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Cell cycle

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Cell cycle

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 DNAand 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

    [hide]

    ; 1 Phases

    o 1.1 Resting (G phase) 0

    o 1.2 Interphase

    ; 1.2.1 G phase 1

    ; 1.2.2 S phase

    ; 1.2.3 G phase 2

    o 1.3 Mitosis (M Phase)

    ; 2 Regulation of eukaryotic cell cycle

    o 2.1 Role of cyclins and CDKs

    ; 2.1.1 General mechanism of cyclin-CDK interaction

    ; 2.1.2 Specific action of cyclin-CDK complexes

    o 2.2 Inhibitors

    ; 3 Checkpoints

    ; 4 Role in tumor formation

    ; 5 Synchronization of cell cultures

    ; 6 See also

    ; 7 References

    ; 8 Further reading

    ; 9 External links

    [edit] Phases

    The cell cycle consists of four distinct phases: G phase, S phase (synthesis), G phase 12

    (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 in

    half 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 G phase. 0

Schematic of the cell cycle. outer ring: I = Interphase, M = Mitosis; inner ring: M =

    Mitosis, G = Gap 1, G = Gap 2, S = Synthesis; not in ring: G = Gap 0/Resting. The 120

    duration of mitosis in relation to the other phases has been exaggerated in this diagram.

    State Phase Abbreviation Description

    quiescent/ A resting phase where the cell has left the cycle and Gap 0 G 0senescent has stopped dividing.

    Cells increase in size in Gap 1. The G checkpoint 1

    Interphase Gap 1 control mechanism ensures that everything is ready G 1

    for DNA synthesis.

    Synthesis DNA replication occurs during this phase. S

    During the gap between DNA synthesis and mitosis,

     checkpoint the cell will continue to grow. The G2Gap 2 G 2control mechanism ensures that everything is ready

    to enter the M (mitosis) phase and divide.

    Cell growth stops at this stage and cellular energy is

    focused on the orderly division into two daughter Cell Mitosis cells. A checkpoint in the middle of mitosis M division (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.

    [edit] Resting (G phase) 0

    The term "post-mitotic" is sometimes used to refer to both quiescent and senescent cells.

    Nonproliferative cells in multicellular eukaryotes generally enter the quiescent G state 0

    from G and may remain quiescent for long periods of time, possibly indefinitely (as is 1

    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.

    [edit] Interphase

    [edit] G phase 1

    The first phase within interphase, from the end of the previous M phase until the beginning of DNA synthesis is called G (G indicating gap). It is also called the growth 1

    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 G is highly variable, even among different cells of the 1[1]same species.

    [edit] 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 [2][3][4] production, most of which occurs during the S phase.

    [edit] G phase 2

    The cell then enters the G phase, which lasts until the cell enters mitosis. Again, 2

    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 G phase prevents the cell from undergoing mitosis. 2

    [edit] 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 [5]nucleus into two identical sets in two daughter nuclei. 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 [6]divide within an intact cell nucleus. 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, [7] to produce two identical daughter cells.

    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 [8]stages of fruit fly embryonic development. Errors in mitosis can either kill a cell

    through apoptosis or cause mutations that may lead to cancer.

    [edit] 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. [edit] Role of cyclins and CDKs

Two key classes of regulatory molecules, cyclins and cyclin-dependent kinases (CDKs), [9]determine a cell's progress through the cell cycle. Leland H. Hartwell, R. Timothy Hunt,

    and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their [10]discovery of these central molecules. 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 [11]cerevisiae; genetic nomenclature in yeast dubs many these genes cdc (for "cell

    division cycle") followed by an identifying number, e.g., cdc25 or cdc20.

    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 [12]response to various molecular signals.

    [edit] General mechanism of cyclin-CDK interaction

    Upon receiving a pro-mitotic extracellular signal, G cyclin-CDK complexes become 1

    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 G cyclin-CDK complexes also promote the degradation of molecules 1

    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 G phase on DNA replication origins. The phosphorylation 1

    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 G 2

    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

    ), Gap 1 (G), S (synthesis) phase, Gap 2 (G). be divided into 4 steps: Gap 0 (G012

    [edit] 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 G to S phase (G/S transition). Cyclin B along with cdc2 (cdc2 - 11

    fission yeasts (CDK1 - mammalia)) forms the cyclin B-cdc2 complex, which initiates the [13]G/M transition. Cyclin B-cdc2 complex activation causes breakdown of nuclear 2

    envelope and initiation of prophase, and subsequently, its deactivation causes the cell to [12]exit mitosis.

    [edit] 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 G phase, 1

    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

     phase, and p14arf which prevents p53 degradation. And the amount of cycle in G1

    chromosomes are able to double at the same rate as in phase 2.

    [edit] Checkpoints

    Main article: Cell cycle checkpoint

    Cell cycle checkpoints are used by the cell to monitor and regulate the progress of the cell [14]cycle. 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 G/S checkpoint and the 1

    G/M checkpoint. G/S transition is a rate-limiting step in the cell cycle and is also known 21[12]as restriction point. 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 G/S and G/M 12

    checkpoints.

    [edit] 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 G phase) in tumors is much 0

    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 G to G phase (due to increased availability of 01

    nutrients, oxygen, growth factors etc.). Radiation or chemotherapy following the [12]debulking procedure kills these cells which have newly entered the cell cycle.

    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 , the most variable phase of the cycle. M and S do not vary much. G1

    In general, cells are most radiosensitive in late M and G phases and most resistant in late 2

    S.

    For cells with a longer cell cycle time and a significantly long G phase, there is a second 1

    peak of resistance late in G 1

    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.

    [edit] Synchronization of cell cultures

    Several methods can be used to synchronise cell cultures by halting the cell cycle at a [15]particular phase. For example, serum starvation and treatment with thymidine or [16][17]aphidicolin halt the cell in the G phase, mitotic shake-off, treatment with colchicine 1[18]and treatment with nocodazole halt the cell in M phase and treatment with 5-

    fluorodeoxyuridine halts the cell in S phase.

    [edit] See also

    ; Cell cycle mathematical model

    ; Mitosis

    ; Meiosis

    ; Interphase

    ; Autoradiography -- Used to determine the duration of each phase of the cell cycle.

    ; Biochemical Switches in the Cell Cycle

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