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BSCI222 Textbook Notes on Chapters 23-26- Dr. O’Brochta Spring 2014Chapter 23- Cancer GeneticsI. 23.1 Cancer Is a Group of Diseases Characterized by Cell Proliferation-Cancer is not a single disease; it is a heterogeneous group of disorders characterized by the presence of cells that do not respond to the normal controls on division-Cancer cells divide rapidly and continuously, creating tumors that crowd out normal cells and rob healthy tissues of nutrients-Tumor formation:- Normal cells grow and divide in response to stimulatory and inhibitory signals- In cancer cells, one or more of the signals has been disrupted, which causes the cell to proliferate at an abnormally high rate, lose their shape, and form a distinct mass of abnormal cells- A localized tumor is referred to as a benign tumor; if the cells invade other tissues it is referred to as a malignant tumor- Cells that travel to other sites in the body and establish a secondary tumor have undergone metastasis-Cancer as a genetic disease: genes play some role in cancer, but one does not necessarily inherit cancer unless…- Knudson’s multistep model of cancer: suggests that cancer is the result of a multistep process that requires several mutations- Cancer is a genetic disease, although few cancers are actually inherited-Clonal evolution: tumor cells acquire more mutations that allow them to become increasingly more aggressive in their proliferation properties- The rate of clonal evolution depends on the frequency with which new mutations arise -Cancer can be influenced by environmental factors (i.e. smoking)II. 23.2 Mutations in a Number of Different Types of Genes Contribute to Cancer-Over 350 different human genes have been identified to contribute to cancer-The signals that regulate cell division fall into two basic types: molecules that stimulate cell division and those that inhibit it-A stimulatory gene can be made hyperactive or active at inappropriate times; mutations in stimulatory genes are usually dominant because even the reduced amount of gene product produced by a single allele is sufficient to produce a stimulatory effect- Mutated dominant-acting stimulatory genes that cause cancer are termed oncogenes (i.e. Rous sarcoma virus)- Proto-oncogenes: genomes of all normal cells that carry DNA sequences that are closely related to viral oncogenes; when mutated they become oncogenes-Cell division can also be stimulated when inhibitory genes are inactive; inhibitory genes have recessive effects because both copies must be mutated to remove all inhibition- Inhibitory genes in cancer are termed tumor-suppressor genes- Tumor-suppressor genes are difficult to identify because they inhibit cancer and are recessive (requires two mutations)- One can inherit one mutation of the gene, where there are heterozygous for thecancer-causing mutation and not have cancero They are predisposed to cancero Inactivation (typically a deletion) of the remaining wild-type allele in heterozygotes is referred to as loss of heterozygosityo The appearance of the trait in an individual cell or organism that is heterozygous for a normally recessive trait is called halpoinsufficiency -Control of the cell cycle:- Cells actively dividing pass through the G1, S, and G2 phases of interphase and then move directly into the M phase, when cell division takes placeo Non dividing cells exit from G1 into the G0 stage, in which they are functional but not actively growing or dividingo Checkpoints are used to direct cell cycle; key events are controlled by cyclin-dependent kinases (CDKs), which are enzymes that phosphorylate proteins (either activating or inactivating them)o CDKs are only functional when they associate with the protein cyclin- G1-to-S transition:o The G1/S checkpoint is in G1, just before cell enters into S phase and replicates into DNAo The cell is prevented from passing through the checkpoint by the molecule retinoblastoma (RB) protein, which binds to another molecule called E2F and keeps it inactiveo In G1, cyclin D and cyclin E increase in concentration and combine with their associated CDKs (when combined with their CDKs, then phosphorylate molecules of RB)o RB is inactivated due to phosphorylation, without it E2F protein is released; E2F is a transcription factor that stimulates the transcription of genes that produce enzymes for DNA replication- G2-to-M transition:o Cyclin B combines with a CDK to form an inactive complex called mitosis-promoting factor (MPF), which is activated by the removal of a phosphate group During G1, cyclin B levels are low so MPF is lowo G2/M checkpoint is at the end of G2, before cell enters mitosiso At the end of G2, MPF levels are high and commits the cell to divide; MPF levels peak in mitosis; low levels of MPF occur in the middle of mitosis and return cell to interphase- Spindle-assembly checkpoint:o Occurs in metaphase and delays the onset of anaphase until all chromosomes are aligned on the metaphase plate and kinetochores are attached to spindle fibers from opposite poleso If not aligned properly, the checkpoint blocks destruction of cyclin B, which keeps MPF active and maintains cell in mitosis- Mutations in cell-cycle control and cancer:o Mutations in genes that encode RB proteins, which normally hold the cell in G1 until the DNA is ready to be replicated, are associated with cancers such as retinoblastomao The gene that encodes cyclin D is overexpressed in about 50% of all breast cancers, as well as esophageal and skin cancero Some proto-oncogenes and tumor-suppressor genes have roles in apoptosis; cancer cells do not undergo apoptosis due to mutation in normal apoptosis-stimulating mechanisms p53 is inactive in human cancers- Signal-transduction pathwayo External signals are initiated by hormones and growth factors by binding to receptors on the cell surface This system, in which an external signal triggers a cascade of intracellular reactions that ultimately produce a specific response, is called a signal-transduction pathway Defects are associated with cancero The binding of the signal molecule to the membrane-bound receptor activates a protein in the pathway, which activates the next molecules by adding or removing phosphate groups or causing changes in the conformation of the protein Cascade of reactions to either stimulate or inhibit cell cycleo Ras signal-transduction pathway is activated when a growth factor, such as epidermal growth factor (EGF), binds to


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UMD BSCI 222 - Notes on Chapters 23-26

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