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The Cell Cycle

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Amanda Sul

on 6 October 2011

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Transcript of The Cell Cycle

The Cell Cycle The cell cycle is started by an extracellular signal, mitogen. Mitogen is a form of a signaling molecule that binds to the receptor on the cell to activate the cell cycle. START: The transmembrane protein, Receptor Tyrosine Kinase (RTK) becomes activated by a mitogen, a signaling molecule. Once RTK is activated, it activates the Grb-2 protein that activates the Ras GEF protein. Once Ras GEF protein becomes activated, it sends signal to the Ras protein to make activate the Ras protein. GDP in Ras protein is replaced by GTP and Ras is able to become activated. Activated Ras protein then sends signal activating Mitogen Activated Protein (MAP) Kinase-Kinase-Kinase, which is RAF in the pathway of making c-myc transcription factor. RAF is then able send a signal to phosphorylate MEK, MAP Kinase-Kinase and activated RAF sends a signal and adds a phosphate onto ERK, MAP Kinase. Activated MAPK is then able to activate c-myc through phosphorylation. Through MAPK pathway, c-myc, a transcription factor becomes activated and it is able to transcribe and produce cyclin D. pRb E2F DP E2F is a transcription factor for S phase genes and it is in a complex with DP. Under normal conditions when there is no extracellular signals, c-myc isn't activated therefore, cyclin D is not transcribed. In this case, pRb is bound to E2F and DP complex, inhibiting E2F from transcribing s phase genes. When cyclin D is produced, it binds with Cyclin Dependent Kinase (CDK) 2 and together they form an active protein complex. This complex is then able to phosphorylate pRb. Phosphorylation of pRb will allow pRb to release E2F complex and this will lead to transcription of some of the s phase genes. One of these genes is cyclin E. c-myc cyclin D CDK 4 Receptor Tyrosine Kinase (RTK) mitogen Grb-2 adaptor
protein Ras GEF Ras protein
(inactive) Ras protein
(active) c-myc
(inactive) c-myc
(active) RAF
(inactive) RAF
(active) MEK
(inactive) MEK
(active) ERK
(inactive) ERK
(active) pRb cyclinD CDK4 DP E2F cyclin E Under an active CDK4/cyclin D complex, cyclin E is transcribed and cyclin E binds with CDK2. This complex allows for hyperphosphorylation of pRb. When pRb is hyperphosphorylated, E2F protein complex will be able to transcribe all the S phase genes. Rest of these S phase genes include cyclin A, CDC25A, CDCG, DHFR, TK (thymidine kinase) 1, and p16. cyclin E CDK2 pRb DP E2F cyclin A p16 cyclin D p16 CDK4 p16 is transcribed by E2F and this protein functions to regulate CDK4 and cyclin D complex. Because CDK4 has a higher affinity to p16, when p16 is present cyclin D is not able to bind with CDK4. This would inhibit the formation of CDK4 adn cyclin D complex and therefore, this would no longer be able to phosphorylate pRb. It is important that there is a decrease in amount of cyclin D and its complex, because s phase genes that induce replication should not be expressed after the cell has entered the S phase. cyclin A CDK2 DP E2F CDK2 can also form a complex with cyclin A. When these two are bound together, they are able to phosphorylate DP. This would cause DP to become inactivated and detach from E2F. If DP is no longer attached to E2F, this would inhibit the function of E2F. cyclin A CDK2 B-myb
(inactive) B-myb
(active) B-myb cyclin B CDK2 and cyclin A complex can also phosphorylate and activate B-myb, which is a transcription factor for cyclin B. cyclin A CDK2 APC cdh1 Anaphase Promoting Complex (APC), allows the cell to go through anaphase. CDK2 and cyclin A complex regulates the function of APC by phosphorylating chd1, which is attached to APC. When cdh1 is phorsphorylated, it is inactive and APC is inhibited from inducing anphase. APC is regulated until the cell has built up enough cyclin B to go through mitosis. cyclin B cyclin B cyclin B cyclin B cyclin B cyclin B cyclin B CDK 1 CDK 1 CDK 1 CDK 1 CDK 1 CDK 1 CDK 1 CDC25 CDC25 CDC25 CAK wee1 cyclin B cyclin B CDK 1 CDK 1 PLK-1 PLK-1 PLK-1 cyclin A CDK2 Activated CDK2/cyclin A complex then can activate a phosphatase
called Polo-Like Kinase1 (PLK-1). This phosphatase is then able to remove
a phosphate from T-161 region on MPF (CDK1/cyclin B complex).
This process is essential in order to activate MPF. After cyclin B has been transcribed, it binds to CDK1, which is another s phase gene transcribed by family of E2F. When CDK1 and cyclin B are bound together, they form a Maturation Promotion Factor or also know as Mitosis Promoting Factor (MPF). When these two are first bound together, they are slightly active. There are two phosphorylation regions, T-161 and y15, on CDK1. Wee1, which is another kinase, binds a phosphate onto y-151 region of CDK1. Wee1 works as an inhibitor of CDK1 and when a phosphate is bound on T-161, this inhibits the function of MPF. CDK Activating Kinase (CDK) adds a phosphate onto y15 region on CDK1. Phosphorylation on y15 region is necessary for the MPF to actually become fully active, but since a phosphate is bound on T161, MPF is still inhibited. Another way that MPF can become active is through activation of CDC25, which is an indirect to activate MPF. CDK1/Cyclin A complex phosphorylates PLK-1 and PLK-1 phosphorylates CDC25 in turn activating CDC25. CDC25 is a phosphatase that can remove a phosphate from T-161 region of CDK1. This will allow for MPF to become activated. 1. Activated MPF is able to phsophorylate other proteins and start a cascade that will lead to the activation of condensin. (Condensin is a complex of proteins that is used to loop the DNA into its structure. Condensin loops DNA around an octamer, which is two sets of histones and this octamer is positively charged so it binds to negatively charged DNA. This gives the DNA a chromosomal structure.)

2. Activated MPF is able to phosphorylate myosin and make myosin inactive. (myosin is an enzyme that promotes cytokinesis so therefore, without the activation of myosin, the cell isn't able to divide.)

3. Activated MPF is able to phosphorylate lamins. (Lamins are filament protiens that form dimers and these dimers come together to form tetramers, which leads to polymerization of long chains of filaments. This is what gives the nuclear structure of the cell. When lamins are phosphorylated, the shape of the dimers change and makes it hard for them to hold together. At then end of mitosis when the membranes come together again, the phosphates are removed.)

4. Activated MPF is then able to activate APC. Functions of MPF p53 is a tumor suppressor protein that activates other necessary proteins to stop the cell cycle or induce apoptosis, a programmed cell death. p53 is a transcription factor for many of the DNA repair proteins and p53 will lead to cell arrest when a DNA needs to be repaired. Under normal circumstances when the cell cycle doesn't need to go through apoptosis or cell arrest, mdm2 is bound to the n-terminal region of p53. Mdm2 is an E3 ligase and marks p53 to be degraded. p53 p53 mdm2 mdm2 When p21 is produced, it binds with CDK2, inhibiting cyclins from binding with CDk2. If CDK2 is unable to form complexes with the cyclins, then it will lose its function and lead to cell arrest. p53 p53 p53 p21 CDK2 p21 cyclin A cyclin E p53 is a transcription factor for p21 and p21 is a CDK inhibitor. When there is a damage on DNA, this results in production of ATM, CHK1, DNA-PK, CAK and these will phosphorylate p53 so mdm2 is no longer able to bind. This means that p53 is able to induce apoptosis or stop the cell cycle from progressing further until it is repaired. ATM
CAK APC cdh1 cyclin B cyclin B Ubiquitination is a process that is used to degrade damaged or unnecessary proteins in the cell. An ubiquitin, a small protein found in cell, that gets attached to E1 (ubiquitin activating enzyme).E1 then transfers ub protein to E2 (ubiquitin conjugating enzyme).E2 is able to bind with E3 (ubiquitin protein ligase). E3 is protein specific and it binds to a substrate that needs to be degraded. E3 allows an ubiquitin to get transferred from E2 to the substrate. This process can repeat and several ubiquitins can get attached to the substrate. These ubiquitins are then recognized by the proteosomes and are degraded. APC is a form of E3 ligase and it marks cyclin B to be broken down. When this happens, cyclin B is no longer able to form MPF. When the concentration of MPF is decreased, the cell is finally allowed to divide, because myosin won't be able to become phosphorylated. If myosin is not phosphorylated, it will be able to promote cytokinesis. Apoptosis:
Under severe conditions when the cell needs to go through an apoptosis, p53 induces the production of apoptosis proteins such as BAX and puma. BAX protein opens up the membrane of mitochondria and this allows for cytochrome c to be released. Under normal conditions, BAX is inhibited by BCl2 which work as a plug on a membrane of mitochondria, but under p53 signal, membrane will open up as the concentration of BAX protein increases. Cytochrome c that is released from the mitochondria binds with APAF-1 and procaspase 9, forming an apoptosome. This apoptosome is then able to cleave procaspase 3 and result in active caspase 3, which is an effecter caspase that cleaves other proteins that are proapoptotic. This will lead to an apoptosis. by Amanda Sul y15 and T161 are switched
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