Worksheet_ The Eukaryotic Cell Cycle and Cancer - BIOL-1406 2007 1 Biology I for Science Majors

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” The Eukaryotic Cell This information is considered lecture material. It is also important for your life since cancer eventually affects everyone in some way. And, we can make choices every day that increase or decrease our probability of developing it. °V Cycle and Cancer INTRODUCTION This handout complements the Click & LearnThe Eukaryotic Cell Cycle and Cancer and is intended as an in- depth examination of the cell cycle and the protein players involved. Answer the questions below. All the answers are in the material or require you to think. You do not need to rephrase or use complete sentences unless you're explaining something. Clickon the “Background” tab on the right side. 1.Why is cell division important for unicellular (single-celled) organisms? Multicellular organisms? The reason why cell division is important is because it is the only was a single celled organisms can reproduce. The reason why it is important for multicellular organisms is because it allows the multi-cellular organisms to grow and to replace dead or damaged cells. 2.Provide an example of why cell division remains important to an adult organism even after it is fully developed. It remains important because it helps the cell to grow cells for the skin and gut. Also, it helps to heal wounds like skin cuts or broken bones. 3. What is the role of growth factors? The role of growth factors is to stimulate proliferation of epithelial cells, fibroblasts, neurons, and astrocytes. 4. Cells divide, differentiate, or die. What is differentiation? Cell differentiate is when a cell stops dividing to specialize in structure and function. 5. What is apoptosis? Explain its purpose. Apoptosis is when a cell undergoes cell death. It purposes is to eliminate the unnecessary cells during development. 6. Organisms maintain the right number of cells by regulating the cell cycle. What are “cell cycle regulators?” Cell cycle regulators are molecular signals that may stimulate or halt cell division, instruct cells to differentiate, or initiate cell death. 7.Watch the video clip of cells in the small intestine. Name the general location along the villus where these processes occur. Cell Division: Crypt Cell Differentiation: ~ Outside the villus Apoptosis: TOp of the villus Cell Cycle Updated March 2021 www.Biolnteractive.org HMS Page 10f6

hhmi Blnlnl.rlctllsv:t Click & Learn The Eukaryotic Cell Cycle and Cancer — In Depth Student Worksheet 8. Name one harmless result of too little cell division. One harmless result of too little cell division is hair loss. 9. Name one harmless result of too much cell division. One harmless result of too much cell division is warts and tumors. Click on the section of the circle labeled “Cell Cycle Phases” in the center purple circle on the right and use the “Overview” information in the window on the left to answer the questions below. 10. List, in order, the 4 events collectively called the “cell cycle.” Then, write the correlating cell cycle phase name a. Growth b. DNA replication c. Preparation to divide 4. Division 11. In general, what is the purpose of a checkpoint in the cell cycle? The purpose is to regulate the process that usually works without errors. 12. What is one potential outcome when errors occur in this highly regulated cell cycle process? They cause catastrophic consequences, such like cancer. Click on “Cell Cycle Regulators and Cancer” in the center purple circle on the right. Use the information under “Regulators Overview” in the window on the left to answer the questions below. 13. What type of protein that regulates the cell cycle is encoded by proto-oncogenes? Stimulating 14. What type of protein that regulates the cell cycle is encoded by tumor suppressor genes? Inhibitory 15. The most important cell cycle regulators are the cyclin-dependent kinases 16. What is a kinase, and what does it do? Kinase are enzymes that add a phosphate to other proteins to activate or inhibit their function. 17. When are CDKs present inside the cell during the cell cycle? CDKs are always present in the cell. 18. When are cyclins present inside the cell during the cell cycle? Cyclins are active only when they are bound to other proteins called cyclins. Cell Cycle Updated March 2021 www.Biolnteractive.org Page 20f6

hhmi Blnlnl.rlctllsv:t The Eukaryotic Cell Cycle and Cancer — In Depth Click & Learn Student Worksheet 19. CDKs form molecular complexes with cyclins. What do activated CDK-cyclin complexes do? CDKs do many things, they stimulate the cell, regulate the progression thought each phase, and sometimes inhibit the cell cycle progression. Using the cell cycle diagram on the right and both links in the center purple circle, complete the table below for each phase. Use asterisks/dashes and focus on major eventsthatoccurduring each phase, checkpoint, and which regulatory proteins (abbreviations OK) are involved in the phase. Complete the entire row before moving on to the next phase. Growth Factors @ CDK-cyclins Gl p53 @ Retinoblastoma protein g‘);glslag ILE;CR‘E: Cae” Checks to see is the CDK-cyclins 4 cell has any damage Duplicates the DNA Growth factors stimulate and errors that can stal @ s the rise in S-phase cyclin the cell c_ycle until the concentrations. problem is corrected. telangiectasia mutated Breaks in the two DNA @Other proteins strands during replication If a cell has been CDK-cyclins damaged, p53 protein @ will stop the cycle until 62 the damage is repaired. p53 protein If there is to much, the @ protein can initiate cell death. Anaphase-promoting Anaphase-promoting complex/cyclosome is @ complex/cyclosome activated, during M metaphase. _— Also anaphase takes (mitotic phase) [ ) - ce during this time. ® 20. Go to Cell Cycle Phases > Interphase. Interphase alternates with the Mitotic (M) phase. What happens during interphase and what phases does it include? In Interphase the cell grows and the DNA replicates. The phases that take place is G1, S, and G2 phase . 21. Go to Cell Cycle Phases > GO. The GO (said G zero) phase is a non-dividing stage. [Cell continues all normal processes except division. It is not dormant nor "resting".] What three factors determine if a cell enters G0O? The three factors that determine of a cell enters GO is if it receives a signal to differentiate, or when resources are insufficient to grow and divide. Cell Cycle www.Biolnteractive.org. Updated February 2020 Page30f6

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hhmi Blnlnl.rlctllsv:t Click & Learn The Eukaryotic Cell Cycle and Cancer — In Depth Student Worksheet 22. What are (a) 2 cell types permanently in GO and (b) 1 cell type that can leave GO, progress through the cell cycle and divide again. Neurons and muscle cells. b, Liver cells. Click on “Cell Cycle Regulators and Cancer” in the center purple circle on the right. Then click on the “Cancer Overview” tab in the window to the left (right tab). 23. Cancer is an improperly regulated cell cycle. Name two reasons why cells can form tumors. 24. What causes uncontrolled cell division at the genetic level? Mutations affecting the proteins that regulate the cell cycle. 25. Watch the video clip. At the cellular level in this example, explain what occurs if the APC gene is mutated. When the APC gene is mutated the cell know had trouble continuing the cell, and then later on piles up which causes a tumor. 26. Normally, proto-oncogenes stimulate the cell cycle. What do mutated proto-oncogenes (i.e. oncogenes) cause? For mutated proto-oncogenes it's purpose is to increase the stimulation. 27. Normally, tumor suppressor genes inhibit the cell cycle. What do mutated tumor suppressor genes cause? For mutated tumor suppressor genes it's purpose is to cause loss of inhibition. 28. To cause cancer, proto-oncogenes require _¥_ 1 (or) ___ 2 allele(s) to be mutated and are therefore considered _Y dominant (or) ___ recessive. This results in a _gain of function. 29. To cause cancer, tumor suppressor genes require 1 (or) _¥_ 2 allele(s) to be mutated and are therefore considered dominant (or) _Y¥_recessive. This results in a _loss of function. 30. Watch the video clip. (Use the cartoon on the slides and Dr. Sawyer's talk to answer these questions.) a. Using the gas pedal analogy. explain the impact on the cell cycle of a proto-oncogene versus an oncogene. Like a gas pedal, a proto-oncogene moves the cell cycle forward in a controlled speed. When it mutates into an oncogene, the gas pedal has been pressed too hard, and the cell cycle proceeds faster than it should. b. Using the brake pedal analogy, explain the impact on the cell cycle of one mutated tumor suppressor gene allele versus two mutated tumor suppressor alleles. Each tumor suppressor gene allele serves as a sort of brake pedal, the cell cycle will be kept under control is the tumor is doing it's purpose. If both are mutated, then this brake is lost and the cell cycle speeds along, out of control. Cell Cycle Updated February 2020 www.Biolnteractive.org Page4of6

Click & Learn hhmi Blnlnl.rlctlls;t Student Worksheet The Eukaryotic Cell Cycle and Cancer — In Depth Now that you have finished the Click & Learn, use your knowledge to answer the following questions. 31. p53 is a protein that is encoded by a tumor suppressor gene. a. Explain its normal role and why it is sometimes called the “guardian of the genome.” p53 protein role that helps the cell continues the cell cycle. The reason why p53 is called the "guardian of the genome", because it's essential for regulating DNA repair and cell division. b. Explain what happens to the cell cycle if both alleles of the gene encoding p53 are mutated. What happens if the cell cycle has both alleles of the gene encoding p53 are mutated is it can damage the DNA cells. 32. Explain why people who inherit one mutated allele of the BRCA7 gene have a higher likelihood of developing cancer. Also, why do we say "likelihood" rather than "they will get breast cancer"? To cause cancer, both alleles of BRCA1 must be mutated. In the case of a mutated allele, the likelihood of both alleles being mutated is much higher. 33. Predict a potential outcome of a mutated mitotic arrest deficient (MAD) protein. When not all chromosomes are properly attached to the mitotic spindle, the MAD proteins prevent entry into anaphase, resulting in an unequal number of chromosomes in the two daughter cells that form after anaphase. Next page Cell Cycle Updated February 2020 www.Biolnteractive.org Page50f6

Signaling cascade molecules 1 Cell proliferation Use the pathway illustrated in the figure to answer the accompanying questions. Watch this video showing the MAPK signaling pathway in action (https://youtu.be/JTY6_LRtUEE) The illustration is one segment of that pathway. (EGFR is a type of RTK) You won't understand everything or maybe much of anything. That's okay! What | want you to notice is the idea of signal transduction, why it's useful to have multiple steps, the intersections of different pathways, and how cellular responses result. Remember, this pathway happens normally. Cells need to do all these things. It's just when it gets activated incorrectly that things go awry. As per usual: It's all about molecular SHAPE and CHARACTER, which dictates which molecules can interact and what happens when they do. 34a. List 10 words in the video that you recognize from what you've learned in our course so far. 34b. In the picture above, which molecule is the ligand for EGFR? GTP and GDP 34c. What is the best analogy for how RAS, BRAF, MEK and ERK work? A relay race. Throwing a ball back-and-forth. A ball rolling up, over, and down a small hill. A car driving around a racetrack. A relay race 34d. What is the normal cell response in this pathway? The normal response of the pathway of the cell is to signal other cells. 34e. Compare the illustration to the animation. What is an advantage of using the illustration to understand the signaling pathway? What is an advantage of using the animation to understand the signaling pathway?

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hhmi Blnlnl.rlctllsv:t Click & Learn The Eukaryotic Cell Cycle and Cancer — In Depth Student Worksheet 35. This next video shows an example of EGFR in a brain cancer called glioblastoma multiforme). The normal EGFR gene codes for the normal EGFR protein that you saw in the illustration in the previous question. EGFR = epidermal growth factor receptor There is a mutant version of the EGFR gene that's found in 30% of gb tumors. It codes for a mutant version of the EGFR protein called EGFRVIII. EGFRVIII behaves differently than EGFR and can lead to cancer formation. Therefore, we call the mutant version of the gene an oncogene (cancer "causing” gene). And, in turn, we call the normal version of the gene a proto-oncogene. (However, proto-oncogenes aren't "pre-cancer genes". They're just normal genes that are essential to life but when disrupted can lead to cell behaviors that may ultimately lead to cancer.) Watch the video. You do not need to understand all the details. Use the visuals and words to help you see what's happening. https://xvivo.com/blog/egfrviii-glioblastoma/ a.At 0:25, 3 features that must be present for a tumor to be considered cancerous are stated. What are they? Rapid Growth, invasions, and resistance to apoptosis. b.The video discusses 4 ways that EGFRvVIII behaves differently than normal EGFR and ultimately results in too much cell division. Explain one of those mechanisms. Show me that you understand, on a basic level, what EGFRUIIl is doing that's abnormal and problematic. One mechanism that results in too much cell division is dissociation of the ligand:receptor complex. What a ligant-receptor complex is complex of a protein bound with a ligand that is formed following molecular recognition between proteins that interact with each other or with various other molecules. 36. As you saw in the illustration and first video, RAS is a G protein that is part of the EGFR signaling pathway Watch this video https://youtu.be/RqdIfZP26BlI It shows how RAS normally works and then one way that RAS can function abnormally and contribute to tumor formation. a.Look at the animation. Where is the RAS protein located in the cell? Plasma membrane b.In the normal scenario, why do they show the RAS protein changing color repeatedly? What do the colors mean? The importance of the colors of to how the difference of the RAS protein, when travelling the cell cycle. The colors show the difference when it changes, and mutates. c.What does G12V mean? Why does it matter? G12V is a mutated oncogenic protein. It matters because it makes it easier to be identified a tumor d.In the mutant scenario, why do they show a clock? How does that relate to the behavior of mutant RAS? The reason why they show a clock is to show the amount of time that it takes to mutant. It relates to RAS because it shows how the RAS works. 37.Using the animation and your answers above, explain how a mutation in the RAS gene can lead to tumors. The way the RAS gene can lead to tumors is by the cell pathway being blocked, and being piling up which then causes a tumors. Cell Cycle Updated February 2020 www.Biolnteractive.org Page60f6

Cancer consists of a group of diseases caused by mutations in the DNA of cells. Some mutations are inherited, but most occur during a person’s lifetime as a result of random errors in replication. Environmental factors that damage DNA, such as smoking, UV from sunlight or tanning beds, the black char on charcoal grilled meat, and cured or processed meat (lunch meat (unless no nitrates - even ones naturally derived from celery), sausage, bacon, various ltalian cured meats), can also cause mutations to occur. Additionally, tumor promoting inflammation must be present to support full tumor development. Inflammation can be increased by obesity/ metabolic syndrome (both the fat tissue itself and genetic changes that occur due to the condition), chronic stress, lack of sleep, and diet (processed foods - even "healthy processed food" - should be limited in favor of food directly from an organism (primarily plant, some animal)).This, of course, doesn't mean that all organisms are safe to eat, that food shouldn't be cleaned properly, or that all food is nutritious. As a single cell in the body accumulates mutations, one of those mutations could provide a survival or a growth advantage to the cell, causing the cell to divide at a faster-than-normal pace or to not die. The resulting daughter cells with that mutation, which are dividing quickly, are more likely to accumulate additional mutations. Additional mutations that affect cell division may cause those cells to divide even faster. Eventually a cell may acquire enough mutations that it starts to grow and divide uncontrollably. Figure 1. Schematic of cancer Normal First Second Third Fourth or Malignant . cell mutation mutation mutation Inter mutation ‘cells. development. Cells accumulate mutations as they divide. (Multiple "hits") Mutations that are most advantageous for cell @ e " - growth and survival are passed on to \ \ daughter cells, which, in turn, acquire I I further mutations and may eventually become malignant cancer cells. (The arrows represent multiple cell divisions.) Genetic and Epigenetic Alterations ChromOoSOMal ADEITAtIONS e ——— > Replication Errors Altered Heterotypic Interactions N20b o] O Evolution and Clonal Selection Environmental Exposure mumm—) @ Acquired Traits (Hallmarks) —_——> -0 o) o) NORMAL MALIGNANT Figure 2. The transformation process. Different insults continuously act on cells leading to transformative alterations in (epi) genetics, chromosomal numbers and arrangements, and heterotypic interactions which, along the path towards malignancy, undergo cycles of evolutionary clonal selection leading to the acquisition of cancer-competent traits, the hallmarks of cancer. Credit: Fouad YA and Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res 2017.7(5):1016-1036 www.ajcr.us /ISSN:2156-6976/ajcr0053932 38. a. What well-known biological process is being described in the info above but instead of a population of individuals it's a_population of cells with differential survival and reproductive success? Differential reproduction b. Cancer isn't just defined as cells growing too much and not dying enough. They also must be able to invade at least the tissues surrounding the tumor. Name/describe 2 properties or behaviors that cells would need to acquire to become invasive. This answer is just from your brain, not a particular source. It will be evaluated based on logic.

Worksheet_ The Eukaryotic Cell Cycle and Cancer - BIOL-1406 2007 1 Biology I for Science Majors

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