CELL CYCLE

(FUNDAMENTAL PROCESS) CONTROL OF CELL DIVISION

Most cells have two major phases: mitosis and interphase often together referred to as the cell cycle For most tissues at any given time, only a few cells are in mitosis while the rest remain in interphase which is the period between divisions of the cytoplasm and is where a typical eukaryotic cell spends most of its life Some cells lose the capacity to divide altogether and stay in interphase indefinitely (for example in humans: nerve cells and muscle cells), while some divide regularly and others only occasionally

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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 sister 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 G0 phase. State Description Abbreviation G0 A resting phase where the cell has left the cycle and has stopped dividing. Cells increase in size in Gap 1. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis. DNA replication occurs during this phase. 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 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.

quiescent/ Gap 0 senescent Gap 1

G1

Interphase

Synthesis

Gap 2

G2

Cell division

Mitosis

DETAILED DISCUSSION OF PHASES: 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. 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 occurs
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in response to DNA damage or degradation that would make a cell's progeny nonviable; it is often a biochemical reaction; division of such a cell could, for example, become cancerous. Some cells enter the G0 phase semi-permanentally e.g., some liver and kidney cells. Interphase Before a cell can enter cell division, it needs to take in nutrients. All of the preparations are done during the interphase.Interphase is a series of changes that takes place in a newly formed cell & its nucleus,before it becomes capable of division again.It is also called intermitosis.Previously it was called resting stage because there is no apparent activity related to cell division. Interphase proceeds in three stages, G1, S, and G2. Cell division operates in a cycle. Therefore, interphase is preceded by the previous cycle of mitosis and cytokinesis. Interphase is also known as preparatory phase. In this stage nucleus and cytosol division does not occur. The cell prepares for division. The inactive x chromose can be seen attached to nuclear membrane in this phase It is the stage between end of mitosis and start of next phase.In this phase many events occur and the most significant event is the replication of genetic material(DNA) 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 the use of 20 amino acids to form millions of proteins and later on 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. It is under the control of the p53 gene. S phase The ensuing S phase starts when DNA replication 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. During this phase, synthesis is completed as quickly as possible due to the exposed base pairs being sensitive to external factors such as any drugs taken or any mutagens (such as nicotine). G2 phase 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 divides

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Mitosis (M phase, mitotic phase) The relatively brief M phase consists of nuclear division (karyokinesis). The M phase has been broken down into several distinct phases, sequentially known as: Prophase- the chromosomes are visible, the centrioles move apart to opposite poles of the cell. Spindle fibers from each centriole attach to the centromeres of the chromosomes. The nucleolus is no longer visible. Metaphase- The chromosomes are lined up at the equator of the cell. The spindle fibers from each centriole attach to the centromeres of the chromosomes. And the nuclear membrane disappears. Anaphase- The centromeres split, spindle fibers shorten, and the chromatids separate as each is pulled to opposite poles. Each pole then has a copy of 46 chromosomes. Telophase- The chromosomes become longer, thinner, and less distinct. New nuclear membranes form. The nucleolus reappears. Cytokinesis (strictly speaking, cytokinesis is not part of mitosis but is an event that directly follows mitosis in which cytoplasm is divided into two daughter cells)

Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets in two nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two 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. This accounts for approximately 10% of the cell cycle. 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. 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. Because cytokinesis usually occurs in conjunction with mitosis, "mitosis" is often used interchangeably with "M phase". However, there are many cells where mitosis and cytokinesis occur separately, forming single cells with multiple nuclei in a process called endoreplication. This occurs most notably among the fungi and slime moulds, but is found in various groups.
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Even in animals, cytokinesis and mitosis may occur independently, for instance during certain stages of fruit fly embryonic development. 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 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. Cyclins and other proteins signal events in the cell cycle

Transitions from G1SG2M depend on activation of a protein called cyclindependent kinase, or Cdk (a kinase is an enzyme that transfers a phosphate from ATP to different protein(s) by a process called phosphorylation) Activated Cdk transfers phosphates from ATP to certain amino acids of proteins that then move the cell in the direction of cycling The Cdk effect on the cell cycle is a common mechanism in eukaryotic cells
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studies in sea urchin eggs uncovered this protein for the first time called the maturation promoting factor (MPF) while a mutant yeast that lacked Cdk was found, which stalled at the G1S boundary. These two proteins were similar in structure and function other Cdks have been found in other organisms, including humans

Cyclin is a protein that interacts with Cdk

binding of Cyclin to Cdk exposes the active site of the kinase and the cyclin-Cdk complex now acts as a protein kinase that triggers transition from G1S. The cyclin then breaks down and the Cdk becomes inactive. Several different cyclins exist, which, when bound to Cdk, phosphorylate different target proteins 1. Cyclin D-Cdk4 acts during the middle of G1. This is the restriction point in G1, beyond which the rest of the cell cycle is inevitable 2. Cyclin E-Cdk2 acts at the boundary of G1 to S to initiate DNA replication 3. Cyclin A-Cdk2 acts during S and also stimulates DNA replication 4. Cyclin B-Cdk1 acts at the G2-to-M boundary, initiating mitosis
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Cyclin-Cdk complexes act as checkpoints. When functioning properly, they allow or prevent the passage to the next cell cycle stage, depending on the extra- and intracellular conditions. An example is the effect of p21 on the G1-to-S phase transition:
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if DNA is damaged by UV radiation, p21 is synthesized (a protein of 21,000 daltons) and it binds to the two different types of G 1 Cdk molecules, preventing their activation until damaged DNA is repaired. The p21 is then degraded, allowing the cell cycle to proceed

Some targets for cyclin-Cdk complexes include proteins that condense chromosomes and others that cause fragmentation of the nuclear envelope Cyclin-Cdk defects have been found in some cancer cells
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a breast cancer with too much cyclin D has been found the protein p53, which inhibits activation of Cdk, is found defective in half of all human cancers.

Growth factors stimulate the cells to divide

Cyclin-Cdk complexes provide internal control for cell cycle decisions, i.e. since the cells in multicellular organisms must divide only when appropriate, they must therefore respond to external signals, controls called growth factors Some cells respond to growth factors provided by other cells, for example:
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platelets release platelet-derived growth factor (PDGF) required for the division of fibroblasts, which diffuses to the surface of cells to stimulate wound healing by binding to tyrosine kinase receptors on surface of cells thus triggering a signal transduction pathway interleukins are released from one type of blood cell to stimulate division of another type resulting in body immune system defenses the cells of the kidney make erythropoietin, which stimulates bone marrow cells to divide and differentiate into red blood cells cancer cells cycle inappropriately because they either make their own growth factors or no longer require them to start cycling

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Regulation of the Cell Cycle

Cell cycle is driven by specific chemical signals in the cytoplasm Cell cycle control system triggers and coordinates key events in the cell cycle Cell cycle checkpoints act as stop and go signals 3 major checkpoints found in G 1, G2, and M phases
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G1 is critical checkpoint. If cells make it past G1, then the entire cell cycle is completed non-dividing cells are in G0 state and can get back into the cell cycle upon appropriate stimulation

Protein kinases are activated by cyclin proteins their activity is correlated with concentration of specific cyclin (hence the term cyclin dependent kinase or "Cdk")

Cyclin level rises during the interphase At G2 enough active M-phase Promoting Factor (MPF), i.e. the cyclin-Cdk complex is present to promote mitosis A number of phosphorylation events carried out by cyclin-CdK complex cause nuclear envelope to fragment and activate other enzymes Cyclin is subsequently broken down by proteolytic cleavage ( MPF becomes inactive) and Cdk is then recycled Proteolysis of the complex also drives M-phase past anaphase by breaking down proteins that hold sister chromatids together

INTERNAL AND EXTERNAL CUES REGULATE THE CELL CYCLE

internal signal delays start of anaphase (separation of chromosomes) until all kinetochores are attached to spindle fibers Anaphase promoting complex (APC) is kept in inactive state by proteins associated with kinetochores Signal ceases when all kinetochores are attached

Density dependent inhibition describes phenomenon whereby cells stop growing after reaching a certain density. Growth is limited by availability of growth factor
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CELL DEATH Occurs in 2 ways: Necrosis- occurs when pathological changes kill a cell caused by disease or injury Apoptosis- occurs as a normal physiological response. It is also called programmed cell death. This process helps the body rid from itself cancerous cells with damaged DNA. It is also important in the functioning of the immune system. There are two ways that lead to apotosis: Extrinsic- which extracellular molecules called death ligands bind to receptor proteins on the plasma membrane called death receptors. And Intrinsic- which apotosis responds to intracellular signals. This can be triggered by DNA damage, or by reactive oxygen species that cause oxidative stress. This cellular stress causes a sequence of events that makes the mitochodrial membrane permeable to some molecules, which leak into the cytoplasm and cause the next phase of apoptosis. It involves activation of cytoplamsic caspases (enzymes) sometimes called the "executioner" of the cell, which lead to cell death.

References: Wikipedia ~ http://en.wikipedia.org/wiki/Cell_cycle Human Physiology 2011 ~ http://humanphysiology2011.wikispaces.com/03.+Cell+Physiology

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