Cell division cycles, stopping

FIG. 3. Stopping the cell division cycles. In Drosophila embryos, the timely arrest of cell proliferation in the epidermis requires the transcriptional activation of dacapo (Lane et al 1996, de Nooij et al 1996) and fi y-related (Sigrist Lehner 1997) which occurs during the final division cycle in parallel to down-regulation of cyclin E expression. 

Podophyllotoxin 87, isolated from Podophyllum species shows antitumor properties it inhibits microtubule assembly, in vivo, the result of which is the destruction of the cytoskeleton in the cytoplasm. As a consequence, the cell division is stopped at the mitotic stage of the cell cycle (3), Semi-synthetic derivatives of podophyllotoxin, i.e., Etoposide 88 and Teniposide 89 have been developed. Tliey do not possess the toxicity of podophyllotoxin 87 and are now being used (alone or in conjunction with odier drugs) in treatment for germinal testicular cancer, small cell lung cancer, and certain form of leukemia (3), They have been shown to induce, both, in... 

Eehner In the epidermis it is quite reproducible. After mitosis 13, when the syncytial division cycle is stopped, cellularization occurs followed by a pulse of string expression that allows cells to go through mitosis 14. Then they go immediately into S phase and wait in the next G2 phase until the next pulse of string comes up, driving mitosis 15. After mitosis 15, they go again immediately into S phase and wait in G2 until string comes up, triggering the final division. 

The periodic recurrence of cell division suggests that globally the cell cycle functions like an autonomous oscillator. An extended model incorporating the sequential activation of the various cyclin-dependent kinases, followed by their inactivation, shows that even in the absence of control by cell mass, this sequence of biochemical events can operate as a limit cycle oscillator [145]. This supports the union of the two views of the cell cycle as dominoes and clock [146]. Because of the existence of checkpoints, however, the cell cycle stops at the end of certain phases before engaging in the next one. Thus the cell cycle looks more like an oscillator that slows down and makes occasional stops. A metaphor for such behavior is provided by the movement of the round plate on the table in a Chinese restaurant, which would rotate continuously under the movement imparted by the participants, were it not for frequent stops. 

Vincristine binds reversibly to tubulin, stopping microtu-xile assembly, which arrests cell division in metaphase. " Ms temporary arrest causes a cell cycle block called slalli-tiAinesis. Resistance to vincristine results from increased zilular levels of P-glycoprotcin. 

Telomeres play an important role in defining the replicative life span of cells, i.e., the maximal number of cell divisions or the so-called Hayflick limit. Normal human somatic cells, such as fibroblasts, after isolation ftom the body are only able to undergo a limited number of cell divisions, dependent on the age of the donor, before they stop cycling and go into the senescent state , which becomes manifest in phenotypic charges like cellular (lattenii and expression of a senescence-associated. alactosidase. Such cells ate arrested in G, which is different from quiescent cells, which arrest in Gq. After acquirir the senescent phenotype cells are still viable and can be maintained in culture for up to several months. The telomeres in fibroblasts shorten with each di ion due to the end-replication problem , because conventional DNA polymerases need a free 3 -hydroxyl toup lor DNA synthesis. This is usually provided by the activity of the polymerase o/ptimase complex, which synthesizes an initial RNA o%onucleotide primer. Durit strand synthesis, the most distally located primer... 

Up to now we have assumed that cells in S are immediately stopped by methotrexate + uridine, and that cells not in S when this inhibitor is present continuously collect just before S. It is on this basis that we can assume that the time from the addition of thymidine to synchronous cell division is a measure of the interval S + G2 + 1/2 D. A second tacit assumption is that cells treated with methotrexate + uridine for some time can be made to progress in the cycle at the normal rate when supplied with thymidine. Neither of the two assumptions may be fully correct, but fortunately errors involved are likely to cancel out. Concerning the first assumption, there is in fact evidence that cells treated with methotrexate + uridine may progress perhaps 10 minutes into S before they are arrested (see Table 5 in Zeuthen, 1968) which might fit the observations by Stone et al. (1965) that acid-soluble thymidine compounds are carried over in the macronucleus from one S period to the next and are used for DNA synthesis. In any case, such effects... 

Cell biologists consider the cell cycle to be divided into five phases Gl, S, G2, M and GO. There are three principal checkpoints at which the cell cycle is stopped if defects are detected the Gl checkpoint, the G2 checkpoint and the spindle checkpoint during the mitosis phase. The tumour suppressors p53, the guardian angel protein , and Rh protein regulate progression from the Gl phase to the S phase. Mutations of p53 and Rb that fail to suppress progression result in uncontrolled cell division, i.e. tumour development. 

In accordance with experimental observations, the model assumes that cells migrate by executing persistent random walks [49,121,122] as they go through their division cycle. In a uniform environment, the direction after each turn is randomly selected. However, cell movement can be biased to simulate chemotaxis or haptotaxis. If the cell does not collide with another cell, this persistent random movement continues until the end of the cell s current division cycle upon which the cell stops and divides into two daughter cells. Cell division is asynchronous and the distribution of cell division time tj is a measurable characteristic of each cell phenotype. 

If we are to understand phenomena such as tissue growth, cell differentiation, and organ development, we must first understand how spindle orientation or direction is regulated during nuclear division. Furthermore, we must understand how the cell cycle is started and stopped. The elucidation of these processes can probably be most readily achieved by using initially homogeneous populations of cells grown in axenic culture because such populations are those that can be most readily manipulated. Theoretically, if the details of the biochemical... 

---