Ch 19 Padilla (Cell Cycle Regulation and Cancer)
Ch 19 Padilla (Cell Cycle Regulation and Cancer) BIOL 3451
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This 14 page Study Guide was uploaded by Jazmine Burnam on Monday May 2, 2016. The Study Guide belongs to BIOL 3451 at University of North Texas taught by Dr. Padilla in Spring 2016. Since its upload, it has received 93 views. For similar materials see Genetics in Biology at University of North Texas.
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Date Created: 05/02/16
Study Guide- Cancer Genetics 1. Define the following: a. Tumor suppressor: prevent tissue overgrowth; nullify cells with damaged genomes, and metastasis. b. Oncogene: Cancer causing genes Protooncogenes that are activated (see below) c. Protooncogene: are normal cellular genes that control cell growth (i.e., proliferation), specialization (i.e., differentiation) and death (i.e., apoptosis). When proto-oncogenes are activated, they are termed oncogenes. d. P53: a tumor suppressor gene that is a precursor to Li-Fraumeni Syndrome Transcription Factor Active p53 protein is a tetramere 50-60% of all cancers are associated with a p53 mutation! Mutation found in a wide range of cancers Activation of p53 can lead to DNA repair, cell cycle arrest, apoptosis (programmed cell death) Individuals with a p53 mutation develop cancer with a frequency of 90- 95%! Dominant Trait e. RAS: family (HRAS, KRAS and NRAS) mediate signaling by receptor tyrosine kinases on the cell surface. RAS proteins have GTPase activity Mutations arise that result in a decrease in the GTPase activity and thus RAS is inactivated more slowly leading to excessive cellular response to the signal from the receptor Ras proteins are in the plasma membrane Transmits signal from extracellular environment to the cytoplasm to the nucleus The signal activates the transcription of genes that initiate cell division Over 30% of all human cancers carry mutant ras oncogene! f. Retinoblastoma: that rare type of eye cancer that usually develops in early childhood, typically before the age of 5. Study Guide- Cancer Genetics An autosomal dominant trait but mutation is actually recessive Phenotypes include o a white "glow" or o photocrossed or "glint" in the pupil misaligned eyes o One eye being a of one or both different color eyes in dim lighting than the other o Misaligned or o white pupil in a color crossed eyes o Red, painful eyes o Poor vision o Affected individuals (red), who inherit one mutant allele of RB, a tumor-suppressor gene, have a high probability of developing retinal tumors in childhood. Since the RB gene is located on chromosome 13, both males and females are affected equally Each child of a parent with familial bilateral retinoblastoma has a 50% risk of inheriting the retinoblastoma gene, of whom 90% will develop retinoblastoma. o g. Cyclins: Proteins that control the progression through the cell cycle. Physical interactions between kinases and cyclins control the movement through the cell cycle. Study Guide- Cancer Genetics o h. Cyclin dependent kinases: These kinases regulate the cell cycle. (Kinases selectively phosphorylate specific proteins) o i. BRCA1: human tumor suppressor gene (to be specific, a caretaker gene), found in all humans; its protein, also called by the synonym breast cancer type 1 susceptibility protein, is responsible for repairing DNA. o Inherited as an autosomal dominant trait 85% of woman with BRCA1 allele develop a mutation in a second allele and get breast cancer. Increased rate of ovarian cancer o j. BRCA2: Inherited in autosomal dominant manner No increase in ovarian cancer o k. double minute chromosome: small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma o l. genome instability: refers to an increased tendency of alterations in the genome during the life cycle of cells o minimized by o high-fidelity DNA replication in S-phase o precise chromosome segregation in mitosis o error free repair of sporadic DNA damage o a coordinated cell cycle progression m.chromosome instability: Abnormal karyotypes (extra chromosomes, missing chromosomes, rearrangements) o n. metastisis: the ability break loose, enter the bloodstream and invade other tissues malignant tumors (as opposed to benign tumors) are difficult to treat o 2. Why is cancer considered a genetic disease? o o Cancer can be inherited (familial) or arise from either spontaneous or induced DNA mutations in somatic cells o 3. In the U.S. what cancer type kills most people on a yearly basis? o o Lung Cancer (leading cause of cancer death) o 4. Why does the incidence of most cancers correlate with an increase in age? o Most cancers rise exponentially with age. Cancer often develops from the accumulation of several mutagenic events in a single cell o 5. Describe how one can classify or distinguish cancers based on: a. tissue origin Carcinomas derived from epithelial cells (skin and internal membranes) (breast, lung, skin, prostate….) Lymphomas from blood cells/ lymphatic tissue Leukemia originates in tissues that form blood cells Myeloma originates in bone marrow Sarcomas from connective tissue (bone, muscle, cartilage) Adenocarcinoma originates in glandular tissue Blastoma originates in embryonic tissue of organs b. Stage Grading: o Tumor cells examined through biopsy under a microscope. The abnormality of the cells determines the grade of the cancer. Increasing abnormality increases the grade, from 1 – 4. Staging: Classification of the extent of the disease. o tumor, node, metastases (TNM) system classifies cancer by tumor size (T), the degree of regional spread or node involvement (N), and distant metastasis (M). A numerical system also is used to classify the extent of disease. o Stage 0 Cancer in situ (limited to surface cells) o Stage I Cancer limited to the tissue of origin, evidence of tumor growth o Stage II Limited local spread of cancerous cells o Stage III Extensive local and regional spread o Stage IV Distant metastasis Important for deciding management and prognosis Refinement of tumor classification by using technology/genetic testing to understand gene expression (microarray data/protein studies), chromosomal arrangements, genetic mutations o 6. Describe the type of DNA abnormalities that are associated with cancer. o Share two fundamental properties o Abnormal cell growth and division o Defcts in restraints that keep cells from spreading and colonizing to other parts of the body o Genetic affects in DNA repair o Chromatin modification o Cell-cyle regulation o Apoptosis o Signal transduction o Cellular function o Abnormal proliferation and loss of control over how cells spread and invade surrounding tissues o o 7. What is meant by the multistep nature of cancer in terms of histology? o o Histology the study of the microscopic structure of tissues. o There is a nice layer of organization and in multi step it becomes increasingly less organism and ultimately becomes a malignant carcinoma o o 8. What is meant by the multistep nature of cancer in terms of genetic mutations? o Cell converted to cancer cell via stages of vcellular evolutions Leads to uncontrolled ccell proliferation and metastasis,so it is transformed to a malignant cell A person might suffer up to 10 ^10 mutations per gene somewhere in the body, during his/her lifetime o o 9. What is a scientifically based Internet resource that one can go to for information on various cancers? What type of information can one obtain from these resources o o http://www.cancer.gov/cancertopics/commoncancers o http://www.cancer.gov o 10.How do cancer cells differ from normal cells? Cancers are aggregates of cells, derived from an initial aberrant founder cell that, although surrounded by normal tissue, is no longer integrated into that environment. o Phenotypic differences: rapid division rate, invasion of new cellular territories, high metabolic rate, and abnormal shape, altered gene expression o Chromosome instability-Abnormal karyotypes (extra chromosomes, missing chromosomes, rearrangements) o Genome instability refers to an increased tendency of alterations in the genome during the life cycle of cells o Metastasis: the ability break loose, enter the bloodstream and invade other tissues; malignant tumors (as opposed to benign tumors) are difficult to treat 11.Review how the cell cycle is regulated in terms of cell cycle checkpoints. Describe how CDK 1 and cyclin B is involved with regulating the transition between G2 to M phase. Cell cycle is controlled at several checkpoints. Mutations that disrupt cell cycle steps are candidates for cancer-causing genes CDK1 is also known as cdc2 (yeast) and phosphorylates histone H1, chromatin condensation This is a highly conserved protein and has transition from G2 to M phase is controlled by CDK and cyclin B Control of G1/S o CDK4 binds to cyclin D o Transcriptional activation of genes required for S phase Control of G2/M o CDK1 binds to cyclin B o Phosphorylation of proteins lead to cellular alterations M checkpoint (metaphase to anaphase transition) o Proteins interfere with the assembly of spindle/kinetochore attachments Mutations that disrupt any of these cell cycle steps are candidates for cancer-causing genes! o 12.What is the cause of retinoblastoma? Describe the mode of inheritance for the familial form of Retinoblasoma. In your answer describe what the genotype is of individuals with retinoblastoma in their normal somatic cells and in the cancer cell. o o Cause of retinoblastoma o 40% familial (inheriting a defective gene) 60% spontaneous (random change in the RB gene during cell replication ) o o Mode of inheritance for the familial form of Retinoblasoma o Autosomal Dominant trait o o Genotype of individuals with retinoblastoma in their normal somatic cells o 46,XX 46XY o o Genotype of individuals with retino blastoma in the cancer cell Lose part of q arm of chromosome 13 at RB gene [46, XX, del( -13q)] [46, XY,del( -13q)] o o o o o o o o o 13.What is the function of Rb protein and how is it regulated relative to the cell cycle (G1/S phase)? How is the cell cycle altered if the Rb gene is mutated such that RB protein is not functional? o Function Encodes a protein called pRB Found in all cell/tissue type and is also in nondividing (G0) and dividing cells o o How is it regulated relative to the cell cycle (G1/S phase) Acts as a molecular switch that controls the progression of cells from G1 into S phase Cells can only progress through G1/S when pRB is inactivated by phosphorylation o o o How is the cell cycle altered if the Rb gene is mutated such that RB protein is not functional In retinoblastoma cells there is no functional RB protein. Thus, E2F activates genes required for G1/S transition. The G1/S checkpoint is overridden and uncontrolled growth and tumor formation occurs o o o o 14.What does the BRCA1 gene code for and what is the function of this protein? What type of cancer is associated with a mutation in BRCA1? o What BRCA1 codes for encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability o o Function of Protein The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC) o o Type of Cancer associated with a mutation in BRCA1 85% of woman with BRCA1 allele develop a mutation in a second allele and get breast cancer. o 15. What does the p53 gene code for? What disease occurs if someone inherits a mutation in the p53 gene? What is the function of p53 protein in the cell? What role do post- translational modifications of p53 have in cell function? o Codes for Encodes a transcription factor that represses/stimulates transcription of more than 50 different genes o o Disease that occurs if someone inherits p53 gene mutation Li-Fraumeni Syndrome o o Function of p53 protein in the cell Activation of p53 can lead to DNA repair, cell cycle arrest, apoptosis (programmed cell death) o o Role that post-translational modifications of p53 have in cell function Genes that are transcriptionally regulated by p53 have an affect on cell cycle progression, apoptosis, G2/M transition: 16. What is the genetic change that leads to Chronic Myelogenous Leukemia? How did an understanding of this lead to the treatment of the cancer with Gleevec? o Genetic Change that leads to Chronic Myelogenous Leukemia Translocation events bring together exons of BCR and ABL o o How understanding led to treatment of the cancer with Gleevec Small-molecule drug targets a particular cancer gene product Minimal side effects Chronic dosing to maintain inhibition of the target Some resistance to Gleevec Best to treat early Drug emerged from a class of compounds, identified in high throughput screens, that act against platelet-derived growth receptor tyrosine kinase. Testing revealed potent activity against the ABL tyrosine kinase o 17.What is the cellular function of RAS proteins? What occurs in the cell if the RAS protein is mutated into an oncogene. o Cellular Function mediate signaling by receptor tyrosine kinases on the cell surface. RAS proteins have GTPase activity Ras proteins are in the plasma membrane Transmits signal from extracellular environment to the cytoplasm to the nucleus The signal activates the transcription of genes that initiate cell division Over 30% of all human cancers carry mutant ras oncogene! o o What occurs in cell if RAS protein is mutated into an oncogene Mutations that convert ras (protooncogene) to an oncogene prevent Ras protein from hydrolyzing GTP to GDP o Ras protein stays in “Active” form which leads to constant stimulation for cells to divide o 18.Describe the multistep process involved with colon cancer. o Step 1: o o Conversion of normal epithelial cell into small cluster of cells known as an adenoma/polyp o o Requires inactivating mutations in the adenomatous polyposis coli gene (encodes protein involved in the normal differentiation of intestinal cells) o o Resulting adenoma grows slowly and is considered benign o Step 2: o o Acquisition of a second genetic alteration in one of the cells within the small adenoma (usually mutation in Kras gene whose product is normally involved with regulating cell growth) o o Kras gene becomes active, reslulting in unregulated cell division o o Cell containing APC and Kras mutation grows and expands to form a larger intermediate adenoma in a the clonal expansion process. o o The cells of the original small adenoma (containing the APC mutation) are now vastly outnumbered by the cells containing the two mutations o Step 3: o o Transforms a large adenoma into a malignant tumor (requires more waves of clonal expansions triggered by the acquisition of defects in several genes o Mutation in APC causes epithelial cells to escape cell cycle and cells then form polyps o o o 19.What types of environmental conditions are known to induce cancer? What can you do to reduce your risk to cancers? o Conditions that induce cancer o o Background radiation o Occupational exposure to chemical agents, Sunlight o Personal behavior (diet, tobacco) o Education and changes in life style prevent cancer o o Sun exposure (sunscreen) o Diet (eat your vegetables and eat less fat) o Stay fit- Obesity causes an increase in certain cancers o Tobacco….stay away from it. o 20.What occurs in cells in which Bcl2 is overexpressed? What is Bcl2 involved with normally? o Cancer cells with over expression of Bcl2 are resistant to chemotherapies and radiation therapies. o p53 will also have a role in preventing apoptosis in cancer cells o Bcl2 Cell is death inhibitor, prevents cells from undergoing cell death. Represses ced-4/APAF-1 o o o o
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