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How do mutations affect cell cycle regulation? Abstract:

The cell cycle goes through four main phases that must be accurately monitored. There are points in the cell cycle where complex molecules check the cells conditions in order to stimulate a reaction that either allows the cell to move to the next level, arrest or sometimes go through apoptosis. These points are called check points. Most of these checkpoints usually work with two regulatory molecules cyclin and protein kinases: cyclin-dependent kinases. if cyclin is expressed, cylin activate the protein kinases and allows it phosphirilate targeted proteins that activated other cellular reactions. changes in the DNA sequences; or mutations, that code for these molecules can cause major problems to a cell. Mutations in the DNA sequences of a cell’s DNA repairing enzyme can result in extreme miss regulation. in mitosis mutated regulatory factors can lead to one extra chromosome and one less chromosome or many irregular control. If the cyclin-dependent protein kinases changes it’s phenotype the cell can go on dividing or arrest when it should be dividing. Mutated cyclins can cause the cell to stop healing itself resulting in death. A tumor-derived growth factor (TGFβ) is an important factor that can inhibit epithelial cells and cells of the immune system in order to hell it recognize cell’s of the body by participating the expression of proteins needed to form the extracellular matrix. If TGFβ is damaged the cell would fail to recognize the body’s cells from others giving and advantage for cancerous cells to dwell in the body. A cell cycle can be said to represent the repeated phases of a cell’s life. These phases can be divided into main parts: Interphase, mitosis and cytokinesis. Interphase is the periods of time were the cell grows and undergoes its life function, synthesizes its DNA to form chromosomes, and prepares for the nucleolus division by rearranging microtubules. interphase can be further more divided into three intermediate phases: cell growth, DNA synthesis and preparation for mitosis. Mitosis if the process by which a cell’s nucleus divides into two nuclei while Cytokinesis is the process that forms two complete and identical cells. There are many factors that regulate the cell cycle. Molecules order the cell to start, pause and exit or enter phases. If this organizing agents lose their function the cell can no longer divide accurately therefore die or divide uncontrollably. What Regulates a Cell Cycle: There are three main regulatory ‘check points’ in the cell cycle: Cell growth Check point, DNA synthesis checkpoint, and Mitosis checkpoint. If a growing cell is ready for division, certain proteins will stimulate the cell to start synthesis. The cell growth check point decides whether a cell will divide or not. If the cell ready it will proceed to the next face if no it will stay in the growing phase. The DNA synthesis checkpoint makes sure DNA sequences where perfectly replicated by the help of DNA repair enzymes and then triggers mitosis. The mitosis check point regulates mitosis and if the cell’s condition are favorable takes it to the next phase; cytokinesis. It also signals the beginning of cell growth in interphase when division is complete. Two important regulatory molecules that can determine what is the cells next step according to where it lies are cyclin-dependent kinases (CDKs) and its partner cyclin. The CDKs are protein kinases while cyclins are groups of proteins generally used to activate CDKS. Cyclin determines whether the cell should proceed to the next phase by activating or deactivating CDKS. One CDK can associate with deferent forms of cyclins to encourage development through phases. In response to various signals cyclins are sythesised by the cell at specific stages when needed. Only when cells are ready to go through the entire cell cycle can external signals affect the synthesis of cyclin. When cyclin is expressed in larger amounts it activates CDKs. CDKS then phosphorylats targeted proteins. The phosphorylation of these proteins changes their activity causing the changes in the events of the cell cycle. In the Cell growth check point a particular type of CDK is activated by a cyclin to allow the cell cycle to continue. A CDK inhibitor can take the place of the cyclin if the cell should not proceed into the next phase. In DNA synthesis check point when the cell is ready a CDK and a cylclin phosphorylate multiple proteins that are needed for mitosis to occur. The Mitosis check point signals a cell onto its next phase by un-inhibiting a protein that corrupts a cyclin that can break down another protein that is involved in regulating steps within mitosis. These regulatory molecules are coded for in the DNA if these molecules are not accurately formed cell will lose its ability to carry out a normal cycle another important molecule is the Rb protein. When this protein is unphosphorylated it binds to transcription factors that start the transcription of genes that code for proteins that are important for DNA synthesis; such as DNA polymerases, and thereby prevent the activation of these proteins that start sythesis. If the Rb molecule was phosphorylated midway through growth phase transcription factors be activated and eventually result in the cell’s irreversible commitment to DNA synthesis. This early on phosphorylation of the Rb molecule is intiated by an overly produced cyclin and it’s CDK. This excessive production of cyclins can be caused by different types of mutation in the genes of regulatory factors. What are Mutations and How can They Affect the Cell Cycle: Mutations are permanent changes in DNA sequences. They can be inherited or acquired. Hereditary mutations would be found in all cells while acquired mutations are found in individual cells and are caused by environmental factors. Environmental factors such as tobacco and radiation can cause damages to the genes encoded in a DNA or mutations during cell division. DNA polymerase; an enzyme that adds nucleotides, is generally prone to mistakes. An enzyme that proofreads added nucleotides is a necessity. If a mutation happens to occur in the genes that make up a regulatory protein then the protein may not function well. Mutations that affect the cell regulatory system can cause all sorts of cellular malfunction. Flawed check points mystify the cell’s ability to make sure DNA replication is complete and perfectly formed; if weather DNA was properly separated and many other mistakes. In the mitosis check point it is insured that spindles have properly aliened chromosomes before proceeding. A faulty check point may fail to recognize miss division of chromosomes resulting in one extra chromosome in one cell. One of the reasons why regulation could be lost is due to mutation in the genes that code for the regulatory proteins. If the change in the phenotype causes the CDKs to misconstrue its function a cell might start dividing earlier than it should or arrest when it should move on. Changes in the phenotype of cyclins can cause late growth or arrest. Other mutations in regulatory factors can cause failure to arrest, week control, failure to exit a phase, arrest during meiosis, or other functional disabilities that might be lethal to the cell. What is the Effect of These mutations:

A tumor-derived growth factor beta (TGFβ) is involved in multiple cellular processes. When the TGFβ’s signal bind to a receptor it activates it therefore causing it to phosphorylates a second receptor which intern phosphorylates another receptor that goes on to to phosphorylate a transcription factor; receptor-regulated SMADs. This R-SMADs then undergoes s specific pathway in order to inter the nucleus where it participate in the activation of the transcription of variety of genes. The TGFβ has the ability to inhibit the cell’s growth including epithelial cells and the cells of the immune system. The loss of this TGFβ causes variety of tumors. A tumor results from mutations in the TGFβ receptor or SMAD proteins that inactivate particular molecules. In pancreatic cancer usually a deletion in the genes encoding for a SMAD causes the tumor. Other cancer causing mutation allows the cell to become unresponsive to TGFβ inhibition. TGFβ also stimulate the expression of genes that code for the formation of a cell’s extracellular matrix. If the genes for a TGFβ formation is damaged the loss of this TGFβ results in the cells inability to synthesize the proteins that form the extra cellular matrix; such as collagens, resulting in the cell’s failure to accurately distinguish a body’s cell from another allowing tumor cells to form without resistance. Cancerous cells result in many muted genes. Mutations in the genes that code for cell cycle regulation during mitosis can be divided as follows. 1.Oncogenes are mutated genes that are usually over expressed and stimulate mitosis before cell growth. Two forms of important oncogenes to be considered are: SIS and EGFR. These oncogenes are dominant and are easily expressed. Mutated SIS is the gene that code for the proteins that regulate cell growth and division. Mutated EGFRs are oncogenes that code for the receptor for epidermal growth factor

2.Tumer suppressor genes. If these genes are expressed they inhibit mitosis. MAD (mitotic arrest defective) is a gene that codes for a protein that makes sure spindle fibers are well formed. Mutation in MAD cause failure in the check point resulting in a cell with too few chromosomes and a cell with excess chromosomes which in turn leads to Aneuploidy. Aneuploidy is the main sign of cancer. P53; another tumor suppressor, acts as a factor that prevents the cell from exiting the growth phase by inhibiting the progression ofthe synthesis phase and the mitosis phase. These suppressor genes are recessive.

3.Mutations In the genes that code for apoptosis can causes the cell to ignore signals that call for apoptosis and therefore continue progression with extreme damages.

4.Genes that stimulate the growth of new red blood cells; Angiogenesis. Can be over expressed and produce blood cells in order to feed tumors.

5.Metastasis genes are genes that code for enabling the cells of the primary tumor to separate and migrate to other parts of the body. Such mutations take place in genes that are responsible in keeping the cells of a tissue adhering to one another. This mutation causes the cell that normally keep the cells adhering to its substrate to separate and go other cells. During DNA synthesis check point, when the cell’s control system receives signals that detected damage in the structure of DNA, the system delays progression until the DNA is fully repaired. If the cell’s complex damage response pathway fails to distinguish and react to DNA damages, disorders and tumors occur violently. Of the natural DNA repair pathway two sets of proteins are going to be discussed: ATM and ATR. ATM is a central signaling protein in the DNA damage response. ATM and ATR target a check point kinesis in order to signal a response for damaged DNA. Any cell lacking these proteins will fail to complete the cellular response. After response if the DNA repair enzyme fails to repair genes the accumulation of mutation can eventually cause cell death or cancer. In a tumor suppressor gene when damages in DNA cause the formation of p53 it increases the level of p53; which under nomarl conditions is kept very low. Theses damages from UV-radiations or γ-irradiation lead to the activation of ATM and a protein kinase which eventually target the formation of p53. P53 then targets the formation of cyclin inhibitor thereby preventing cyclin from binding to a CDK and halting the progression of the cell through phases.In oncogenes the SIS gene encodes for the formation of the PDGF B-chain which is the chain regulatory proteins undergo for cell growth and division. When this is overly expressed the cell undergoes continues cell division at a rate much too faster. Cancer: One extremely widespread result of check point malfunction is cancer. Cancer is one of the most threatening diseases because it has many advantages over other cells. Cancer can start from an adult stem cell or a cell that is specialized but has the tendency to differentiate into specific types of cells. Targeting these types of cells, a cancer has the ability to divide faster. As the division progresses the formed cells are prone to further mutations. As the cell losses control its dividing rate increases dramatically losing its growth phase causing a tumor. Stem cells; through mitosis, can divide into two stem cells or two daughter cells, one that goes on to differentiate and another with the same properties as the stem cell which keeps produces the same way. Furthermore a single mutation cannot be a primary cause for cancer. Cells must undergo several mutations that can cause irreversible damages or mutation in genes that code for proteins critical to cell regulation. The Cancer Genome Project that aims to understand and identify changes in mutations that leads to cancer. This understanding can lead to eventually understanding how and why exactly do a healthy cells turn into a tumor. One experiment in this project involved a skin cancer cell; malignant melanoma, of 45 year old women and a lung cell from a 55 year old smoker with lung cancer. With the help of advanced machines that can read genetic sequences to compare the healthy cells with the cancer cells of each patients scientists came to a better understanding of the mutations that are found in cancerous tissue. In the cells of lung cancer scientists discovered thousands of mutations that resulted in unhealthy cells; all caused b around 60 chemicals in cigarette smoke. Cells from Malignant melanoma revealed mutations caused by exposure to direct sun light. Scientist where most importantly ably to understand the specific changes in DNA sequesnces that cause these mutations allowing them to hopefully develop anti-cancerous drugs that can reverse or control these mutations. '''Conclusion: '''the control system of all cells is responsive to back and forth signals that make sure the cell is ready to go from one phase to another with everything it needs. Once mutations takes over the genes that code for the regulatory proteins; such as cyclins and CDks, are mutated then the cell will lose its full control and intern its functional ability. The consequences of the mutation that cause irregular cell cycle control and cancer to develop or the inappropriate arrest of the cell where the body will no longer repair itself. '''References '''Johnson G. B., Raven P. H.(2004) Hotl bioloy: The Cell Cycle. ISBN: 0-03-066473-X Heuvel S. v. (2011)cell-regulation WormBook, ed. 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