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The Cell Cycle Gone Awry Cancer and Mitosis Cancer Cells • Mutagens give rise to cancer cells. • There are a wide variety of mutagens which cause changes to our DNA: • Chemicals • UV radiation • Ionizing radiation • Mutations can also arise spontaneously due to cellular errors. Cancer Cells • Cancer cells don’t respond normally to the body’s control mechanisms. • They don’t heed the normal signals which regulate the cell cycle. • Some don’t need growth factors to grow and divide, while other cancer cells even make their own. Cancer Cells • Many cancer cells also fails to exhibit what is known as density dependent inhibition--an external physical factor regarding mitosis that stops the division of crowded cells. Cancer Cells • Normal cells usually divide 20-50x in the process of aging and then die. • Cancer cells are seemingly immortal because they will continue to divide forever if they are given a continuous supply of nutrients. • HeLa cells. Cancer Cells • Cancer cells have a high mitotic index. That is with cancer, there are often more cells undergoing mitosis compared to the number not undergoing mitosis. Metastasis • Primary tumors are the original tumor in the organism. • From there, tumors metastasize, or spread to other parts of the body where they form new, secondary tumors. Cancer Development • There is a multistep model that explains cancer development. • Numerous changes must occur in the DNA in order for a cell to become cancerous. • But before we begin, there are a few terms we need to discuss. Cancer Cells • These terms will help you to understand what’s going on. • Apoptosis • Gate Keepers (Promoters) • Caretakers • p53 • Oncogene • Proto-oncogene • Tumor Suppressor Genes Apoptosis • Apoptosis is programed cell death, and is a normal process that occurs in living organisms. Gate Keepers and Caretakers • There are 2 general groups of tumor suppressor genes: • Gate Keepers (Promoters) • Caretakers Gate Keepers and Caretakers • Gate Keepers act as “a set of breaks” on cellular proliferation. • Caretaker genes are genes whose products protect the integrity of the genome by repairing damaged DNA. Gate Keepers and Caretakers • When gate keeper genes mutate or are damaged, they lose their ability to regulate cell division, kick-start repair mechanisms, or both. • Mutations in these genes, therefore, allow mutations in other areas of the genome go unchecked, potentially giving rise to tumors. Gate Keepers and Caretakers • When caretaker genes mutate or are damaged, they lose their ability to repair DNA damage (or care for the genome). • Thus, mutations in other areas of the genome accumulate and often give rise to tumors. • BRCA1 and BRCA2 genes. BRCA1 17q21: This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomi Inherited mutations in BRCA1 and this gene, BRCA2, confer increased stability, and it also acts as a tumor suppressor. The encoded protein combines with other tumor eloping breast or ovarian cancer. Both BRCA1 and BRCA2 are suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein nance of genome stability, specifically the homologous recombination complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product e-strand DNA repair. The BRCA2 protein contains several copies ofassociates a with RNA polymerase II, and through the C-terminal domain, also interacts with histone the BRC motif, and these motifs mediate binding to the RAD51 deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded h functions in DNA repair. BRCA2 is considered a tumor suppressor breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited ith BRCA2 mutations generally exhibit loss of heterozygosity (LOH)breast of cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays p53 • p53 is a tumor suppressor gene known as the “guardian of the genome”-it acts as a gate keeper. • The p53 gene makes p53 protein which does many different things. •It can arrest cell proliferation by holding the cell cycle at the G1/S checkpoint when DNA damage is p53 17q13.1: This gene encodes a tumor suppressor protein containing recognized. transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons (PMIDs: 12032546, 20937277). [provided by RefSeq, Feb 2013] - See more at: http://www.cancerindex.org/geneweb/TP53.htm#sthash.FG0ISunq.dpuf p53 •This protein is what binds to the DNA and regulates the expression of genes that control the cell cycle. •p53 also activates repair proteins when the DNA has sustained damage. •It can initiate apoptosis if the DNA damage is irreparable. p53 • Once activated, it functions as an activator for a number of different genes most notably, p21. • When tumor suppressor genes such as p53 get damaged or undergo a mutation, they lose their ability to regulate cell proliferation. Oncogenes and Proto-Oncogenes • Proto-oncogene is the name given to the normal form of genes which promote and regulate cell proliferation. • Oncogenes are mutant forms of protooncogenes that cause cancer. Oncogenes and Proto-Oncogenes • When a proto-oncogene undergoes a mutation that doesn’t get repaired, it becomes an oncogene. Oncogenes and Proto-Oncogenes • Under normal conditions, cells undergo a programmed form of cell death when damaged beyond repair (apoptosis). Oncogenes and Proto-Oncogenes • Activated oncogenes now promote cell proliferation by encoding proteins that increase expression of the normal genes involved in regulating the cell cycle. • Thus, it is easy to see how damaged DNA leads to runaway cell division resulting in tumor growth. Tumor Suppressor Gene • Tumor suppressor genes are found in the genomes of cells and work to inhibit cell division. • They encode proteins that bind to various parts of the cell cycle machinery preventing runaway cell division. So What’s Going On? • How does this all fit in with mitosis? • Recall that the cell cycle is a carefully coordinated sequence of events that gives rise to genetically identical daughter cells. Cancer • In its simplest form, cancer is runaway cell division; an out of control cell cycle. • If unchecked, that initial rogue cell becomes a tumor--a group of cells with an aberrant cell cycle. Cancer Cells p53 • There are genes for certain components of the pathway that act as tumor suppressors. • The p53 gene codes for a transcription factor protein that promotes the synthesis of cell cycle-inhibiting proteins. Cancer Cells • Some tumor suppressor proteins from p53 can repair damaged DNA, while others control the adhesion of cells to each other or to the extracellular matrix (density dependence). • Still others are components of the cellsignaling pathway that inhibits the cell cycle. Cancer Cells • Normal p53 acts to control tumor formation using two mechanisms: • 1. It activates p21 in response to DNA damage/stress. • 2. It controls tumor formation by inducing apoptosis. 1. p21 Activation • Most notably, p53 expression activates p21 whose protein product halts the cell cycle at G1 and S by binding to and inhibiting the cyclin-dependent kinases needed by the S phase. • This is the halt step that allows time for the cell to repair the DNA. 1. p21 Activation • Under normal conditions, p53 activates an inhibitor gene (p21) when DNA is damaged. • As a result, p21 protein arrests the cell cycle and prevents cell proliferation. •We don’t want a damaged cell dividing. • If p53 function is lost, the p21 gene is not activated and p21 protein will not be available to act as the stop signal for cell division. 1. p21 Activation • Since the p21 protein is not available and there is no stop signal for cell division, the cell will continue through the cell cycle despite damage to DNA. • An increase in mutant cell proliferation (tumor formation) often results. Cancer Cells p53 • p53 also activates expression of a group of miRNAs that act to inhibit the cell cycle. • It can also directly turn on genes involved in DNA repair. • When the DNA is beyond repair, it activates suicide genes stimulating apoptosis. 2. Induction of Apoptosis • 2. When a cell is damaged beyond repair, a normal-functioning p53 gene acts to induce cell death (apoptosis) and stops the cell from proliferating. • The immune system recognizes the dead cell and cleans it up. Cancer Cells p53 • For example, exposure to UV light can damage DNA. This triggers the signaling pathway-through p53--that blocks the cell cycle until the damage has been repaired. • If the damage cannot be repaired, apoptosis is stimulated. • If p53 does not act this way, the damage could contribute to the formation of a tumor as a result of the chromosomal abnormalities and cell division would perpetuate the abnormality. Cancer Cells and p53 • Thus, we can see how p53 acts as a gate keeper and is involved in a number of different pathways to prevent a cell from passing on mutations. Ras • Another group of proto-oncogenes belongs to the Ras is a family of genes. • When a mutation occurs in a Ras gene, it can become an oncogene and possibly result in the formation of a tumor. • Ras genes code for Gproteins that relay signals from growth factor receptors on the plasma membrane to a cascade of protein kinases. • At the end of the pathway is the synthesis of a protein that stimulates the cell cycle. Ras 37 Ras • Under normal conditions, the pathway will not operate unless triggered by the appropriate growth factor. Ras • Certain mutations in the ras gene lead to production of a hyperactive Ras protein that triggers the kinase cascade in the absence of growth factor. • This then turns on genes associated with cell growth and differentiation. Ras • Since these signals result in cell growth and mitosis, overactive Ras signaling can lead to cancer. The Takeaway • There are a number of other genes that have been shown to play a role in caring for the genome and suppressing tumor formation. • The study of these genes and their proteins have enabled us to better understand the cell cycle and how it works.