Despite the lopsidedness of the introductory example, cell division is integral to the evolution and life of single-celled and multicellular life. The purpose of cell division in single-celled organisms is to duplicate the whole individual! In complex multicellular life forms, such as Homo sapiens, serial cellular divisions and differentiation give rise to extraordinary physiology from single-celled starting material. Also in humans, cell division occurs to regenerate certain tissues hence organs that degrade through time. Among these are our red blood cells, skin, hair, and certain glands. Many interesting factoids have been quipped about estimates of turnover during this process and other interesting phenomena. Check a couple out here and here. Most of my discussion will focus on eukaryotic cells and attempt to avoid these.
Dividing cells spend their time in one of two states, (1) Interphase (growth and duplication) and (2) mitosis (splitting into two new cells). These two processes can be broken down into a series of smaller phases. Overall, the cell cycle, or cell division cycle or however it may be called, always involves the following phases in sequential order under normal conditions: G1 phase, S phase, G2 phase, and mitosis. Here, G stands for "gap" so that G1 means "gap" 1, S stands for "synthesis," and G2 refers to "gap" 2. Beyond these, mitosis is traditionally split into several phases, itself. These, also in sequence, are termed (a) prophase, (b) prometaphase, (c) metaphase, (d) anaphase, and (e) telophase + cytokinesis. New cells formed during mitosis are called daughter cells. This early institution of organization may be helpful. On the contrary, you may be asking what I first asked when I heard these terms for the first time, "What does all this mean?" Discussing the cell ultrastructure involved often helps alleviate this pain. This will be touched on after describing the cell cycle.
While there are distinct phases of the cell cycle, all three non-mitotic phases are similar; in each, the cell grows as it duplicates chemicals, organelles and proteins. The S phase is unique, because it is the phase where DNA is duplicated. Interestingly, the S phase is considered the longest phase of the cell cycle, filling about half the total amount of time necessary for average human cell division (Campbell and Reece 2005).
Cell Cycle Regulation (van den Heuvel 2005; Campbell and Reece 2005; others)
The cell cycle is controlled by several different types of membrane-bound enzymes and other factors conserved (i.e., found) in most dividing animal cells. Studies indicate major importance of three or four different kinds of kinases and other genes in this mosaic of regulatory pathways. Also, the cell cycle may be controlled by extrinsic or intrinsic factors. Generally, external signals only regulate whether or not animal cells reproduce up to a point called the restriction point or G1 checkpoint. On the other hand, a number of important internal factors regulate the cell cycle intrinsically from this point.
The main paradigm of cell cycle control is one of activation-inactivation cycles generated by changes in the amounts of regulatory factors, cyclins and kinases. Kinases "activate" or "inactivate" different proteins controlling cell division by substrate-level phosphorylation at checkpoints such as the restriction point. Kinases themselves may also exist in active or inactive states corresponding to their position with respect to cyclins. Activated and inactivated kinases are attached or unattached to cyclins, respectively. This is why these kinases are called cyclin-dependent kinases, CDKs. As cyclins increase and decrease in thier relative concentrations in the cell (and CDKs remain relatively constantly concentrated), CDK activity changes disproportionately, with activity increasing abruptly after gap 2 then falling as cyclin is degraded during mitosis. Actually, synthesis of cyclins occurs from S phase through gap 2 phase. While cyclins are degraded, CDKs are thought to be recycled during this process. So, why is this a regulatory pathway anyway? Because without cyclin accumulation, mitosis is not signaled. An important CDK complex called "M-phase promoting factor" signals spindle formation, nuclear envelope breakdown, and chromosome condensing. Without these, M phase, thus the cell cycle, would never be completed.
MitosisAs I mentioned in an earlier post, DNA (of eukaryotes) is housed within the nuclei in the form of a substance called chromatin, in which histone proteins and tangled nucleotide strands are incorporated together. This chromatin is loosely distributed in long thin fibers. During S phase all the genetic material replicates itself, but chromatin is still in loose form. Later, during mitosis, the chromosomes condense and the cell actually divides. A unique set of machinery is involved in these processes. Most notably, cytoskeletal structures provide substrates (analogous to small roads or steady surfaces in the cell) for chromosomes to be transported along by motor proteins; also, centromeres play a pivotal role. Perhaps the best way to describe mitosis is the common way, or detailing the events at each phase of the process.
Prophase: The prefix pro- means this stage is "before, or preceding" the following other phases of mitosis. During prophase, chromatin is condensed into recognizable chromosomes. Originally, these were single units. After duplication and condensation they represent a pair, each called sister chromatids of the other. At the center of these chromatids is a region known as the centromere, which connects the chromatids, or copies of the original DNA molecule. Tan cuidado! The centrosome-centromere problem may confuse you. At the same time these chromatids assemble, the centrosomes begin sending out microtubules, which push the centrosomes farther apart by physical force.
Prometaphase: Here, the prefix meta- means "growth" or "unification, or important" phase, so this phase precedes the really unifying step. Prometaphase includes breakdown of the nuclear envelope (microfilaments and pore complexes), which degrade substantially to clear space for metaphase and anaphase. Also, the staging of the microtubules becomes much more complex, extending across the cell to connect with special structures formed at the centromeres, called kinetochores. Kinetochores are specialized proteins. There is a name for microtubules which are now very obvious in the cell--they're called spindles. Some spindles connect with kinteochores, others connect with other spindles across the cell.
Metaphase: Metaphase is one of the most time consuming and important phases of mitosis. During this time, chromosomes are aligned on a plane bisecting the distance between the centrosomes, which is termed the metaphase plate. It's not a real plate or plane, but rather an imaginary one. Microtubule spindles attach at kinetochores closest to them such that chromosomes line up with kinetochores facing each pole of the cell signified by centrosome position.
Anaphase: Ana- means "true" or "original." However true or original this step is, a fact is that it's the shortest phase of normal mitosis. It is during anaphase that the chromatids are ripped apart from one another by the microtubules, thus taken to their respective poles of the cell. For some reason--ah, because the end products are called daughter cells--the chromatids become called daughter chromosomes after this point. Remeber the spindles that hooked up with one another, not the kinetochores? At this point, those push off one another to help distance the chromosomes and increase the distance between the poles of the cell.
Telophase + Cytokinesis: Finally, telophase unites the genetic material of each daughter cell into an enclosed nucleus while cytokinesis splits the cytoplasm via invagination of the plasma membrane (involving microfilaments) and segregation of the fluid matrix making up the innermost cellular space. And mitosis is over, just like that. You can remember the order of these phases by memorizing the names, memorizing the prefix meanings, and or memorizing the order like this P2MAT.
Cell division from the standpoint of evolution and disease
According to Campbell and Reece (2005), "As eukaryotes evolved, along with their larger genomes and nuclear envelopes, the ancestral process of binary fission [bacterial division] somehow gave rise to mitosis." Researchers have actively been seeking answers to persistent questions about the mechanisms involved in mitosis. This work has included plants, many of which reproduce asexually through mitotic cell-lineages (Fagerstrom et al. 1998), as well as diatoms and bacteria.
Save the best for last. That ability is one of the greatest given to the human condition, and exactly what I think I've done waiting to talk about the coolest parts of the cell cycle, apoptosis and disease! Trust me on this one.
Scientists' understanding of CDKs' functions in cell cycle regulation and their interactions with other chemicals are just beginning to be explored. We have discussed what we know about what happens when things go right in cell cycling, but what about what we know about what happens when things go awry? For me, this was one of the most interesting and exciting facets of my introductory cell biology class. I hope your decision about which part of the cell cycle and its regulation, like mine, hinges upon the next few pieces of information.
If S phase replication goes wrong and DNA is damaged, this can have negative effects. So, cells halt the cell cycle by slipping into "gap zero" phase, or G0, while damaged components are repaired. Also, it is integral that mitotic spindle fibers attached to kinetochores, and the right ones at that. So, cells can halt motion to the next phase of the cycle in the even this happens. HOWEVER, if things don't get fixed or something else dysfunctions at these crucial times, the cell may induce suicide, or apoptosis (a.k.a., "programmed cell death").
An important gene regulating both of these processes is p53. p53 is in a special group of tumor suppressor genes, which keep the cell from slipping into cancerous states. Of course, I haven't talked about cancer. So, what I mean is that if things go awry (e.g., if DNA is damaged by an environmental factor instigated by a physical action, such as smoking), the cell may never be able to turn off (step into gap zero states or die via apoptosis), thus it may continue dividing infinitely with misreplicated genetic information. Cells in this state cause cancer by creating many clones of themselves (a tumor), which are harmful to the body because they fail to recognize tissue boundaries and may travel to other areas of the body, depleting normal tissues. p53 blocks the cell cycle by inactivating CDKs and has the power to induce programmed cell death in abnormal cells. WHEN p53 is doubly recessive (mutant), these functions are not carried out and cancer will develop beginning, perhaps, with a single damaged cell.
A report on wikipedia.com resounds a common statistic, that cancer is responsible for approximately 10-20% (13%) of all human deaths. In this way, we see that the cell cycle is not only important to our growth and complexity, but also that factors along the way play a critical role influencing our health and well-being. Similarly, mistakes during mitosis result in genetic variation among individual offspring of parents, ensuring natural selection has lots of material to work with in healthy populations. Now that you know so much about a process that led to your diversity and uniqueness, watch this time-lapse video of cell division!
References:
van den Heuvel, S. Cell-cycle regulation (September 21, 2005), WormBook, ed. The C. elegans Research Community, WormBook,
doi/10.1895/wormbook.1.28.1, http://www.wormbook.org.
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