Gap 1 (G1), S (synthesis) phase, Gap 2 (G2).

Specific action of cyclin-CDK complexes

Cyclin D is the first cyclin produced in the cell cycle, in response to extracellular signals (eg. growth factors). Cyclin D binds to existing CDK4, forming the active cyclin D-CDK4 complex. Cyclin D-CDK4 complex in turn phosphorylates the retinoblastoma susceptibility protein (Rb). The hyperphosphorylated Rb dissociates from the E2F/DP1/Rb complex (which was bound to the E2F responsive genes, effectively "blocking" them from transcription), activating E2F. Activation of E2F results in transcription of various genes like cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. Cyclin E thus produced binds to CDK2, forming the cyclin E-CDK2 complex, which pushes the cell from G1 to S phase (G1/S transition). Cyclin B along with cdc2 (cdc2 - fission yeasts (CDK1 - mammalia)) forms the cyclin B-cdc2 complex, which initiates the G2/M transition.[13] Cyclin B-cdc2 complex activation causes breakdown of nuclear envelope and initiation of prophase, and subsequently, its deactivation causes the cell to exit mitosis.[12]

Inhibitors

Overview of signal transduction pathways involved in apoptosis, also known as "programmed cell death".

Two families of genes, the cip/kip family and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.

The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53 (which, in turn, is triggered by DNA damage eg. due to radiation). p27 is activated by Transforming Growth Factor β (TGF β), a growth inhibitor.

The INK4a/ARF family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14arf which prevents p53 degradation. And the amount of chromosomes are able to double at the same rate as in phase 2.

Checkpoints

Main article: Cell cycle checkpoint

Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell cycle.[14] Checkpoints prevent cell cycle progression at specific points, allowing verification of necessary phase processes and repair of DNA damage. The cell cannot proceed to the next phase until checkpoint requirements have been met.

Several checkpoints are designed to ensure that damaged or incomplete DNA is not passed on to daughter cells. Two main checkpoints exist: the G1/S checkpoint and the G2/M checkpoint. G1/S transition is a rate-limiting step in the cell cycle and is also known as restriction point.[12] An alternative model of the cell cycle response to DNA damage has also been proposed, known as the postreplication checkpoint.

p53 plays an important role in triggering the control mechanisms at both G1/S and G2/M checkpoints.

Role in tumor formation

A disregulation of the cell cycle components may lead to tumor formation. As mentioned above, some genes like the cell cycle inhibitors, RB, p53 etc., when they mutate, may cause the cell to multiply uncontrollably, forming a tumor. Although the duration of cell cycle in tumor cells is equal to or longer than that of normal cell cycle, the proportion of cells that are in active cell division (versus quiescent cells in G0 phase) in tumors is much higher than that in normal tissue. Thus there is a net increase in cell number as the number of cells that die by apoptosis or senescence remains the same.

The cells which are actively undergoing cell cycle are targeted in cancer therapy as the DNA is relatively exposed during cell division and hence susceptible to damage by drugs or radiation. This fact is made use of in cancer treatment; by a process known as debulking, a significant mass of the tumor is removed which pushes a significant number of the remaining tumor cells from G0 to G1 phase (due to increased availability of nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the debulking procedure kills these cells which have newly entered the cell cycle. [12]

The cell cycle for mammalian cells can be divided into four phases: mitosis (M), followed by G1, followed by the DNA synthetic phase (S), then G2, and into mitosis again.

The fastest cycling mammalian cells in culture, and crypt cells in the intestinal epithelium, have a cycle time as short as 9 to 10 hours. Stem cells in resting mouse skin may have a cycle time of more than 200 hours. Most of this difference is due to the varying length of G1, the most variable phase of the cycle. M and S do not vary much.

In general, cells are most radiosensitive in late M and G2 phases and most resistant in late S.

For cells with a longer cell cycle time and a significantly long G1 phase, there is a second peak of resistance late in G1

The pattern of resistance and sensitivity correlates with the level of sulfhydryl compounds in the cell. Sulfhydryls are natural radioprotectors and tend to be at their highest levels in S and at their lowest near mitosis.

Synchronization of cell cultures

Several methods can be used to synchronise cell cultures by halting the cell cycle at a particular phase. For example, serum starvation[15] and treatment with thymidine or aphidicolin[16] halt the cell in the G1 phase, mitotic shake-off, treatment with colchicine[17] and treatment with nocodazole[18] halt the cell in M phase and treatment with 5-fluorodeoxyuridine halts the cell in S phase.

See also

References

  1. ^ Smith JA, Martin L (April 1973). "Do cells cycle?". Proc. Natl. Acad. Sci. U.S.A. 70 (4): 1263–7. PMID 4515625. 
  2. ^ Wu RS, Bonner WM (December 1981). "Separation of basal histone synthesis from S-phase histone synthesis in dividing cells". Cell 27 (2 Pt 1): 321–30. doi:10.1016/0092-8674(81)90415-3. PMID 7199388. 
  3. ^ Nelson DM, Ye X, Hall C, Santos H, Ma T, Kao GD, Yen TJ, Harper JW, Adams PD (November 2002). "Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity". Mol. Cell. Biol. 22 (21): 7459–72. PMID 12370293. 
  4. ^ Cameron IL, Greulich RC (July 1963). "Evidence for an essentially constant duration of DNA synthesis in renewing epithelia of the adult mouse". J. Cell Biol. 18: 31–40. PMID 14018040. 
  5. ^ Rubenstein, Irwin, and Susan M. Wick. "Cell." World Book Online Reference Center. 2008. 12 January 2008 <http://www.worldbookonline.com/wb/Article?id=ar102240>
  6. ^ De Souza CP, Osmani SA (2007). "Mitosis, not just open or closed". Eukaryotic Cell 6 (9): 1521–7. doi:10.1128/EC.00178-07. PMID 17660363. 
  7. ^ Maton, Anthea; Hopkins, Jean Johnson, Susan LaHart, David, Quon Warner, David, Wright, Jill D (1997). Cells: Building Blocks of Life. New Jersey: Prentice Hall. pp. 70–4. ISBN 0-13423476-6. 
  8. ^ Lilly M, Duronio R (2005). "New insights into cell cycle control from the Drosophila endocycle". Oncogene 24 (17): 2765–75. doi:10.1038/sj.onc.1208610. PMID 15838513. 
  9. ^ Nigg EA (June 1995). "Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle". Bioessays 17 (6): 471–80. doi:10.1002/bies.950170603. PMID 7575488. 
  10. ^ "Press release". Nobelprize.org. http://nobelprize.org/nobel_prizes/medicine/laureates/2001/press.html. 
  11. ^ Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB, Brown PO, Botstein D, Futcher B (December 1998). "Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization". Mol. Biol. Cell 9 (12): 3273–97. PMID 9843569. 
  12. ^ a b c d Robbins and Cotran; Kumar, Abbas, Fausto (2004). Pathological Basis of Disease. Elsevier. ISBN 81-8147-528-3. 
  13. ^ Norbury C (1995). "Cdc2 protein kinase (vertebrates)". in Hardie, D. Grahame; Hanks, Steven. Protein kinase factsBook. Boston: Academic Press. pp. 184. ISBN 0-12-324719-5. 
  14. ^ Stephen J. Elledge (6 December 1996). "Cell Cycle Checkpoints: Preventing an Identity Crisis". Science 274 (5293): 1664-1672. doi:10.1126/science.274.5293.1664. PMID 8939848. http://www.sciencemag.org/cgi/content/abstract/274/5293/1664. 
  15. ^ Kues WA, Anger M, Carnwath JW, Paul D, Motlik J, Niemann H (February 2000). "Cell cycle synchronization of porcine fetal fibroblasts: effects of serum deprivation and reversible cell cycle inhibitors". Biol. Reprod. 62 (2): 412–9. doi:10.1095/biolreprod62.2.412. PMID 10642581. 
  16. ^ Pedrali-Noy G, Spadari S, Miller-Faurès A, Miller AO, Kruppa J, Koch G (January 1980). "Synchronization of HeLa cell cultures by inhibition of DNA polymerase alpha with aphidicolin". Nucleic Acids Res. 8 (2): 377–87. doi:10.1093/nar/8.2.377. PMID 6775308. 
  17. ^ Prather RS, Boquest AC, Day BN (1999). "Cell cycle analysis of cultured porcine mammary cells". Cloning 1 (1): 17–24. doi:10.1089/15204559950020067. PMID 16218827. 
  18. ^ Samaké S, Smith LC (October 1997). "Synchronization of cell division in eight-cell bovine embryos produced in vitro: effects of aphidicolin". Theriogenology 48 (6): 969–76. doi:10.1016/S0093-691X(97)00323-3. PMID 16728186. 

Further reading

  • Morgan DO (2007). The Cell Cycle: Principles of Control. London: Published by New Science Press in association with Oxford University Press. ISBN 0-87893-508-8. 
  • Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2008). "Chapter 17". Molecular Biology of the Cell (5th ed.). New York: Garland Science. ISBN 978-0-8153-4111-6. 
  • Krieger M, Scott MP; Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C; Berk A (2004). Molecular cell biology. New York: W.H. Freeman and CO. ISBN 0-7167-4366-3. 
  • Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R (2004). "Chapter 7". Molecular biology of the gene (5th ed.). San Francisco: Pearson/Benjamin Cummings. ISBN 0-8053-4642-2. 

External links

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