The+Cell+Cycle

** The Cell Cycle **

**The Cell Cycle** **Stages, Mitosis, Cell Cycle Control, Cdk, and Telomeres**

**Madi Bader, Rohit Krishnan, and Michael Roytman**

**The Cell Cycle **

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//Above is a video that summarizes the different stages of the cell cycle and their purpose// [1].

__**What is the cell cycle?**__

The cell cycle is a process by which cell reproduce and divide to form genetically identical cells called daughter cells.

An animation by McGraw Hill that details both the different stages of the cell cycle can be found [|here]. Another McGraw Hill animation that discusses mitosis and cytokinesis in particular is located [|here].

__**What is the purpose of cell reproduction?**__

Depending upon the organism in question, cell reproduction can have a number of vital roles. For smaller, unicellular organisms such as the //Amoeba// cell division creates a new organism. For larger, multicellular organisms, cell division functions in the development of new organisms from a single cell – as in the case of sexually reproducing organisms – and in the renewal and repair of tissues and cells in the body in fully grown organisms.

__**What are some important terms to know before further discussion?**__



//The figure above explains the proper terminology to use in referring to chromosomes [2].//


 * **Chromatid**- A chromatid is one side or one half of a duplicated or replicated chromosome produced by chromosome replication during mitosis or meiosis. The two chromatids are held together by a centromere. They are referred to as sister chromatids, and a single chromosome as long as they are joined by their centromeres (before separation in the anaphase stage of mitosis or anaphase II stage of meiosis). After these stages, when the chromosomes are pulled apart, they become chromatids.


 * **Chromatin**- Chromatin is the complex of DNA and proteins that makes up a eukaryotic chromosome. It resembles a thin, long fiber and contains thousands of genes. The associated proteins in chromatin help maintain the DNA’s structure and regulate the activity of the genes. When the cell is not dividing, chromatin exists as a mass of very long, thin fibers that are not visible with a light microscope.


 * **Chromosomes**- Chromosomes contain chromatin and are threadlike, gene-carrying structures found in the nucleus. Each chromosome consists of one very long DNA molecule and associated proteins. Chromosomes are important because they compactly condense and package a cell’s DNA to facilitate cell division. Every eukaryotic species has a specific number of chromosomes.


 * **Genome** – A cell’s genome is the entirety of its genetic material – that is, its DNA.


 * **Histones**- Histones are small proteins with a high proportion of positively charged amino acids that bind to the negatively charged DNA and play a key role in its chromatin structure.


 * <span style="font-family: Arial,Helvetica,sans-serif;">**Kinetochore**- A kinetochore is a specialized region on the centromere that links each sister chromatid to the mitotic spindle.


 * <span style="font-family: Arial,Helvetica,sans-serif;">**Nucleosomes**- Nucleosomes are the basic, beadlike units of DNA packing in eukaryotes, consisting of a segment of DNA wound around a protein core composed of two copies of each of four types of histone.


 * <span style="font-family: Arial,Helvetica,sans-serif;">**Somatic cells –** Somatic cells are all cells in a multicellular organism with the exception of the reproductive cells. In humans, all somatic cells have 46 chromosomes.


 * <span style="font-family: Arial,Helvetica,sans-serif;">**Gametes** - Gametes are the reproductive cells of an organism and contain half the number of chromosomes as the somatic cells. In the case of humans, gametes have 23 chromosomes.


 * <span style="font-family: Arial,Helvetica,sans-serif;">**Sister chro****matids** – Sister Chromatids are two identical Chromatids which are held together by a centromere. Prior to the separation of the chromatids during mitosis, the Sister chromatids exist in their state for a short period of time.

<span style="font-family: Arial,Helvetica,sans-serif;">__**What are the stages of the cell cycle?**__

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//Above is an excellent interactive animation from Harvard University that details the different stages of the cell cycle. Click the play button in the lower right-hand corner to start the animation [3].//

<span style="font-family: Arial,Helvetica,sans-serif;">The cell cycle is composed of the following two main stages:
 * <span style="font-family: Arial,Helvetica,sans-serif;">Interphase
 * <span style="font-family: Arial,Helvetica,sans-serif;">Mitotic phase

<span style="font-family: Arial,Helvetica,sans-serif;">Within each of these two general phases there exist a number of other phases:
 * <span style="font-family: Arial,Helvetica,sans-serif;">Interphase:
 * G1
 * S
 * G2


 * <span style="font-family: Arial,Helvetica,sans-serif;">Mitotic phase:
 * Prophase
 * Prometaphase
 * Metaphase
 * Anaphase
 * Telophase
 * Cytokinesis

//"Above is a diagram that show the different parts of the cell cycle [4].//

<span style="font-family: Arial,Helvetica,sans-serif;">__**What happens in interphase?**__

<span style="font-family: Arial,Helvetica,sans-serif;">**Interphase** is the longest phase in the cell cycle, comprising approximately 90% of the cycle’s duration.

<span style="font-family: Arial,Helvetica,sans-serif;">During **interphase**, the cell grows and copies its chromosomes in order to prepare for the impeding cell division. Interphase is further divided into the following subsequent subphases: the G1 phrase, the S phase, and G2 phase.

<span style="font-family: Arial,Helvetica,sans-serif;">In all three subphases, the cell undergoes growth by producing proteins and cytoplasmic organelles.

In the **G1 phase**, which stands for “first gap,” the cell mainly undergoes the aforementioned growth in preparation for cell division. During the G1 phase, the biochemical processes related to cell growth accelerate; there is no specific length to the G1 phase, and the length of the phase determines how quickly the cell is dividing. [4] Before passing onto the rest of the cell cycle, the cell has to pass through a number of checkpoints in order to assess its readiness to continue the cell cycle. There is one of these checkpoints in the G1 phase, referred to as the G1 checkpoint. This checkpoint is the most important for many cells. These checkpoints will be discussed in more detail later.

<span style="font-family: Arial,Helvetica,sans-serif;">In the **S phase**, which stands for “synthesis of DNA,” the cell replicates its DNA, which is still in the form of chromatin, and continues to undergo cellular growth.

<span style="font-family: Arial,Helvetica,sans-serif;">In the **G2 phase**, which stands for “second gap,” the cell continues to grow. Like in the G1 phase, the cell has to pass a checkpoint before continuing to the M phase. These checkpoints will be discussed in more detail later.

<span style="font-family: Arial,Helvetica,sans-serif;">In the **G2 phase**, the replicated chromosomal DNA remains in the form of chromatin. The parent cell’s original centrosome has been replicated, and the two centrosomes remain outside of the nucleus. Animal cells’ centrosomes contain two centrioles, while plants cells’ centrosomes do not. From the centrosomes extend a number of microtubules in a star-like array referred to as asters.

<span style="font-family: Arial,Helvetica,sans-serif;">During the **G2 phase**, the nucleus is well-defined, the nuclear envelope remains intact, and there are one or more nucleoli.

<span style="font-family: Arial,Helvetica,sans-serif;">__**What are the stages of mitosis?**__

<span style="font-family: Arial,Helvetica,sans-serif;">Simply speaking, mitosis is the process by which the cell’s nucleus divides in two.





// The two figures above show graphic representations as well as light micographs that show the different stages of mitosis [5]. //

<span style="font-family: Arial,Helvetica,sans-serif;">Although mitosis is more of a gradual, spectral process, it can be divided into a number of subphases to facilitate clarity and understanding. Mitosis is normally divided into the following subphases: **prophase**, **prometaphase**, **metaphase**, **anaphase**, and **telophase**.

<span style="font-family: Arial,Helvetica,sans-serif;">In **prophase**, the now duplicated chromatin begins to change in form; the fibers of chromatin start to become more compactly coiled and condense into chromosomes. The cell’s genetic material now resembles a duplicated chromosome, composed of two sister chromatids joined at the center by a centromere. Also in the nucleus, the nucleoli disappear. Within the cytoplasm, changes also occur. The mitotic spindle begins to form and will eventually pull the chromosomes apart in nuclear division. The spindle network is made up of microtubules that originate from the two centrosomes, which begin to move toward the poles of the cell by the force of the microtubules forming between them.

<span style="font-family: Arial,Helvetica,sans-serif;">During **prometaphase**, the nuclear membrane disintegrates and the microtubules which emerge from the centromeres enter the chromosomes, which are the which are the condensed chromatin fibers. The chromosomes are now in the formation of sister chromatids and each chromatid is in the formation of a kinetochore. Some of the spindle fibers of the centrosome attach to the kinetochore.

<span style="font-family: Arial,Helvetica,sans-serif;">In the **metaphase** portion of the cell cycle, the spindle fibers connect with the kinetochores of the chromatids. These are called kinetochore microtubules and once connected, they begin the process of metaphase. Accounting for over 4% of the cell cycle, the metaphase involves the chromosomes aligning in the center of the cell to begin the separation into two daughter cells. In addition, the chromosomes' centromere aligns in the metaphase plate. They are evenly aligned in the middle by the evenly balanced pulling of the fibers. During the metaphase, there are still certain fibers in the prometaphase process.

<span style="font-family: Arial,Helvetica,sans-serif;">In the **anaphase**, which accounts for 1% of the cell cycle, the chromosomes move to opposite poles of the cell and is it triggered by the destruction of Cyclin. It is also started by the cleavage of the protein, securin, which occurs during the end of metaphase. The cleavage of securin promotes the secretion of separase. Separase then contributes to the separation of the sister chromatids.

<span style="font-family: Arial,Helvetica,sans-serif;">During the **telophas//e//**, the remains of the nuclear membrane in the parent cell, are then used in forming the membrane in the two newly forming cells. During this phase, two new daughter nuclei also form in the cell and the chromatids also decondense into chromatin. In a plant cell, the process of forming a cell wall also starts at this time. Telophase also occurs before the separation of the cell during cytokinesis.

<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: left;">//Mitotic Spindle// <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: left;">The mitotic spindle that begins to form during prophase is very important in mitosis, so it is important to understand its form and function in greater detail. The mitotic spindle is composed of fibers that are made up of microtubule and other related proteins. One theory that explains where the spindle comes from is that the cytoskeleton’s microtubules partially break apart and the fragments are used to create the spindle fibers, in addition to subunits of tubulin, which is a protein. <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: left;">The centrosome’s general purpose is to organize the cell’s microtubules, which explains why it is also often referred to as the “microtubule-organizing center.” This nonmembranous organelle’s structure differs between those of animal cells and those of plant cells. In animal cells, there exist two centrioles in the center of the centrosome, while most plants do not have centrioles in their centrosomes; this means that centrioles are not essential to cell division.

<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: left;">When a cell is in interphase, its centrosome is replicated. When mitosis begins, the two centrosomes are located near the nucleus and begin to move apart toward opposite poles of the cell during prophase and prometaphase. They are located at opposite poles of the cell, called spindle poles, by the end of prometaphase.

<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: left;">//Kinetochores// <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: left;">The kinetochore, like the mitotic spindle, is a cellular component vital to nuclear division. Kinetochores are structures of proteins and parts of chromosomal DNA that occur at the centromere of sister chromatids; each sister chromatid has a kinetochore, and they face in opposite directions. The kinetochore serves as an anchorage point for the spindle microtubules. When a cluster of spindle microtubules attach to the kinetochore sometime during prometaphase, the chromosome, centriole first, move in the direction of the microtubule. However, because microtubules from both sides attach to one of the two kinetochores, the movement of the chromosome is limited to a “tug-of-war-esque” movement. Because of this, the chromosomes eventually line up in the middle of the cell at a plane called the metaphase plate, which is an imaginary line equidistant from the poles of the cell.

<span style="font-family: Arial,Helvetica,sans-serif;">The kinetochores are important to nuclear division in anaphase. Anaphase begins when the proteins holding together the chromosomes’ sister chromatids become inactivated, allowing the chromatids to separate and become individual chromosomes. Once this occurs, the chromosomes begin to move toward opposite poles of the cell. It is hypothesized that this occurs by means of motor proteins within the kinetochore of each centriole. It is believed that the motor proteins move a kinetochore along the spindle fibers toward whichever spindle pole is closest. As this occurs and the chromosomes approach the cell’s pole, the ends of the microtubules depolymerize into tubulin subunits.

<span style="font-family: Arial,Helvetica,sans-serif;">Microtubules that do not attach to kinetochores, also called nonkinetochore microtubules, are also important during mitosis. In animal cells, the microtubules lengthen and extend toward the opposite end of the cell, forcing the cell to elongate in preparation for cytokinesis. The lengthening of the microtubule occurs by motor proteins attached to the microtubules, which use ATP energy to drive the microtubules past one another, and by the addition of tubulin subunits to their ends.

<span style="font-family: Arial,Helvetica,sans-serif;">In **prometaphase**, the material within the chromosomes continues to condense.

<span style="font-family: Arial,Helvetica,sans-serif;">The microtubules of the mitotic spindle begin to extend toward the center of the cell. Because the nuclear envelope has begun to disintegrate, the microtubules are able to enter the former nuclear region and interact with the chromosomes. The centromere region of the chromosomes now has two kinetochores, one for each sister chromatid, structures that allows a cluster of mitotic spindle fibers to attach to the chromosomes. The microtubules that do not attach to the chromosomes, called nonkinetochore microtubules, interact with those that extend from the other centrosome.

<span style="font-family: Arial,Helvetica,sans-serif;">In **metaphase**, the centrosomes have migrated to opposite poles of the cell. Attached to the spindle fibers, the chromosomes have moved to the center of the cell, and have horizontally lined up their centromeres along an imaginary line called the metaphase plate, which is equidistance from the poles of the cell.

<span style="font-family: Arial,Helvetica,sans-serif;">In **anaphase**, the chromosomes composed of two sister chromatids, separate at the centromere and become chromosomes. Once the sister chromatids have separated from each other, the kinetochore microtubules begin to shorten, drawing the chromosomes toward the centrosomes. While the kinetochore microtubules shorten, the nonkinetochore microtubules grow in length, causing the cell to begin to stretch. At the end of anaphase, the opposite poles of the cell now contain equal numbers of chromosomes.

<span style="font-family: Arial,Helvetica,sans-serif;">There is a checkpoint in the anaphase subphase of the M phase of the cell cycle. This checkpoint essentially ensures that the daughter cells receive the correct number of chromosomes.

<span style="font-family: Arial,Helvetica,sans-serif;">In **telophase**, the nonkinetochore microtubules continue to lengthen and expand the cell. At opposite end of the expanded cell, two daughter nuclei begin to form, using pieces of the original parent cell’s fragmented nuclear envelope and other parts of the cell’s endomembrane system. At the same time, the chromatin that makes up the cell’s chromosomes begins to uncoil.

<span style="font-family: Arial,Helvetica,sans-serif;">__**What is cytokinesis?**__

<span style="font-family: Arial,Helvetica,sans-serif;">Cytokinesis is the last part of the mitotic phase of the cell cycle and is the portion of the cycle in which the cell divides in half.

<span style="font-family: Arial,Helvetica,sans-serif;">__**How does cytokinesis occur in animal cells and plant cells?**__

<span style="font-family: Arial,Helvetica,sans-serif;">The process of cytokinesis is different in animal cells and plant cells.

<span style="font-family: Arial,Helvetica,sans-serif;">In animal cells, cytokinesis occurs by means of a process called cleavage. In this process, a contractile ring of actin microfilaments forms, and when it interacts with molecules of the protein myosin, it contracts. This ring forms a cleavage furrow, a shallow indentation in the cell’s membrane near the old metaphase plate. As the contractile ring contracts and the cleavage furrow deepens, eventually the cell is split in half, forming two identical daughter cells.

<span style="font-family: Arial,Helvetica,sans-serif;">Because, unlike animal cells, plant cells have cell walls, the process of cytokinesis is different. In plant cells, a cell plate is formed in the center of the expanded cell through the deposition of cell wall materials by vesicles from the Golgi apparatus. As the vesicles collect in the center of the cell, a cell plate is formed, which eventually grows and fuses with the plasma membrane of the original cell, creating a cell wall and cell membranes on either side, which divides the parent cell into two daughter cells.



The diagram above shows the differences in cytokinesis between animal and plant cells [6].

<span style="font-family: Arial,Helvetica,sans-serif;">__**How has mitosis evolved?**__

<span style="font-family: Arial,Helvetica,sans-serif;">Given that prokaryotes preceded the emergence of eukaryotes by billions of years, it is very likely that mitosis evolved from cell reproduction in prokaryotic organisms, namely bacteria. Cellular reproduction in bacteria is referred to as binary fission, which means “division in half.”

<span style="font-family: Arial,Helvetica,sans-serif;">The current understanding of binary fission is explained in the diagram below.



//The diagram above illustrates the process of binary fission, or cellular division, in bacteria [7].//

<span style="font-family: Arial,Helvetica,sans-serif;">The evolutionary basis for mitosis is hypothesized in the figure below. It summarizes both binary fission and mitosis and two hypothetical evolutionary steps in between the two: the cellular reproduction if dinoflagellates and diatoms.



//The figure above explains the proposed evolutionary path that prokaryotic binary fission has taken in evolving into mitosis [8].//

** Cell Cycle Control **

<span style="font-family: Arial,Helvetica,sans-serif;">__**Is the cell cycle controlled or regulated in any sense?**__

<span style="font-family: Arial,Helvetica,sans-serif;">Yes. In fact, although different types of cells undergo cell division with different frequency, the regulation of the cell cycle is paramount to the healthy functioning of a cell, and in a larger sense, the organism to which the cell belongs.

<span style="font-family: Arial,Helvetica,sans-serif;">__**How does the cell control and regulate the cell cycle?**__

<span style="font-family: Arial,Helvetica,sans-serif;">Modern science’s understanding of how the cell cycle is moderated is that it is controlled by chemical signals that exist in the cell’s cytoplasm. In this way, a cell’s cycle is controlled by a cell cycle control system, which is a “cyclically operating set of molecules in the cell that both triggers and coordinates key events in the cell cycle.” Although this system is able to proceed on its own, “driven by a built-in clock,” it is also “regulated at certain checkpoints by both internal and external controls.”

<span style="font-family: Arial,Helvetica,sans-serif;">__**What are cell cycle checkpoints?**__

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//Above is an excellent interactive animation from Harvard University that summarizes the different checkpoints in the cell cycle. Click the play button in the lower right-hand corner to start the animation [9].//

<span style="font-family: Arial,Helvetica,sans-serif;">A cell cycle checkpoint is a point in the cell cycle where the cycle can be regulated by either signaling a cell to continue the cycle or to stop. In the case of animal cells, cells have built-in signals that stimulate the cell cycle to stop at given checkpoints. Until that signal is overridden by a go-ahead signal, the cell will not continue the cell cycle. The purpose of a checkpoint is in part to allow signals to check whether or not processes paramount to a successful completion of the cell cycle has been undergone and whether the cell is ready to proceed.

<span style="font-family: Arial,Helvetica,sans-serif;">The three main checkpoints, as mentioned in the discussion of the stages of the cell cycle, occur in the G1, G2, and M phases.

Of these three checkpoints, it appears that the G1 checkpoint is the most important for many cells; in fact, it is so important that it is referred to as the “restriction point” in mammalian cells. The term represents the fact that the G1 is often an ultimate checkpoint in the sense that if a cell received a go-ahead signal at this point, it will usually complete the cycle, and if it does not, it will exit the cycle by entering a nondividing state referred to as the G0 state. The G1 cell checkpoint essentially checks whether a cell is ready to replicate its chromosomes in the S phase [10].

The G2 cell checkpoint exists to check whether the cell is ready to divide its sister chromatids during the M phase. [10]

The M phase cell checkpoints checks the accuracy of the mitosis and signals the cells exit from mitosis. [11]

<span style="font-family: Arial,Helvetica,sans-serif;">Most cells in the human body are in the G0 state, including highly specialized nerve and muscle cells and liver cells, unless induced to re-enter the cell cycle.



//The above diagram shows a schematic of where in the cell cycle the main checkpoints appear [12].//

<span style="font-family: Arial,Helvetica,sans-serif;">__**What are cyclins and cyclin-dependent kinases? How do they function in regulating the cell cycle’s built-in clock?**__

<span style="font-family: Arial,Helvetica,sans-serif;">The events in the cell cycle, including the cell cycle checkpoints, are regulated by fluctuations in the chemical control molecules. These regulatory molecules exist largely in two varieties: protein kinases, enzymes that serve to activate or inactivate other proteins through phosphorylation, and cyclins.

<span style="font-family: Arial,Helvetica,sans-serif;">Cyclins are important because most of the kinases that regulate the cell cycle are constantly ubiquitous in the cell, but because they are often in inactive form, they do not become functional until they are activated. To become activated, these kinases must be attached to a cyclin protein, whose concentration in the cell fluctuates. For this reason, these kinases are also referred to as cyclin-dependent kinases, or Cdks. Like many other signal molecules, the activity of Cdks alternate according to changes in the concentration of its cyclin.

<span style="font-family: Arial,Helvetica,sans-serif;">In order to understand the way Cdks function, it is helpful to consider the first cyclin-Cdk complex to be discovered by scientific researched, MPF. MPF stands for “M-phase-promoting factor.” MPF functions to stimulate the cell’s transition into M phase from the G2 checkpoint. As is shown in the figures displayed below, as the concentration of the associated cyclin rises, the Cdk partners with the cyclin to form a MPF complex which initiates the cell’s transition into the M phase by phosphorylating a number of different proteins.

//The figure above explains the linkage between cyclins and Cdks in the case of MPF and shows how the cyclin-Cdk complex induces passage into the M phase from the G2 phase [13].// <span style="font-family: Arial,Helvetica,sans-serif;">A number of other Cdk proteins and their cyclin partners are involved in regulating all stages of the cell cycles; for example, at least three Cdk proteins are believed to be involved in controlling the G1 checkpoint. Some of these other Cdk proteins are summarized below.

<span style="font-family: Arial,Helvetica,sans-serif;">**MPF (Maturation Promoting Factor)** - This triggers progression of the cell cycle and includes both a cyclin and Cdk. <span style="font-family: Arial,Helvetica,sans-serif;">**p53** - This is a protein that blocks the cell cycle if DNA is damaged. It can also initiate apoptosis (programmed cell death). <span style="font-family: Arial,Helvetica,sans-serif;">**p27** - This is a protein that binds to both cyclin and Cdk to block entry into the S phase of the cell cycle [14]

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">__**What, in specific, to cyclin-dependent kinases do?**__

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Despite the sophistication of modern day science, scientific researchers do not yet have a complete understanding of exactly that Cdks do. They do, however, know some steps of the signaling pathways involved in the cell cycle, including internal signals such as kinetochore messages and external signals such as growth factors.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">__**How do internal and external controls regulate the cell cycle?**__


 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">//Internal Signals: Messages from Kinetochores// **

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">As was discussed earlier, kinetochores are the cellular components of chromosomes, located in the centromeres, to which the spindle microtubules begin to attach during prometaphase. Kinetochores are also important because they can delay anaphase if all the kinetochore microtubules have not attached to the chromosomes.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">During anaphase, the sister chromatids separate and the individual chromosomes are pulled in the direction of the kinetochore poles. However, if all the kinetochore microtubules have not attached to the chromosomes, anpahase will nto continue. This is due to a signal released by the kinetochores, which triggers a pathway that inactivates anaphase-promoting complex (APC). Once all the kinetochore microtubules have attached to the kinetochores, APC is activated and goes on to trigger the breakdown of the cyclin and the inactiviation of the proteins that hold together the sister chromatids.


 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">//External Signals: Growth Factors// **

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">The cell cycle, like cells in general, also responds to physical and chemical signals. One of these signals is a growth factor.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Growth factors are proteins that signal other cells to divide. Therefore, growth factors can affect and regulate the progression of the cell cycle. An example of a growth factor that stimulates cell division is platelet-derived growth factor (PDGF). This protein, created by platelets in the blood, encourages the division of fibroblasts near wounds to promote healing.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Growth factors are also important in regulating cell division in density-dependent inhibition and anchorage dependence, which are other ways of regulating cell growth to maintain cells at an “optimal density and location.”

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Density-dependent inhibition is the cessation of cell division when a single layer of cells has proliferated on a surface. The cells stop dividing in part because there are no longer enough growth factors.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Anchorage dependence is the process by which cells will not divide unless they are attached to a surface. A cell’s “anchorage status” is relayed to the cell cycle control mechanisms by various proteins of the cytoskeleton and plasma membrane.

**<span style="color: #ff0000; display: block; font-family: Arial,Helvetica,sans-serif; font-size: 200%; text-align: center;">Telomeres **

// Above is an artistic rendering of chromosomes; the pink highlighted portions on the ends of the chromosomes' arms represent the telomeres [15]. //

<span style="font-family: Arial,Helvetica,sans-serif;">__**What are telomeres?**__

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Telomeres are strands of repeated DNA sequences at the end of chromosomes or the ends of the arms. Telomeres exist to preserve DNA from degradation. Because of the structure of eukaryotic DNA, which is linear, - unlike prokaryotic DNA, which does not have this problem – the replication of DNA produces shorter and shorter DNA strands. Consequently, continued replication of DNA would theoretically erode the ends of the DNA strand and result in a loss of critical parts of the genome. The diagram below explains this end-replication problem.

//The diagram above details the end-replication problem and why successive DNA replications lead to shortened chromosomes [16].//

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<span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 10pt; text-align: center;">//Above is an excellent video that details the end-replication problem discussed above and explains how telomeres function to preserve the ends of chromosomes from degradation [17].//

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Telomeres aim to solve this potential problem by extending the length of DNA strand and preventing accidental chromosomal fusions, which ensures stability. A telomere is a short, non-gene-containing DNA sequence that is repeated from around 100 to 1,000 times per DNA strand in humans, reaching a length of up to 15,000 base pairs [18]. The entire telomere fragment, including all the repeated segments, is referred to as the terminal restriction fragment (TRF) [19]. In eukaryotes, the typical telomere unit is the six-nucleotide sequence TTAGGG. Primitive eukaryotes have sequences different than the typical TTAGGG [19].



<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">//Above is a microscopic photo of actual human chromosomes; the white portions are the telomeres [20].//

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Because telomeres are single-stranded nucleotide sequences, the cell’s DNA monitoring system should be triggered by this “double-strand break,” but because of the telomeric DNA and its associated proteins, somehow this monitoring system is not activated, which allows for the telomeres to exist undisturbed.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Essentially, “t elomeres function by protecting chromosome ends from recombination, fusion to other chromosomes, or degradation by nucleases [or the end-replication problem]. They permit cells to distinguish between random DNA breaks and chromosome ends. They also play a significant role in determining the number of times that a normal cell can divide. Unicellular forms whose cells have no true nuclei (prokaryotes) possess circular chromosomes that, therefore, have no ends. Thus, prokaryotes can have no telomeres [19].”

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">__**What is telomerase?**__

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Obviously, eventually the telomeres themselves become eroded by successive DNA replications – around 25-200 base pairs are lost in each cell division [18]. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">When the telomeres are eroded to a certain point, the chromosomes reach a “critical length”, which means that they are no longer able to replicated [18]. When this happens, a cell dies via a process called apoptosis, which is essentially programmed cell death [18]. Therefore, there needs to be a method by which eukaryotic organisms re-extend the length of their telomeres. The enzyme telomerase, also known as telomere terminal transferase [18], does this by catalyzing the extension of telomeres. Telomerase is unique in that it carries with it a small strand of RNA that acts as a DNA template for new telomeres. An enzyme that transcribes a single strand of RNA into a single strand of DNA, as telomerase does, is classified as a reverse transcriptase or a RNA-dependent DNA polymerase [21][22].



// The figure above graphically shows how telomerase extends the length of the chromosomal DNA [23]. //

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Although theoretically telomerase sounds extremely useful and promising, most multicellular organisms' cells do not contain telomerase at useful levels after conception. Telomerase is present in “fetal tissues, [stem cells], adult germ cells [which are gamete-producing cells], and tumor cells,” but it is present in “very low, almost undetectable” concentrations and activity levels in somatic cells [18]. At conception, all human cells are able to express tolemerase, but as human embryos and fetuses develop in the womb, telomerase begins to become repressed “in all but the germ cells and stem cell populations” [19]. In fact, as adults, the only non-cancerous, adult, somatic cells that express telomerase are cells in stem cell populations “found, for example, in skin, the hematopoeitic system, germ cells, and gut epithelia [19]."

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">__**How is telomerase important to cell aging and the progression of cancer?**__

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">For this reason, somatic, or body, cells do not have a way to replenish their telomeres. This means that they undergo senescence, or cell aging [18]; ever-shortening telomeres are linked to the limited life span of given tissues and even of the organism as a whole. That is why a hefty portion of scientific research is invested in studying the nature of telomerase; it yields promise in extending our life spans and retarding the aging process.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Telomerase also seems to be important in preserving the life spans of cancerous tumors. In fact, 90% of all human tumors appear to produce telomerase. [19] “ In fact, the presence or absence of telomerase is the most specific property that distinguishes cancer cells from normal cells.” [19]

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">Theoretically speaking, the cells contained in a tumor have been dividing extensively and should be approaching the end of their life spans due to shortened telomeres. However, in cancer cells, telomerase is 10-20 times more active that in somatic cells [18], which means that cancer cells do not age and naturally die, effectively making them “immortal.” This is because cancer cells switch on a gene that expresses telomerase [19]. Scientific researchers are currently searching for ways to turn off telomerase activity, which would prevent cancer cells from diving uncontrollably in their beginning development stages. In already developed tumors, telomerase could be removed to encourage the eventual death of the tumor, and anti-telomerase therapies could be employed to avoid relapse of the cancerous tumor [18].

media type="youtube" key="5PU_jZwt8KY" height="315" width="420" align="center"

<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">//Above is part one of a video of a lecture made by Elizabeth Blackburn on telomeres and telomerase and their roles in human physiology. Blackburn is won a Nobel Prize for her work on telomeres, so she really knows her stuff! The lecture is rather long and consists of three parts. For those interested in continuing to view the lecture, click the YouTube button in the lower right-hand corner and follow the links to parts two and three in the right-hand sidebar [24].//

<span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 10pt; text-align: center;">**Review Questions** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">**1. In which phase would the nucleoli begin to reappear?** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) Prophase <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) Prometaphase <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) Telophase <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) The nucleoli does not reappear

**<span style="font-family: Arial,Helvetica,sans-serif;">2. The Cyclin Dependent Kinase binds to which of these? ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) Cyclins <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) Telomeres <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) Phosphates <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) ATP

**<span style="font-family: Arial,Helvetica,sans-serif;">2. Which of these is the restriction point? ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) G0 Phase <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) Chromatins <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) Centromeres <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) G1 Phase

**<span style="font-family: Arial,Helvetica,sans-serif;">3. Cdk binds with the Cyclins to form ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) Phosphates <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) ATP <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) MPF <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) Proteins

**<span style="font-family: Arial,Helvetica,sans-serif;">4. P53 is a protein which functions in ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) Increased MPF <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) Stopping the cell cycle <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) Increased CDK’s <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) Organelle synthesis

**<span style="font-family: Arial,Helvetica,sans-serif;">5. The mitotic spindle begins to form during ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) prophase <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) metaphase <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) anaphase <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) telophase

**<span style="font-family: Arial,Helvetica,sans-serif;">6. A cellular component vital to nuclear division is the ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) flagella <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) cilia <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) kinetochore <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) cell wall

**<span style="font-family: Arial,Helvetica,sans-serif;">7. In prometaphase, the material within the chromosomes ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) replicates <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) continues to condense <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) expands <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) disintegrates

**<span style="font-family: Arial,Helvetica,sans-serif;">8. Cells mainly replicate for ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) reproduction of the species <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) growth purposes <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) maintenance and repair <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) all of the above

**<span style="font-family: Arial,Helvetica,sans-serif;">10. A karyotype is ** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">a) a list of chromosomal data from a single cell <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">b) a photographic representation of the mutations in a set of chromosomes <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">c) another word for a chromosome <span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">d) a photographic representation of an entire set of chromosomes from a single cell

<span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 10pt; text-align: center;">**Essay Question**

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 10pt;">** How has natural selection contributed to the development of checkpoints during the cell cycle? Use at least 3 examples. Discuss the current process of animal cell division during mitosis in your answer. **

<span style="color: #000000; display: block; font-family: Arial,Helvetica,sans-serif; font-size: 10pt; text-align: center;">**Annotated Links**

[|This is a website with succinct explanations and pictures of each stage of the cell cycle. It is a great place to start if you are looking to get an introduction to the cell cycle.]

[|This is a website with an excellent animation that details the different stages of the cycle. It certainly helps to clearly illustrate what happens in each stage of mitosis, especially.]

[|This website has an interesting read in the “What is the cell cycle” section on the front page. It goes into a bit more detail about what happens during the different stages of the cell cycle.]

[|This website features a good overview of all aspects of both the prokaryotic and eukaryotic cell division cycles.]

[|This website is an excellent resource for learning all about the cell cycle, among other numerous topics. Each topic is divided into basic, intermediate, and advanced content, so you can the reading level and content that is most suitable for you.]

[|This website has a number of simple, introductory animations to familiarize individuals with the cell cycle and mitosis. It is definitely a useful resource to see mitosis in action.]

[|This is an animation featuring dialogue that gives an overview of the three main checkpoints in the cell cycle.]

[|This is an animation that also talks about cell checkpoints.]

[|This is an excellent game released by the official website for the Nobel Prize that helps to explain how the cell cycle is controlled. Not only is it fun, but it’s also educational. Yay!]

[|This is a website that discusses cancer, but it also has a very detailed, informative page about the cell cycle and the control mechanisms that govern it, especially in terms of cyclins and cyclin-dependent kinases.]

[|This website has a great outline that explains what telomeres are, what they do, and where they are applied.]

<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: center;">Sources [1] http://www.youtube.com/watch?v=lf9rcqifx34&feature=player_embedded

[2] Figure 12.3 Chromosome duplication and distribution during mitosis. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 217. Print.

[3] "The Cell Cycle." //Harvard U Outreach//. N.p., n.d. Web. 13 Mar. 2012.<http://outreach.mcb.harvard.edu/animations/cellcycle.swf>.

[4] Figure 12.4 The cell cycle. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 217. Print

[5] Figure 12.5 The stages of mitotic cell division in an animal cell. //Biology//. By Neil A.

Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 218-219. Print.

[6] Figure 12.8 Cytokinesis in animal and plant cells. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 222. Print.

[7] Figure 12.10 Bacterial cell division (binary fission). //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 224. Print.

[8] Figure 12.11A hypothesis for the evolution of mitosis. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 224. Print.

[9] "Checkpoints and Cell Cycle Control." //Harvard U Outreach//. N.p., n.d. Web. 13 Mar. 2012. <http://outreach.mcb.harvard.edu/animations/checkpoints.swf>.

[10] "Cyclin-dependent kinases and the cell cycle." //Genetics//. Ed. Richard Robinson. New York: Macmillan Reference USA, 2010. //Gale Science In Context//. Web. 13 Mar. 2012.

[11] "Control of Cell Cycle." //1Lec//. N.p., n.d. Web. 13 Mar. 2012. <http://www.1lec.com/Genetics/Cell%20Cycle/index.html>.

[12] Figure 12.13 Mechanical analogy for the cell cycle control system. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 226. Print.

[13] Figure 12.14 Molecular control of the cell cycle at the G2 checkpoint. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 227. Print.

[14] "The Cell Cycle & Mitosis Tutorial." //The Biology Project//. Dept. of Biochemistry and Molecular Biophysics U of Arizona, Aug. 2004. Web. 13 Mar. 2012. <http://www.biology.arizona.edu/cell_bio/tutorials/cell_cycle/cells2.html>.

[15] SpectraCell Laboratories Inc. "Telomere Lengthening Captures the Attention of ABC News and the World." //SpectraCell Blog//. SpectraCell Laboratories - Advanced Clinical Testing, 9 Dec. 2010. Web. 13 Mar. 2012. <http://info.spectracell.com/bid/50775/Telomere-Lengthening-Captures-the-Attention-of-ABC-News-and-the-World>.

[16] Figure 16.18 The end-replication problem. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 300. Print.

[17] http://www.youtube.com/watch?v=AJNoTmWsE0s&feature=player_embedded

[18] "Facts about Telomeres and Telomerase." //Shay/Wright Laboratory//. The U of Texas Southwestern Medical Center, n.d. Web. 13 Mar. 2012. <http://www4.utsouthwestern.edu/cellbio/shay-wright/intro/facts/sw_facts.html>.

[19] "Telomere." //Genetics//. Ed. Richard Robinson. New York: Macmillan Reference USA, 2008. //Gale Science In Context//. Web. 13 Mar. 2012.

[20] "Telomere." //Wikipedia//. Wikipedia, 9 Mar. 2012. Web. 13 Mar. 2012. <http://en.wikipedia.org/wiki/Telomere>.

[21] "Reverse Transcriptases." //Restriction Endonucleases and DNA Modifying Enzymes//. Colorado State U,n.d. Web. 3 Jan. 2000. <http://www.vivo.colostate.edu/hbooks/genetics/biotech/enzymes/rt.html>.

[22] Nugent, Constance I, and Victoria Lundblad. "The telomerase reverse transcriptase: componentsand regulation." //Genes & Development// 12 (1998): n. pag. //Genes & Development//. Web. 13 Mar.2012. <http://genesdev.cshlp.org/content/12/8/1073.full#cited-by>.

[23] Figure 16.19 Telomeres and telomerase. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 300. Print.

[24] http://www.youtube.com/watch?v=5PU_jZwt8KY&feature=player_embedded <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[1] http://www.youtube.com/watch?v=lf9rcqifx34&feature=player_embedded <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;"> [2] Figure 12.3 Chromosome duplication and distribution during mitosis. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 217. Print. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;"> [15] SpectraCell Laboratories Inc. "Telomere Lengthening Captures the Attention of ABC News and the World." //SpectraCell Blog//. SpectraCell Laboratories - Advanced Clinical Testing, 9 Dec. 2010. Web. 13 Mar. 2012. <http://info.spectracell.com/bid/50775/Telomere-Lengthening-Captures-the-Attention-of-ABC-News-and-the-World>. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[16] Figure 16.18 The end-replication problem. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 300. Print. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[17] http://www.youtube.com/watch?v=AJNoTmWsE0s&feature=player_embedded <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[18] "Facts about Telomeres and Telomerase." //Shay/Wright Laboratory//. The U of Texas Southwestern Medical Center, n.d. Web. 13 Mar. 2012. <http://www4.utsouthwestern.edu/cellbio/shay-wright/intro/facts/sw_facts.html>. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[19] "Telomere." //Genetics//. Ed. Richard Robinson. New York: Macmillan Reference USA, 2008. //Gale Science In Context//. Web. 13 Mar. 2012. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[20] "Telomere." //Wikipedia//. Wikipedia, 9 Mar. 2012. Web. 13 Mar. 2012. <http://en.wikipedia.org/wiki/Telomere>. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[21] "Reverse Transcriptases." //Restriction Endonucleases and DNA Modifying Enzymes//. Colorado State U,n.d. Web. 3 Jan. 2000. <http://www.vivo.colostate.edu/hbooks/genetics/biotech/enzymes/rt.html>. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[22] Nugent, Constance I, and Victoria Lundblad. "The telomerase reverse transcriptase: componentsand regulation." //Genes & Development// 12 (1998): n. pag. //Genes & Development//. Web. 13 Mar.2012. <http://genesdev.cshlp.org/content/12/8/1073.full#cited-by>. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[23] Figure 16.19 Telomeres and telomerase. //Biology//. By Neil A. Campbell and Jane B. Reece. Ed. Beth Wilbur. 6th ed. San Francisco: Benjamin Cummings, 2002. 300. Print. <span style="display: block; height: 1px; left: -40px; overflow-x: hidden; overflow-y: hidden; position: absolute; top: -25px; width: 1px;">[24] http://www.youtube.com/watch?v=5PU_jZwt8KY&feature=player_embedded