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Control of the Cell Cycle

Control of the Cell Cycle

The process of cell division in mammalian cells can readily be observed in the light microscope. In some types of bacteria, cell division involves a simple elongation of the bacterial cell and the pinching off of two equally sized daughter cells. But the process of cell division as seen in mammalian cells is much more complicated. This process - termed mitosis - involves the condensation of chromosomes, which were hitherto invisible in the microscope; the breakdown of the nuclear membrane, so that the nuclear contents are no longer separated from the cytoplasm; the segregation of half sets of chromosomes to the two ends of the dividing cell; the constriction through the equator of the cell that results in the pinching off of two daughter cells, each endowed with its own share of the parental chromosomes; and finally the decondensation of the chromosomes and the reassembly of the nuclear membrane in the daughter cells. A detailed discussion of the multiple steps in mitosis is given in pages 191-196 of Purves.

This process of cell division in mammalian cells is one of spectacular visual complexity. The schedule of events in mitosis happens with regularity, precision and perfect timing in order to ensure that each of the daughter cells receives the proper, equal allotment of chromosomes and is able, following cell division, to re-form into a perfect, independently functioning cell, separate and distinct from its sister. But there are other parts of the cell's life cycle that are equally important but not readily observed in the microscope. We know about them through techniques other than light microscopy, and will step back from the process of mitosis and now confront the entire cycle of growth and division that characterizes the life of a mammalian cell. Mitosis, as will soon become apparent, is only a small part of its life history.

Eukaryotic cell cycle

While we discuss the mammalian cell life cycle here almost exclusively, it is true that naturally identical behavior is associated with almost all other types of eukaryotic cells. The steps of cellular growth and division that we observe today in our own cells were already developed in the original eukaryotic cells more than 1.5 billion years ago. These processes have been conserved in almost unaltered form in the ensuing time. We conclude this from the almost identical behavior of all types of eukaryotic cells as they proceed through their cycles of growth and division. For example, the life cycle of the yeast cell is almost identical to that of a human cell.

The entire life cycle of a cell is termed simply the cell cycle. We will discuss specifically how the mammalian life cycle is organized. Following cell division (i.e. mitosis), the daughter cells confront two possible fates. They may decide to enter immediately into another round of growth and division, thereby remaining in the active growth cycle. This leads to repeated rounds of cell division and results in turn in an exponentially increasing cell population.

As an alternative, the daughter cells may decide to cease active growth for a while. In that case, they will exit the active cell cycle and enter into a state of quiescence which is termed the GO (''G zero'') phase of the cell life cycle. Most of the cells in our body are in GO, in the sense that they are not actively growing, but instead have retreated into a non-growing state. Should conditions require, a cell may leave GO and reenter the active cell cycle.

In fact, only a small percentage of cells in our body are in an active growth state at any particular time. In certain tissues, such as the bone marrow, skin, and the gut, continual cell division occurs to replenish the constantly dying cells in those organs. In other tissues, such as the brain, cell division is a rare event.

We can now examine the consequences of the decision of daughter cells emerging from mitosis to remain in the active growth cycle. Each of these cells, recently formed through cell division, must now begin immediately to prepare itself for the next round of cell division. The time between mitoses in most mammalian cells is on the order of 12 to 24 hours. This represents the period of its life cycle. Bacteria by contrast may divide every 20-30 minutes, and yeast cell and other protozoans may divide in 6-8 hours.

Given these facts, it is apparent that a population of mammalian cells, all of which are actively growing, will double in number every 12-24 hours. During early embryogenesis, most of the cells in an embryo will be involved in active growth, and the number of cells will increase exponentially. But as the embryo approaches maturity in late embryogenesis, an ever-decreasing proportion of cells are involved in active growth. In adults, only a small proportion of cells are in the active growth cycle, proliferating in order to replace cells that have died as a consequence of normal cell turnover or tissue damage. Some of the remaining cells are in G0. Yet others are in a quiescent state that precludes them from ever re-entering the active growth cycle. Such cells are sometimes termed ''post-mitotic'', in the sense that they have given up the option of ever growing and passing through mitosis again.

Growth vs. Division

In our discussions here, we will repeatedly make the distinction between the terms ''growth'' and ''division''. Growth will imply the build-up of new molecules by a cell and the associated increase in its mass and volume. Division implies the actual process of mitosis. It is obvious that in most exponentially growing populations of cells, cells must grow by a factor of 2 between successive divisions in order to ensure that the mass of the 2 daughter cells (including all their constituent parts) will equal that of the mother cell prior to division.

Replication of the Cell's Genome

The most complex structure that must be doubled in size in preparation for cell division is the cell's chromatin--it's chromosomal DNA together with associated proteins. This process of doubling the genome must occur with extraordinary precision, as we have discussed earlier. In the absence of precise, exact genomic duplication, one of the daughter cells will receive a flawed, mutant genome that will threaten its ability to survive, or even worse, cause it to start to grow uncontrollably like a cancer cell.

The period during which DNA replication occurs is not spread evenly throughout the cell cycle between successive mitoses. Instead, DNA replication is accomplished during a discrete window of time, termed S (synthetic) phase. S phase in mammalian cells usually takes 6-8 hours, during which time the entire complement of chromosomal DNA is replicated. The period of mitosis, termed M phase, usually takes less than an hour, and encompasses the aforementioned processes of chromosomal condensation, breakdown of the nuclear membrane, alignment of the condensed chromosomes in the mitotic apparatus, segregation of two sets of condensed chromosomes to opposite poles of the cell, reformation of two nuclear membranes around the two sets of recently segregated chromosomes, decondensation of the chromosomes, and the pinching off and separation of the two daughter cells.

Importantly, S phase does not follow hard on the heels of M phase. Instead, there is a period, often as long as 10-12 hours, after M phase during which time the recently divided cell prepares itself for S phase. This long preparation period allows the cell to synthesize a number of macromolecular constituents and build up mass. Cells that rush too quickly into S phase following mitosis end up being abnormally small.

This period after M but before S is termed the first gap period, or G1 phase of the cell cycle. Similarly, following successful completion of DNA synthesis and chromosomal replication in S phase, there is a long period of time - often 4-5 hours - when the cell prepares itself for mitosis. This period after S phase and before M phase is the second gap phase in the cell cycle, termed its G2 phase. In sum, the active cell cycle is divided into 4 phases: M, G1, S and G2; the time spent outside of M (encompassing therefore G1,S & G2) is sometimes termed its interphase. We can assemble all the facts that we have just learned into the following unifying scheme that diagrams the phases of the cell cycle:

Control of the cell cycle

Few if any cells in the body commit themselves to passage through the cell cycle on the basis of their own, autonomous, internally generated decisions. A normal cell does not have a ''mind of its own''. Instead, its growth and division invariably depend upon and are prompted by extracellular signals. These signals encourage or discourage the cell to grow and divide. Such dependence by a cell on extracellular, contextual signals is extraordinarily important for maintaining the integrity and function of a complex tissue. Each normal cell must constantly be consulting the signals emanating from its neighbors in order to ensure that the community of cells as a whole behaves like a well-integrated, co-ordinated team rather than a loose collection of randomly behaving, ''selfish'' individuals. Soon, we will study how the breakdown of this communication network results in cancer.

Precisely how can we understand the control of a cell's proliferation (growth and division) by its extracellular environment? Such study is virtually impossible if we peer into the complicated environment of a living tissue where a cell co-exists with a multitude of cell types in the midst of a complex tissue architecture. Instead, we are forced to study isolated cells growing in a culture dish, where we can control cell number and define the extracellular environment of each cell. More information on cell cultures is available, but not necessary for you to know.

shanec@mit.edu