Cell cycle and cell division

The series of stages that a cell undergoes while progressing to division is known as cell cycle. In order for an organism to grow and develop, the organism's cells must be able to duplicate themselves. Three basic events must take place to achieve this duplication: the deoxyribonucleic acid DNA , which makes up the individual chromosomes within the cell's nucleus must be duplicated; the two sets of DNA must be packaged up into two separate nuclei; and the cell's cytoplasm must divide itself to create two separate cells, each complete with its own nucleus. The two new cells, products of the single original cell, are known as daughter cells.

Although prokaryotes (e.g. bacteria , non-nucleated unicellular organisms) divide through binary fission, eukaryotes (including, of course, human cells) undergo a more complex process of cell division because DNA is packed in several chromosomes located inside a cell nucleus. In eukaryotes, cell division may take two different paths, in accordance with the cell type involved. Mitosis is a cellular division resulting in two identical nuclei that takes place in somatic cells. Sex cells or gametes (ovum and spermatozoids) divide by meiosis. The process of meiosis results in four nuclei, each containing half of the original number of chromosomes. Both prokaryotes and eukaryotes undergo a final process, known as cytoplasmatic division, which divides the parental cell in new daughter cells.

Mitosis is the process during which two complete, identical sets of chromosomes are produced from one original set. This allows a cell to divide during another process called cytokinesis, thus creating two completely identical daughter cells.

During much of a cell's life, the DNA within the nucleus is not actually organized into the discrete units known as chromosomes. Instead, the DNA exists loosely within the nucleus, in a form called chromatin. Prior to the major events of mitosis, the DNA must replicate itself, so that each cell has twice as much DNA as previously.

Cells undergoing division are also termed competent cells. When a cell is not progressing to mitosis, it remains in phase G0 ("G" zero). Therefore, the cell cycle is divided into two major phases: interphase and mitosis. Interphase includes the phases (or stages) G1, S and G2 whereas mitosis is subdivided into prophase, metaphase, anaphase and telophase.

Interphase is a phase of cell growth and metabolic activity, without cell nuclear division, comprised of several stages or phases. During Gap 1 or G1 the cell resumes protein and RNA synthesis, which was interrupted during previous mitosis, thus allowing the growth and maturation of young cells to accomplish their physiologic function. Immediately following is a variable length pause for DNA checking and repair before cell cycle transition to phase S during which there is synthesis or semi-conservative replication or synthesis of DNA. During Gap 2 or G2, there is increased RNA and protein synthesis , followed by a second pause for proofreading and eventual repairs in the newly synthesized DNA sequences before transition to mitosis.

The cell cycle starts in G1, with the active synthesis of RNA and proteins, which are necessary for young cells to grow and mature. The time G1 lasts, varies greatly among eukaryotic cells of different species and from one tissue to another in the same organism. Tissues that require fast cellular renovation, such as mucosa and endometrial epithelia, have shorter G1 periods than those tissues that do not require frequent renovation or repair, such as muscles or connective tissues.

The first stage of mitosis is called prophase. During prophase, the DNA organizes or condenses itself into the specific units known as chromosomes. Chromosomes appear as double-stranded structures. Each strand is a replica of the other and is called a chromatid. The two chromatids of a chromosome are joined at a special region, the centromere. Structures called centrioles position themselves across from each other, at either end of the cell. The nuclear membrane then disappears.

During the stage of mitosis called metaphase, the chromosomes line themselves up along the midline of the cell. Fibers called spindles attach themselves to the centromere of each chromosome.

During the third stage of mitosis, called anaphase, spindle fibers will pull the chromosomes apart at their centromere (chromosomes have two complementary halves, similar to the two nonidentical but complementary halves of a zipper). One arm of each chromosome will migrate toward each centriole, pulled by the spindle fibers.

During the final stage of mitosis, telophase, the chromosomes decondense, becoming unorganized chromatin again. A nuclear membrane forms around each daughter set of chromosomes, and the spindle fibers disappear. Sometime during telophase, the cytoplasm and cytoplasmic membrane of the cell split into two (cytokinesis), each containing one set of chromosomes residing within its nucleus.

Cells are mainly induced into proliferation by growth factors or hormones that occupy specific receptors on the surface of the cell membrane, being also known as extra-cellular ligands. Examples of growth factors are as such: epidermal growth factor (EGF), fibroblastic growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), or by hormones. PDGF and FGF act by regulating the phase G2 of the cell cycle and during mitosis. After mitosis, they act again stimulating the daughter cells to grow, thus leading them from G0 to G1. Therefore, FGF and PDGF are also termed competence factors, whereas EGF and IGF are termed progression factors, because they keep the process of cellular progression to mitosis going on. Growth factors are also classified (along with other molecules that promote the cell cycle) as pro-mitotic signals. Hormones are also promitotic signals. For example, thyrotrophic hormone, one of the hormones produced by the pituitary gland, induces the proliferation of thyroid gland's cells. Another pituitary hormone, known as growth hormone or somatotrophic hormone (STH), is responsible by body growth during childhood and early adolescence, inducing the lengthening of the long bones and protein synthesis. Estrogens are hormones that do not occupy a membrane receptor, but instead, penetrate the cell and the nucleus, binding directly to specific sites in the DNA, thus inducing the cell cycle.

Anti-mitotic signals may have several different origins, such as cell-to-cell adhesion, factors of adhesion to the extracellular matrix, or soluble factor such as TGF beta (tumor growth factor beta), which inhibits abnormal cell proliferation, proteins p53, p16, p21, APC, pRb, etc. These molecules are the products of a class of genes called tumor suppressor genes. Oncogenes, until recently also known as proto-oncogenes, synthesize proteins that enhance the stimuli started by growth factors, amplifying the mitotic signal to the nucleus, and/or promoting the accomplishment of a necessary step of the cell cycle. When each phase of the cell cycle is completed, the proteins involved in that phase are degraded, so that once the next phase starts, the cell is unable to go back to the previous one. Next to the end of phase G1, the cycle is paused by tumor suppressor gene products, to allow verification and repair of DNA damage. When DNA damage is not repairable, these genes stimulate other intra-cellular pathways that induce the cell into suicide or apoptosis (also known as programmed cell death). To the end of phase G2, before the transition to mitosis, the cycle is paused again for a new verification and "decision": either mitosis or apoptosis.

Along each pro-mitotic and anti-mitotic intra-cellular signaling pathway, as well as along the apoptotic pathways, several gene products (proteins and enzymes ) are involved in an orderly sequence of activation and inactivation, forming complex webs of signal transmission and signal amplification to the nucleus. The general goal of such cascades of signals is to achieve the orderly progression of each phase of the cell cycle.

Mitosis always creates two completely identical cells from the original cell. In mitosis, the total amount of DNA doubles briefly, so that the subsequent daughter cells will ultimately have the exact amount of DNA initially present in the original cell. Mitosis is the process by which all of the cells of the body divide and therefore reproduce. The only cells of the body that do not duplicate through mitosis are the sex cells (egg and sperm cells). These cells undergo a slightly different type of cell division called meiosis, which allows each sex cell produced to contain half of its original amount of DNA, in anticipation of doubling it again when an egg and a sperm unite during the course of conception.

Meiosis, also known as reduction division, consists of two successive cell divisions in diploid cells. The two cell divisions are similar to mitosis, but differ in that the chromosomes are duplicated only once, not twice. The result of meiosis is four haploid daughter cells. Because meiosis only occurs in the sex organs (gonads), the daughter cells are the gametes (spermatozoa or ova), which contain hereditary material. By halving the number of chromosomes in the sex cells, meiosis assures that the fusion of maternal and paternal gametes at fertilization will result in offspring with the same chromosome number as the parents. In other words, meiosis compensates for chromosomes doubling at fertilization. The two successive nuclear divisions are termed as meiosis I and meiosis II. Each is further divided into four phases (prophase, metaphase, anaphase, and telophase) with an intermediate phase (interphase) preceding each nuclear division.

The events that take place during meiosis are similar in many ways to the process of mitosis, in which one cell divides to form two clones (exact copies) of itself. It is important to note that the purpose and final products of mitosis and meiosis are very different.

Meiosis I is preceded by an interphase period in which the DNA replicates (makes an exact duplicate of itself), resulting in two exact copies of each chromosome that are firmly attached at one point, the centromere. Each copy is a sister chromatid, and the pair are still considered as only one chromosome. The first phase of meiosis I, prophase I, begins as the chromosomes come together in homologous pairs in a process known as synapsis. Homologous chromosomes, or homologues, consist of two chromosomes that carry genetic information for the same traits, although that information may hold different messages (e.g., when two chromosomes carry a message for eye color, but one codes for blue eyes while the other codes for brown). The fertilized eggs (zygotes) of all sexually reproducing organisms receive their chromosomes in pairs, one from the mother and one from the father. During synapsis, adjacent chromatids from homologous chromosomes "cross over" one another at random points and join at spots called chiasmata. These connections hold the pair together as a tetrad (a set of four chromatids, two from each homologue). At the chiasmata, the connected chromatids randomly exchange bits of genetic information so that each contains a mixture of maternal and paternal genes. This "shuffling" of the DNA produces a tetrad, in which each of the chromatids is different from the others, and a gamete that is different from others produced by the same parent. Crossing over does explain why each person is a unique individual, different even from those in the immediate family. Prophase I is also marked by the appearance of spindle fibers (strands of microtubules) extending from the poles or ends of the cell as the nuclear membrane disappears. These spindle fibers attach to the chromosomes during metaphase I as the tetrads line up along the middle or equator of the cell. A spindle fiber from one pole attaches to one chromosome while a fiber from the opposite pole attaches to its homologue. Anaphase I is characterized by the separation of the homologues, as chromosomes are drawn to the opposite poles. The sister chromatids are still intact, but the homologous chromosomes are pulled apart at the chiasmata. Telophase I begins as the chromosomes reach the poles and a nuclear membrane forms around each set. Cytokinesis occurs as the cytoplasm and organelles are divided in half and the one parent cell is split into two new daughter cells. Each daughter cell is now haploid (n), meaning it has half the number of chromosomes of the original parent cell (which is diploid-2n). These chromosomes in the daughter cells still exist as sister chromatids, but there is only one chromosome from each original homologous pair.

The phases of meiosis II are similar to those of meiosis I, but there are some important differences. The time between the two nuclear divisions (interphase II) lacks replication of DNA (as in interphase I). As the two daughter cells produced in meiosis I enter meiosis II, their chromosomes are in the form of sister chromatids. No crossing over occurs in prophase II because there are no homologues to synapse. During metaphase II, the spindle fibers from the opposite poles attach to the sister chromatids (instead of the homologues as before). The chromatids are then pulled apart during anaphase II. As the centromeres separate, the two single chromosomes are drawn to the opposite poles. The end result of meiosis II is that by the end of telophase II, there are four haploid daughter cells (in the sperm or ova) with each chromosome now represented by a single copy. The distribution of chromatids during meiosis is a matter of chance, which results in the concept of the law of independent assortment in genetics.

The events of meiosis are controlled by a protein enzyme complex known collectively as maturation promoting factor (MPF). These enzymes interact with one another and with cell organelles to cause the breakdown and reconstruction of the nuclear membrane, the formation of the spindle fibers, and the final division of the cell itself. MPF appears to work in a cycle, with the proteins slowly accumulating during interphase, and then rapidly degrading during the later stages of meiosis. In effect, the rate of synthesis of these proteins controls the frequency and rate of meiosis in all sexually reproducing organisms from the simplest to the most complex.

Meiosis occurs in humans, giving rise to the haploid gametes, the sperm and egg cells. In males, the process of gamete production is known as spermatogenesis, where each dividing cell in the testes produces four functional sperm cells, all approximately the same size. Each is propelled by a primitive but highly efficient flagellum (tail). In contrast, in females, oogenesis produces only one surviving egg cell from each original parent cell. During cytokinesis, the cytoplasm and organelles are concentrated into only one of the four daughter cells—the one that will eventually become the female ovum or egg. The other three smaller cells, called polar bodies, die and are reabsorbed shortly after formation. The concentration of cytoplasm and organelles into the oocyte greatly enhances the ability of the zygote (produced at fertilization from the unification of the mature ovum with a spermatozoa) to undergo rapid cell division.

The control of cell division is a complex process and is a topic of much scientific research. Cell division is stimulated by certain kinds of chemical compounds. Molecules called cytokines are secreted by some cells to stimulate others to begin cell division. Contact with adjacent cells can also control cell division. The phenomenon of contact inhibition is a process where the physical contact between neighboring cells prevents cell division from occurring. When contact is interrupted, however, cell division is stimulated to close the gap between cells. Cell division is a major mechanism by which organisms grow, tissues and organs maintain themselves, and wound healing occurs.

Cancer is a form of uncontrolled cell division. The cell cycle is highly regulated by several enzymes, proteins, and cytokines in each of its phases, in order to ensure that the resulting daughter cells receive the appropriate amount of genetic information originally present in the parental cell. In the case of somatic cells, each of the two daughter cells must contain an exact copy of the original genome present in the parental cell. Cell cycle controls also regulate when and to what extent the cells of a given tissue must proliferate, in order to avoid abnormal cell proliferation that could lead to dysplasia or tumor development. Therefore, when one or more of such controls are lost or inhibited, abnormal overgrowth will occur and may lead to impairment of function and disease.

See also Amino acid chemistry; Bacterial growth and division; Cell cycle (eukaryotic), genetic regulation of; Cell cycle (prokaryotic), genetic regulation of; Chromosomes, eukaryotic; Chromosomes, prokaryotic; DNA (Deoxyribonucleic acid); Enzymes; Genetic regulation of eukaryotic cells; Genetic regulation of prokaryotic cells; Molecular biology and molecular genetics