Chapter 12

Cell division involves two processes: the division of the nucleus and the division of the cytoplasm. Cytoplasmic division is called cytokinesis. Nuclear divisions in eukaryotes are of either of two types mitotic or meiotic. We will discuss meiosis is the next chapter, but will concentrate on mitosis here. To understand mitosis we must appreciate the alternative arrangements of DNA within the cell. Most of the time DNA is relatively unwound and because it is very thin during this time it is not distinctly visible unless an electron microscope is used. In this state the DNA is used as a template for the synthesis of both RNA and DNA. The DNA is bound to a variety of histone and nonhistone proteins in this state and is said to be in a chromatin configuration. If we put this in context with regard to the cell cycle this represents interphase, which includes the G1 (gap 1), S (synthesis) and G2 (gap 2) phases of the cell cycle (Fig. 12.5). The cell is growing and actively producing RNA and proteins during all stages of interphase and during the S phase synthesizes DNA. Interphase constitutes approximately 90% of a cell's life. The remaining portion of the cell cycle is the M stage (mitosis or meiosis). During the M stage the DNA condenses (twists and bends on itself) forming one or more chromosome. The chromosomes are visible with a light microscope and soon after the onset of the M phase each appears as two thick rods (sister chromatids) that are united together at a constricted region (centromere). (Fig. 12.4) The lengths of the chromatids and the location of the centromere are unique for each type of chromosome. Each chromatid represents one continuous double stranded DNA molecule together with some associated proteins. The sister chromatids each are identical copies of DNA and result from the process of DNA replication that took part in the S phase. Since sister chromatids are united by a common centromere they are members of the same chromosome. Each centromere has two kinetochores, one associated with each sister chromatid. These kinetochores will interact with microtubules that will direct the movement of chromosomes during the M phase.

At the end of G2, the centrosome (a region near the nucleus where tubulin can be efficiently organized into microtubules) replicates and each centrosome becomes the base site for an array of emanating microtubules (asters). The M phase (Fig. 12.6)begins with prophase during which the centrosomes (and asters) begin moving apart. This movement is influenced by the interaction of microtubules extending from each aster. The DNA begins condensing and chromosomes become visible (they each contain two sister chromosomes united at a common centromere). The next stage recognized is prometaphase. The nuclear lamina disassociates and the nuclear envelope breaks down temporarily adding to the endoplasmic reticulum. Some of the microtubules emanating from the centrosomes attach to the centromeres, with those coming from one aster binding to the same kinetochore of each chromosome and those coming from the other aster binding to the other kinetochore. These microtubules are called kinetochore fibers and they direct the movement of the chromosomes toward the midpoint of the cell (the metaphase plate) (Fig. 12.7). Other microtubules do not attach to the kinetochores but extend past each other and form the spindle fibers. The interactions between the spindle fibers cause the asters to migrate to opposite sides of the nucleus. When the centromeres of all chromosomes reach the equator (the metaphase plate) we have reached the metaphase stage. At metaphase the imaginary equator bisects each centromere such that one member of each its pair of its kinetochores is oriented toward each aster and is joined to a kinetochore fiber leading to that aster. The next stage (anaphase) begins with the two sister chromatids separating from each other when their common centromeres split and become two complete centrosomes one each attached to what was formally a member of the sister pair of chromatids. At this point the chromatids are all individually given the rank of chromosome. You can always tell how many chromosomes there are in a cell by counting the number of centromeres. These chromosomes begin migrating to opposite poles under the direction of the kinetochore fibers. At the same time the asters are moving further apart do to the interactions of the spindle fibers. The cell is becoming elongated at this stage. When the chromosomes arrive near the poles toward which they are migrating, the nuclear envelope begins to reassociate, and the chromosomes begin to unwind into the chromatin configuration. At the same time cytokinesis begins if it occurs at all. These events all signal the telophase stage of mitosis. After telophase is complete the cell leaves the M phase of the cell cycle and enters the G1 phase. The end result of mitosis (if cytokinesis simultaneously occurs) is two cells with exactly the same number of chromosomes as the original cell, although each of the new chromosomes has only one chromatid each. The cells have identical copies of DNA. In animals mitotic cell divisions are the method by which the fertilized eggs divide giving rise to all the mature cells of their body except their reproductive cells (sperm and eggs) called gametes. These body cells are called somatic cells.

Cytokinesis is different in plant and animal cells. In animal cells a cleavage furrow forms around the cell membrane and under the influence of actin microfilaments interacting with myosin molecules the cell is pinched inward forming two cells. In plants, vesicles produced by the golgi apparatus coalesce at the midpoint of the cell. These vesicles contain material that becomes the middle lamella. These vesicles form what is called the cell plate; it initially forms deep within the cell and eventually expands to the perimeter of the cell forming two cells.

The cell cycle has a variety of checkpoints. Certain events must occur before the cell proceeds past these check points. The most significant of these is called the restriction point which occurs during G1. Many cell types discontinue the normal cell cycle at this restriction point and remain in an arrested state of G1, called G0. If cells get past the retriction point they will replicate their DNA and typically complete the cell cycle. It is normal for some cell types (e.g., muscle and nerve cells) to not divide after they are produced. Others cell types remain in G0 until replacements are needed. Other checkpoints occur at the end of G2 to determine if M is to be entered, and at metaphase to prevent the onset of anaphase until all kinetochores are attached to kinetochore fibers. (Fig. 12.14, 12.15)

Understanding the chemical clock that runs the cell cycle requires knowledge of two types of molecules. Cyclins are chemicals whose concentrations build up gradually through time and then drop quickly. These cyclins interact with kinases called Cdks (cyclin-dependent kinases). Often the complex itself activates enzymes that destroy its own cyclin component. In unison, these cyclins and cyclin-dependent kinases operate to phosphorylate other enzymes thereby turning on or off various cell cycle pathways. (Fig. 12.17)

Cells can be stimulated to divide by growth factors binding to their transmembrane receptor proteins. Cell division normally may be inhibited if growth factors or nutrients are in short supply or if they are unable to anchor to a substrate. Cells that do not obey these normal inhibitory controls develop into tumors that represent cancer.