The Cell Cycle

I.         Cell division functions in reproduction, growth, and repair.

            A.        The division of a unicellular organism reproduces an entire organism, increasing the population.

            B.        Cell division on a larger scale can produce progeny for some multicellular organisms as in organisms that can grow by cuttings.

            C.        Cell division enables a multicellular organism to develop from a single fertilized egg or zygote.

            D.        In a multicellular organism, cell division functions to repair and renew cells that die from normal wear and tear or accidents.

            E.        Cell division is part of the cell cycle, the life of a cell from its origin in the division of a parent cell until its own division into two.

II.        Cell division requires the distribution of identical genetic material—DNA—to two daughter cells.

            A.        A dividing cell duplicates its DNA, allocates the two copies to opposite ends of the cell, and then splits into two daughter cells.

            B.        A cell’s genetic information, packaged as DNA, is called its genome.

                        1.         In prokaryotes, the genome is often a single long DNA molecule.

                        2.         Eukaryotic chromosomes are made of chromatin, a complex of DNA and associated protein.

                        3.         Each single chromosome contains one long, linear DNA molecule carrying hundreds or thousands of genes.

                        4.         The associated proteins maintain the structure of the chromosome and help control gene activity.

                        5.         When a cell is not dividing, each chromosome is in the form of a long, thin chromatin fiber but before cell division, chromatin condenses, coiling and folding to make a smaller package.

                        6.         Each duplicated chromosome consists of two sister chromatids, which contain identical copies of the chromosome’s DNA. The chromatids remain attached at a narrow area called the centromere.

                        7.         Later in cell division, the sister chromatids are pulled apart and repackaged into two new nuclei at opposite ends of the parent cell.

                        8.         Once the sister chromatids separate, they are considered individual chromosomes.

            C.        Mitosis, the formation of the two daughter nuclei, is usually followed by division of the cytoplasm, cytokinesis.

            D.        These processes start with one cell and produce two cells that are genetically identical to the original parent cell.

III.       The mitotic (M) phase of the cell cycle alternates with the much longer interphase (which accounts for 90% of the cell cycle).

            A.        The M phase includes mitosis and cytokinesis.

            B.        During interphase, the cell grows by producing proteins and cytoplasmic organelles, copies its chromosomes, and prepares for cell division.

            C.        Interphase has three subphases: the G₁ phase (“first gap”), the S phase (“synthesis”), and the G₂ phase (“second gap”).

                        1.         During all three subphases, the cell grows by producing proteins and organelles.

                        2.         Chromosomes are duplicated only during the S phase.

            D.        A typical human cell might divide once every 24 hours. Of this time, the M phase would last less than an hour, while the S phase might take 10–12 hours, or half the cycle.

            E.        The rest of the time would be divided between the G₁ and G₂ phases.

            F.        For convenience, mitosis is usually broken into five subphases: prophase, prometaphase, metaphase, anaphase, and telophase.

                        1.         In late interphase, the chromosomes have been duplicated but are not condensed.

                                    a.         A nuclear membrane bounds the nucleus, which contains one or more nucleoli.

                                    b.         The centrosome has replicated to form two centrosomes.

                                    c.         In animal cells, each centrosome features two centrioles.

                        2.         In prophase, the chromosomes are tightly coiled, with sister chromatids joined together.

                                    a.         The nucleoli disappear.

                                    b.         The mitotic spindle begins to form. It is composed of centrosomes and the microtubules that extend from them.

                                    c.         The centrosomes move away from each other, apparently propelled by lengthening microtubules.

                        3.         During prometaphase, the nuclear envelope fragments, and microtubules from the spindle interact with the condensed chromosomes.

                                    a.         Each of the two chromatids of a chromosome has a kinetochore, a specialized protein structure located at the centromere.

                                    b.         Kinetochore microtubules from each pole attach to one of two kinetochores.

                                    c.         Nonkinetochore microtubules interact with those from opposite ends of the spindle.

                                    d.         The spindle fibers push the sister chromatids until they are all arranged at the metaphase plate, an imaginary plane equidistant from the poles, defining metaphase.

                        4.         At anaphase, the centromeres divide, separating the sister chromatids.

                                    a.         Each is now pulled toward the pole to which it is attached by spindle fibers.

                                    b.         By the end, the two poles have equivalent collections of chromosomes.

                        5.         At telophase, daughter nuclei begin to form at the two poles.

                                    a.         Nuclear envelopes arise from the fragments of the parent cell’s nuclear envelope and other portions of the endomembrane system.

                                    b.         The chromosomes become less tightly coiled.

                        6.         Cytokinesis, division of the cytoplasm, is usually well underway by late telophase.

                                    a.         In animal cells, cytokinesis involves the formation of a cleavage furrow, which pinches the cell in two.

                                    b.         In plant cells, vesicles derived from the Golgi apparatus produce a cell plate at the middle of the cell.

IV.      The mitotic spindle, fibers composed of microtubules and associated proteins, is a major driving force in mitosis.

            A.        As the spindle assembles during prophase, the elements come from partial disassembly of the cytoskeleton. The spindle fibers elongate by incorporating more subunits of the protein tubulin.

            B.        Assembly of the spindle microtubules starts in the centrosome, the organelle that organizes the cell’s microtubules.

            C.        In animal cells, the centrosome has a pair of centrioles at the center, but the centrioles are not essential for cell division.

            D.        An aster, a radial array of short microtubules, extends from each centrosome.

            E.        Each sister chromatid has a kinetochore of proteins and chromosomal DNA at the centromere.

            F.        When a chromosome’s kinetochore is “captured” by microtubules, the chromosome moves toward the pole from which those microtubules come.

            G.        When microtubules attach to the other pole, this movement stops and a tug-of-war ensues. Eventually, the chromosome settles midway between the two poles of the cell, on the metaphase plate. Nonkinetochore microtubules from opposite poles overlap and interact with each other.

            H.        The chromatids are pulled apart and they move, as full-fledged chromosomes, toward opposite poles of the cell. The leading hypothesis suggests that the chromosomes are “reeled in” by the shortening of microtubules at the spindle poles.

            I.         Experimental evidence supports the hypothesis that motor proteins on the kinetochore “walk” the attached chromosome along the microtubule toward the nearest pole. Meanwhile, the excess microtubule sections depolymerize at their kinetochore ends.

            J.         Nonkinetochore microtubules are responsible for lengthening the cell along the axis defined by the poles. During anaphase, the area of overlap of nonkinietochore microtubules is reduced as motor proteins attached to the microtubules walk them away from one another, using energy from ATP.

            K.        As microtubules push apart, the microtubules lengthen by the addition of new tubulin monomers to their overlapping ends, allowing continued overlap.

V.        Cytokinesis, division of the cytoplasm, typically follows mitosis.

            A.        In animal cells, cytokinesis occurs by a process called cleavage.

                        1.         On the cytoplasmic side of the cleavage furrow is a contractile ring of actin microfilaments associated with molecules of the motor protein myosin.

                        2.         Contraction of the ring pinches the cell in two.

            B.        Cytokinesis in plants, which have cell walls, involves a completely different mechanism.

                        1.         During telophase, vesicles from the Golgi join at the metaphase plate, forming a cell plate.

                        2.         The plate enlarges until its membranes fuse with the plasma membrane at the perimeter.

VI.      Mitosis in eukaryotes may have evolved from binary fission in bacteria.

            A.        Prokaryotes reproduce by binary fission, not mitosis.

            B.        Most bacterial genes are located on a single bacterial chromosome that consists of a circular DNA molecule and associated proteins.

            C.        The circular bacterial chromosome is highly folded and coiled in the cell.

            D.        While the chromosome is replicating, the cell elongates.

            E.        When replication is complete, its plasma membrane grows inward to divide the parent cell into two daughter cells, each with a complete genome.

            F.        The movement of bacterial chromosomes is similar to the poleward movements of the centromere regions of eukaryotic chromosomes. However, bacterial chromosomes lack visible mitotic spindles or even microtubules.

            G.        How did mitosis evolve?

                        1.         There is evidence that mitosis had its origins in bacterial binary fission.

                        2.         Some of the proteins involved in binary fission are related to eukaryotic proteins.

                        3.         Two of these are related to eukaryotic tubulin and actin proteins.

                        4.         As eukaryotes evolved, the ancestral process of binary fission gave rise to mitosis.

                        5.         Possible intermediate evolutionary steps are seen in the division of two types of unicellular algae.

                                    a.         In dinoflagellates, replicated chromosomes are attached to the nuclear envelope.

                                    b.         In diatoms, the spindle develops within the nucleus.

                                    c.         In most eukaryotic cells, the nuclear envelope breaks down and a spindle separates the chromosomes.

VII.     The timing and rates of cell division in different parts of an animal or plant are crucial for normal growth, development, and maintenance.

            A.        The frequency of cell division varies with cell type.

            B.        The cell cycle appears to be driven by specific chemical signals present in the cytoplasm or from signals from outside the cell.

            C.        Cyclically operating molecules trigger and coordinate key events in the cell cycle. The control cycle has a built-in clock, but it is also regulated by external adjustments and internal controls.

            D.        A checkpoint in the cell cycle is a critical control point where stop and go-ahead signals regulate the cycle. The signals are transmitted within the cell by signal transduction pathways.

            E.        Animal cells generally have built-in stop signals that halt the cell cycle at checkpoints until overridden by go-ahead signals. Many signals registered at checkpoints come from cellular surveillance mechanisms. These indicate whether key cellular processes have been completed correctly.

            F.        For many cells, the G₁ checkpoint, the “restriction point” in mammalian cells, is the most important.

                        1.         If the cell receives a go-ahead signal at the G₁ checkpoint, it usually completes the cell cycle and divides.

                        2.         If it does not receive a go-ahead signal, the cell exits the cycle and switches to a nondividing state, the G₀ phase.

            G.        Rhythmic fluctuations in the abundance and activity of cell cycle control molecules pace the events of the cell cycle.

            H.        These regulatory molecules include protein kinases that activate or deactivate other proteins by phosphorylating them.

                        1.         These kinases are present in constant amounts but require attachment of a second protein, a cyclin, to become activated.

                        2.         Levels of cyclin proteins fluctuate cyclically.

                        3.         Because of the requirement for binding of a cyclin, the kinases are called cyclin-dependent kinases, or Cdks.

                        4.         Cyclin levels rise sharply throughout interphase, and then fall abruptly during mitosis.

                        5.         Peaks in the activity of one cyclin-Cdk complex, MPF, correspond to peaks in cyclin concentration.

                        6.         MPF (“maturation-promoting factor” or “M-phase-promoting-factor”) triggers the cell’s passage past the G₂ checkpoint to the M phase.

                                    a.         MPF promotes mitosis by phosphorylating a variety of other protein kinases.

                                    b.         MPF stimulates fragmentation of the nuclear envelope by phosphorylation of various proteins of the nuclear lamina.

                                    c.         It also triggers the breakdown of cyclin, dropping cyclin and MPF levels during mitosis and inactivating MPF.

                                    d.         The noncyclin part of MPF, the Cdk, persists in the cell in inactive form until it associates with new cyclin molecules synthesized during the S and G2 phases of the next round of the cycle.

                                    e.         At least three Cdk proteins and several cyclins regulate the key G₁ checkpoint.

                                    f.         Similar mechanisms are also involved in driving the cell cycle past the M phase checkpoint.

VIII.    Internal and external cues help regulate the cell cycle.

            A.        The M phase checkpoint ensures that all the chromosomes are properly attached to the spindle at the metaphase plate before anaphase. This ensures that daughter cells do not end up with missing or extra chromosomes.

            B.        A signal to delay anaphase originates at kinetochores that have not yet attached to spindle microtubules. This keeps the anaphase-promoting complex (APC) in an inactive state. When all kinetochores are attached, the APC activates, triggering breakdown of cyclin and inactivation of proteins holding sister chromatids together.

            C.        A variety of external chemical and physical factors can influence cell division. For example, cells fail to divide if an essential nutrient is left out of the culture medium.

            D.        Particularly important for mammalian cells are growth factors, proteins released by one group of cells that stimulate other cells to divide. At least 50 different growth factors can trigger specific cells to divide.

            E.        The effect of an external physical factor on cell division can be seen in density-dependent inhibition of cell division.

                        1.         Cultured cells normally divide until they form a single layer on the inner surface of the culture container.

                        2.         If a gap is created, the cells will grow to fill the gap.

            F.        Most animal cells also exhibit anchorage dependence for cell division.

                        1.         To divide, they must be anchored to a substratum, typically the extracellular matrix of a tissue.

                        2.         Control appears to be mediated by pathways involving plasma membrane proteins and elements of the cytoskeleton linked to them.

IX.      Cancer cells have escaped from cell cycle controls.

            A.        Cancer cells exhibit neither density-dependent inhibition nor anchorage dependence.

            B.        Cancer cells divide excessively and invade other tissues because they are free of the body’s control mechanisms.

            C.        Cancer cells do not stop dividing when growth factors are depleted. This is either because a cancer cell manufactures its own growth factors, has an abnormality in the signaling pathway, or has an abnormal cell cycle control system.

            D.        If and when cancer cells stop dividing, they do so at random points, not at the normal checkpoints in the cell cycle.

            E.        Cancer cells may divide indefinitely if they have a continual supply of nutrients. In contrast, nearly all mammalian cells divide 20 to 50 times under culture conditions before they stop, age, and die. Cancer cells may be “immortal.”

            F.        The abnormal behavior of cancer cells begins when a single cell in a tissue undergoes a transformation that converts it from a normal cell to a cancer cell.

                        1.         Normally, the immune system recognizes and destroys transformed cells.

                        2.         Cells that evade destruction proliferate to form a tumor, a mass of abnormal cells.

                                    a.         If the abnormal cells remain at the originating site, the lump is called a benign tumor. Most do not cause serious problems and can be fully removed by surgery.

                                    b.         In a malignant tumor, the cells become invasive enough to impair the functions of one or more organs.

            G.        In addition to chromosomal and metabolic abnormalities, cancer cells often lose attachment to nearby cells, are carried by the blood and lymph system to other tissues, and start more tumors in an event called metastasis.

            H.        Cancer cells may secrete signal molecules that cause blood vessels to grow toward the tumor.

            I.         Treatments for metastasizing cancers include radiation and chemotherapy with toxic drugs.

                        1.         These treatments target actively dividing cells.

                        2.         Chemotherapeutic drugs interfere with specific steps in the cell cycle.

                        3.         The side effects of chemotherapy are due to the drug’s effects on normal cells.