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Lecture 17

BISC403 Lecture 17: Lecture 17
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Department
Biological Sciences
Course
BISC403
Professor
Olabisi Oyenike
Semester
Spring

Description
Lecture XVII I. 19.4 How mutations cause cancer phenotypes II. Oncogenes = accelerator; signals to keep dividing III. Tumor suppressor gene = brake IV. Proto-oncogenes are normal; there is a mutation and you get an oncogene V. Transition from G1 to S is the most efficient place to stop before it begins replicating and going through the process VI. Even after replication, there can be errors in the DNA; genes that are supposed to fix these errors a. DNA pol has proofreading mechanism VII. Oncogenes act in a dominant fashion to promote cancer a. Nonmutant allele is a proto-oncogene b. Proto-oncogenes often encode proteins needed for cell cycle progression i. Normally functioning gene c. Gain of function mutation results in increased proliferation d. TFs, cyclins, many kinases; involved in some sort of activation that are going to lead to more proliferation and growth e. Over-actively promoting growth and division VIII. Abnormal cell growth: oncogenes IX. Oncogenes act dominantly and cause increased proliferation a. Oncogenes are produced when mutations cause improper activation of a gene b. Two approaches to identifying oncogenes: i. Tumor-causing viruses 1. Virus affects cell, inserts genetic material, uses host’s machinery to replicate; can’t replicate itself 2. Many tumor viruses in animals are retroviruses 3. Some DNA viruses carry oncogenes (like HPV) 4. Can insert and affect expression in humans of certain oncogenes ii. Tumor DNA 1. Transform normal mouse cells in culture with human tumor DNA X. Identifying oncogenes through association with tumor viruses a. Will have a promoter for the virus; while the virus is integrating into the genome, it can integrate its promoter close enough to the human genome that it causes it to be oncogenic b. After infection, retroviral genome integrates into host genome and may activate a proto-oncogene c. Genes near viral integration sites in cancer cells may be oncogenes d. Host protooncogenes may be packaged into RNA virus particles i. Oncogenes may be identified in viruses ii. Examples of RNA tumor viruses iii. When sequence a viral genome, sometimes find parts of human genome XI. Identifying oncogenes through cell transformation assays a. Human gene that is oncogenic can be identified and cloned from transformed mouse cells b. If the gene transforms the mouse cells, it’s conformation that it’s an oncogene XII. HPV is the most common sexually transmitted infection in the U.S. a. Common cancers associated with HPV infection: cervical, anal, oropharyngeal cancers b. Viruses insert into the genome; no cure; prevention only possibility of avoiding these effects c. Causes cervical cancer d. HPV virus inside the patient’s genome; causes uncontrolled cell growth, cancer XIII. HPV pathophysiology a. HPV effects i. Oncoproteins ii. E6 binds p53 blocking apoptosis iii. E7 releases E2F from pRb driving cells into cycle XIV. Examples of oncogenes a. All have a gain of function effect i. Ras 1. Usually active when bound to GF 2. Oncogenic point mutation makes constitutively active protein ii. c-Abl 1. Chromosomal translocation fuses the c-abl and bcr genes 2. Hybrid protein encodes a constitutively active tyrosine kinase iii. Her2 1. Found in 20% of all breast cancers 2. Overexpressed GF receptor XV. The Ras oncogene is the mutant form of the Ras proto-oncogene a. Normal Ras is inactive until it becomes activated by binding of growth factors to their receptors b. Oncogenic forms of Ras are constitutively activated XVI. Her2 overexpression is due to gene amplification a. High levels/overexpression of this receptor due to amplification of the gene b. Causing duplications and amplifications in the genome XVII. Cancer can be caused by mutations that improperly inactivate tumor suppressor cells a. Function of normal allele of TS genes is to control cell proliferation b. Mutant TS alleles act recessively and cause increased cell proliferation c. Need to pause cycle d. TS genes identified through genetic analysis of families with inherited predisposition to cancer i. Inheritance of a mutant TS allele ii. One normal allele sufficient for normal cell proliferation in heterozygotes iii. Wild-type allele in somatic cells of heterozygote can be lost or mutated  abnormal cell proliferation e. If heterozygote – if something happens to the functioning copy  BAD XVIII. Some families have a dominant genetic predisposition to certain types of cancer a. Don’t inherit cancer-causing gene; you inherit predisposition b. Individuals who inher-t retinoblastoma caused by mutations in RB gene c. One copy of the RB allele are prone to cancer of the retina d. During proliferation of retinal cells, the RB allele is lost or mutated e. Tumors develop as a clone of RB /RB cells XIX. The RB tumor-suppressor gene a. Dominant predisposition i. Every cell has one mutant allele b. The cancer is a recessive trait i. One cell gained a second mutant allele XX. How does the G1 checkpoints work a. GF’s stimulate production of i. E2F protein, which triggers expression of genes required for S phase ii. G1 cyclins b. Rb protein is a tumor suppressor i. It suppresses E2F activity ii. Keeps the cell in G0 XXI. How do social controls and cell-cycle checkpoints fail a. In some cancers, the G1 cyclin is overproduced i. Permanently activates CDK ii. Continuously phosphorylates Rb so it can’t bind E2F b. In some cancers, Rb is missing or defective i. Doesn’t bind to E2F ii. E2F activates genes to start S phase c. Two mechanisms, same result XXII. Mechanisms resulting in loss of heterozygosity a. If lose the second allele that was
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