Cell cycle in Eukaryotes

A typical eukaryotic cell divides every 24 hours.

The eukaryotic cell cycle is divided into two basic parts: mitosis and interphase.

Mitosis is the phase at which the daughter chromosomes separate and in which cell division occurs.

During interphase, chromosomes decondense and distribute throughtout the nucleus. Cell growth and DNA replication also occur during interphase.

More specifically, the eukaryotic cell cycle is divided into the following 4 phases:

• M phase = mitosis followed by cytokinesis. This phase may last 1 hour.
• G1 phase = the cell is metabolically active and continuously growing. This phase may last 11 hours.
• S phase = DNA replication takes place. This phase may last 8 hours
• G2 phase = the cell growth continues and proteins are synthesized in preparation for mitosis. This phase may last 4 hours.

Cell cycles in vivo

• Embryonic cell cycles only consist of the M phase and S phase and undergo rapid cell division.
• Nerve cells, muscle cells or red blood cells are highly specialized cells and have lost the ability to divide. To cease cell division, these cells must exit the cell cyle at the G1 phase to enter a quiescent stage of the cycle called Go. In Go, the cells remain metabolically active but no longer proliferate unless stimulated to do so. Cells also have reduced rates of protein synthesis.
• Cells that normally do not divide but can be induced to begin DNA synthesis and divide when given an appropriate stimuli include liver cells and lymphocytes.
• Cells that normally possess a relatively high level of mitotic activity are the gonial cells (oogonia and spermatogonia), hematopoietic stem cells (precursos of red and white blood cells) and the epithelial cells (that line the gut and make up the skin surface).

Control of the Cell Cycle

• In yeast, START is the regulatory point just before the end of G1. Once cells have passed START, they are committed to entering S phase and undergoing one cell division cycle. Passage through START is controlled by the availability of nutrients, cell size, mating factors.
• In animal cells, this regulatory point in the G1 phase is called the restriction point. The passage of animal cells through the cell cycle is regulated primarily by the extracellular growth factors.
• Substrates for the G1-activated Cdk are thought to include transcription factors that activate genes involved in DNA replication.
• Passage from G2 to mitosis requires activation of cdc2 by a different group of cyclins (the mitotic cyclins).
• The entry of a cell into M phase is initiated by the maturation-promoting factor (MPF). MPF consists of a catalytic subunit and a regulatory subunit called cyclin. The catalytic subunit of MPF is a cyclin dependent kinase 2 (cdk2).
• The G2-activated Cdk, phosphorylate histones, whose phosphorylation may help compact the chromosomes, and the nuclear lamins, whose phosphorylation leads to the disassembly of the nuclear envelope. The G2-activated Cdk also phosphorylates proteins required for the dynamic changes in the organization of the cytoskeleton that characterize the shift from interphase to mitosis.
• G1 and mitotic cyclins are synthesized or degraded as the cells progress through the cell cycle. The activity of MPF is controlled by the periodic accumulation and degradation of cyclin B during cell cycle progression. Cyclin B synthesis begins in S phase. Cyclin B then accumulates and forms complexes with Cdc2 throughout S and G2. Cdc2 activity triggers the degradation of cyclin B.
• Passage through START requires the cdc2/cyclin E complex. Cdk1/cyclin B is active at the G2-M transition.
• Cdks are activated by prhosphorylation at threonine 161, which is accomplished by a protein kinase called CAK (Cdk-activating kinase).
• Inactivation of Cdk occurs by phosphorylation at Thr 14 and Tyr 15. Phosphorylation during G2 inactivates the cdc2 enzyme.
• At the end of G2, a phosphatase called cdc25 removes phosphate Thr 14 and Tyr 15, driving the cell into mitosis.

Regulation of the cell cycle by checkpoints

• Checkpoints are mechanisms that halt progress of the cell cycle if DNA replication has not been completed or if any of the chromosomal DNA is damaged.
• Checkpoint in G2 prevents the initiation of mitosis until DNA replication is completed. Cell cycle is also arrested at G2 checkpoint if DNA is damaged.
• DNA damage also arrests the cell cycle at a checkpoint in G1.
• The checkpoint at the end of mitosis monitors the alignment of chromosomes on the mitotic spindle, thus ensuring that a complete set of chromosomes is distributed accurately to the daughter cells.

Events of M phase: Mitosis and Cytokinesis

• During the M phase, chromosomes condense, the nuclear envelope of most cells breaks down, the cytoskeleton reorganizes to form the mitotic spindle, and the chromosomes move to opposite poles. Chromosome segregation is then usually followed by cell division (cytokinesis).
• Mitosis can be divided into prophase, prometaphase, metaphase, anaphase and telophase.
• MPF and the progression to metaphase. MPF affects chromatin condensation, nuclear envelope breakdown, fragmentation of Golgi and ER and spindle formation by phosphorylating and activating downstream protein kinases, but also acts directly by phophorylating some of the structural proteins involved in this cellular reorganization: Histone H1, lamins.
• Degradation of cyclin B is required to exit mitosis and return to interphase.

Cytokinesis

• Cytokinesis usually initiates in late anaphase and is triggered by the inactivation of MPF.
• Cytokinesis of animal cells is mediated by a contractile ring of actin and myosin II filaments that forms beneath the plasma membrane.
• In higher plants, Golgi vesicles carrying cell wall precursors associate with polar microtubules at the former site of the metaphase plate. Fusion of these vesicles yields a membrane-enclosed disclike structure (the early cell plate) that expands outward and fuses with the parental plasma membrane.

Meiosis and fertilization

• Whereas somatic cells undergo mitosis to proliferate, the germ cells undergo meiosis to produce haploid gametes (the sperm and the egg).
• Meiosis results in the division of a diploid parental cell into haploid progeny, each containing only one member of the pair of homologous chromosomes that were present in the diploid parent.
• The pairing of homologous chromosomes after DNA replication allows recombination between chromosomes of paternal and maternal origin. This pairing of homologous chromosomes takes place during an extended prophase of meiosis I, which is divided into five stages: leptotene, zygotene, pachytene, diplotene and diakinesis.
• The pachytene stage lasts for days or weeks whereas the leptotene and zygotene stages last only for a couple of hours.
• Meiosis II initiates immediately after cytokinesis, and resembles normal mitosis.
• Diplotene is an extremely extended phase of oogenesis during which the bulk of oocyte growth occurs. Thus the diplotene stage is a period of intense metabolic activity, during which the oocytes accumulate stockpiles of matierials, including RNAs and proteins, that are needed to support early embryonic development.
• Diakinesis is the final stage of meiotic prophase I. Diakineses ends with the disappearance of the nucleolus, breakdown of the nuclear envelope, and the movement of the chromosomes. In vertebrate oocytes, these events are triggered by an increase in the level of the protein kinase activity of MPF.
• Progression of meiosis in vertebrate oocytes stops at metaphase II The factor that arrest mitosis is called cytostatic factor (CSF). The protein-serine/threonine kinase Mos is an essential component of CSF. Mos inhibits degradation of cyclin B of MPF. Mos induces the activation of MAP kinase. In oocytes, MAP kinase activation inhibits the ubiquitin proteolysis pathway responsible for cyclin B degradation. Oocytes can remain arrested at this point in the meiotic cell cycle for several days, awaiting fertilization. Metaphase II arrest is released only when the oocyte (now an egg) is fertilized, which leads to the destruction of Mos and incativation of Cdk.

Fertilization

• Fertilization induces a number of changes in the egg cytoplasm that lead to the completion of oocyte meiosis and initiation of the mitotic cell cycles of the early embryo.
• A key signal resulting from the binding of a sperm to its receptor on the plasma membrane of the egg is an increase in the level of Ca2+ in the egg cytoplasm. One effect of this elevation in intracellular Ca2+ is the induction of surface alterations that prevent additional sperm from entering the egg.
• The fertilized egg (a zygote) contains two haploid nuclei. In mammals, the two pro-nuclei then enter S phase and replicate their DNA as they migrate toward each other. As they meet, the zygote enters M phase of its first mitotic division.

A carefully regulated balance between cell proliferation and cell death is thus required for both the development and maintenance of animal tissues and organs.

Cell proliferation in Adults

• A few types of differentiated cells, including lens cells, nerve cells, and cardiac muscle cells in humans, are no longer capable of cell division. These cells are produced during embryonic development, differentiate, and are then retained throughout the life of the organism.
• Most cells in adult animals enter the Go stage but resume proliferation as needed to replace cells that have been injured or have died. Cells of this type include skin fibroblasts, smooth muscle cells, the endothelial cells that line blood vessels, and the epithelial cells of most internal organs, such as the liver, pancreas, kidney, lung, prostate, and breast.
• Other cells types of differentiated cells, including blood cells, epithelial cells of the skin, and the epithelial cells lining the digestive tract, have short life spans and must be replaced by continual cell proliferation in adult animals. These cells are replaced via the proliferation of cells that are less differentiated - stem cells. The continual proliferation of stem cells is provided by blood cell differentiation. All of the different types of blood cells develop from a pluripotent stem cell in the bone marrow (e.g. erythrocyte, platelets, macrophages, glanulocytes, B lymphocytes, T lymphocytes). All these cells have limited life spans, ranging from less than a day to a few months.

Programmed Cell Death

• Programmed cell death (PCD) is a normal physiological form of cell death that plays a key role both in the maintenance of adult tissues and in embryonic development.
• In adults, programmed cell death is responsible for balancing cell proliferation and maintaining constant cell numbers in tissues undergoing cell turnover.
• PCD provides a defense mechanism. Virus-infected cells frequently undergo programmed cell death.
• Other types of insults, such as DNA damage, also induce programmed cell death.
• During development, PCD plays a key role by eliminating unwanted cells from a variety of tissues. For example, PCD is responsible for the elimination of larval tissues during amphibian and insect metamorphosis, as well as for the elimination of tissue between the digits during the formation of fingers and toes. Neurons are produced in excess, and up to 50% of developing neurons are eliminated by PCD. Those that survive are selected for having made the correct connections with their target cells.
• In contrast to the accidental death of cells that results from an acute injury, PCD is an active process characterized by a distinct morphological change known as apoptosis. During apoptosis, chromosomal DNA is usually fragmented as a result of cleavage between nucleosomes. The chromatin condenses and the nucleus then breaks up into small pieces. Finally, the cell itself shrinks and breaks up into membrane-enclosed fragments called apoptotic bodies. Such apoptotic bodies and cell fragments are readily recognized and phagocytosed by both macrophages and neighboring cells, so cells that die by apoptosis are efficiently removed from tissues. In contrast, cells that die as a result of acute injury swell, and lyse, releasing their contents into the extracellular space and causing inflammation. In mammals, apoptosis is regulated by the Bcl-2 protein. Induction of apoptosis seems to be regulated by a family of mammalian cysteine proteases, known as the ICE protease family.

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