Exam 4 Notes
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This 20 page Study Guide was uploaded by Rachael Couch on Monday November 23, 2015. The Study Guide belongs to Biol 2311 at University of Texas at Dallas taught by John Burr in Fall 2014. Since its upload, it has received 93 views.
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Date Created: 11/23/15
Cancer Epidemiology 0 Cancer is the 2rld leading cause of death in the US 0 The incidence of cancer is increasing because more people are living long enough to develop cancer 0 Chance of dying of cancer at age 80 is 1000K greater than chance at age 30 0 After adjusting for the increasing fraction of the population that is older now compared to 1940 there is no increase in cancer except for lung cancer Lung Cancer 0 Most frequent cancer in the US 0 Responsible for 13 of all cancer deaths 0 The incidence of lung cancer has steadily increased through the century Many thought it was due to cigarette smoking 0 Tobacco companies pointed out though that there is no correlation between cigarette consumption in various countries and the lung cancer rates in the respective countries 0 This is because there is a 30 year interval between the time at which a group of people start to smoke and the time that they show a measurable increase in lung cancer 0 After plotting the cigarette consumption in various countries versus the annual rate of lung cancer deaths in each country 30 years later there is a very high correlation Life Style Variations 0 Worldwide there are very large variations in the incidence of the various kinds of cancer 0 How much of this variation is due to genetic differences between one population and another versus environmental factors 0 In the case of lung cancer USA versus India most of the variation in incidence is environmental cigarette smoking 0 Other studies support this as well 0 EX Wellknown study of Japanese immigrants to California Rates of cancers are less common in Japanese that immigrate to California stomach cancer 0 Similar results from study of Jews who migrate to Israel from Europe or US 0 Also well known study there is a strong correlation between high consumption of meat especially red meat andor reduced consumption of cereals and increased rates of colon cancer 0 One proposal is that various carcinogens are created within the large intestine by bacterial decomposition of certain bile sterols 0 Sometimes it is not particularly helpful to know a contributing lifestyle basis for a cancer though 0 EX Having a baby early in life age 15 significantly reduces your chances of getting breast cancer Cancer Terminology 90 of cancers in humans are carcinomas the remaining 10 are sarcomas and leukemias Major types of cancers Carcinomas derive from endoectoderm cancers that originate in the skin lungs breasts pancreas and other organs and glands Lymphomas cancers of lymphocytes Leukemia derive from bloodforming tissues cancer of the blood Sarcoma derive from mesoderm cancer of the bone muscle fat or cartilages Melanomas cancers that arise in cells that make the pigment in the skin Properties of Benign versus Malignant Tumors Benign Malignant Encapsulated Nonencapsulated Noninvasive Invasive Highly differentiated Poorly differentiated Slow growth Rapid growth Little or no anaplasia Usually anaplastic No metastasis Metastasis How Cancer Arises The 30 trillion cells of the normal body are interdependent and regulate one another s proliferation growthreproduction Cancer cells become deaf to controls on proliferation and reproduce on their own accord Also unlike normal cells they migrate and invade nearby tissues or distant sites of the body Tumors composed of these malignant cells become more aggressive over time and become lethal when they disrupt the tissues and organs needed for the survival of the organism O The cells in a tumor descend from a common ancestral cell that at one point long ago initiated a program of inappropriate reproduction 0 The malignant transformation of a cell comes about through the accumulation of mutations in specific classes of the genes within it Two gene classes which together constitute only a small proportion of the full genetic set play major roles in triggering cancer 0 Protooncogenes encourage normal growth I When mutated can become carcinogenic oncogenes that promote excessive proliferation 0 Tumor suppressor genes inhibit abnormal growth I When mutated contribute to cancer O For a cancerous tumor to develop mutations must occur in half a dozen or more of the founding cell s growthcontrolling genes 0 Altered forms of another class of genes may also participate in the creation of a malignancy by specifically enabling a proliferating cell to become invasive or capable of spreading metastasizing throughout the body 0 Many protooncogenes code for proteins involved in growthsignaling 0 These pathways within a cell receive and process growthstimulatory signals transmitted by other cells in a tissue 0 Celltocell signaling usually begins when one cell secretes growth factors 0 Growth factors proteins move between cells and bind to receptors on the surface of other cells nearby I Receptors span the outer membrane of the target cells 0 When a growthstimulatory factor attaches to a receptor the receptor creates a proliferative signal to proteins in the cytoplasm 0 These downstream proteins then emit stimulatory signals to other proteins in a chain that ends in the cell s nucleus 0 Within the nucleus transcription factors respond by activating genes that help to push the cell through its growth cycle 0 Cell growth becomes deregulated when a mutation in one of its protooncogenes causes excessive signaling in a critical growth stimulatory pathway keeping it continuously active when it should be silent 0 Some oncogenes force cells to overproduce growth factors 0 Sarcomas cancer of connective tissue and gliomas cancer of nonneuronal brain cells release excessive amounts of plateletderived growth factor 0 A number of other cancer types secrete too much transforming growth factor alpha 0 These factors act on nearby cells but may also turn back and drive proliferation of the same cells that just produced them 0 Researchers have also identified oncogenic versions of receptor genes 0 These versions of receptor genes release a ood of proliferative signals into the cell cytoplasm even when no growth factors are present 0 Other oncogenes in human tumors perturb parts of the signal cascade found in the cytoplasm 0 Ex Proteins encoded by normal ras oncogenes transmit stimulatory signals from growth factor receptor to other proteins far down the line The proteins encoded by mutant ras genes however fire continuously even when growth factor receptors are not prompting them Hyperactive Ras proteins are found in about a quarter of all human tumors Summary of tumor development 0 1 Tumor development begins when a cell within a normal population sustains a genetic mutation that promotes proliferation when it would normally rest 2 The altered cell and its descendants continue to look normal but they reproduce too much hyperplasia After years one in a million of these cells has another mutation that further loosens controls on cell growth 3 In addition to proliferating excessively the offspring of this cell appear abnormal in shape and orientation This tissue is now said to exhibit dysplasia Once again after a time a rare mutation that alters cell behavior occurs 4 The affected cells become more abnormal in growth and appearance If the tumor has not yet broken through any boundaries between tissues it is called in situ cancer This tumor may remain contained indefinitely However some cells eventually acquire additional mutations 5 If the genetic changes allow the tumor to begin invading underlying tissue and to shed cells into the blood or lymph the mass is considered to have become malignant The renegade cells are likely to establish new tumors metastases throughout the body These may become lethal by disrupting a vital organ Fighting Cancer by Attacking Its Blood Supply Capillaries tiny blood vessels extend into almost every tissue in the body replenishing nutrients and carrying off waste products Usually capillaries do not increase in size or number because they are lined with endothelial cells that do not divide However for example during menstruation or when tissue is damaged the vessels begin to grow rapidly This proliferation of new capillaries is called angiogenesis or neovascularization and is typically shortlived and turned off after one or two weeks Tumor cells can turn on angiogenesis by releasing angiogenic proteins and suppressing angiogenesis inhibitors As new blood vessels bring in fresh nutrients and proteins known as growth factors angiogenic growth factors vascular endothelial growth factors VEGF the tumor mass can expand Neovascularization appears to be one of the crucial steps in a tumor s transition from a small harmless cluster of mutated cells to a large malignant growth capable of spreading to other organs throughout the body Tumor cells usually can t trigger angiogenesis when they first arise in healthy tissue Unless the deranged cells become vascularized the mass will not become larger than the size of a pea If researchers can determine how mutated cells trigger angiogenesis and thus how to interrupt the process they could have a new anticancer therapy 1989 First clinical trial of an antiangiogenic agentinterferon alpha 1992 First antiangiogenic drug for cancer patients TNP470 entered clinical trials Endothelial cells that make up the walls of a capillary have receptors for vascular endothelial growth factor VEGF Binding of VEGF to these receptors causes the endothelial to proliferate and form new capillaries growing towards the source of VEGF the cancer cells Metastasis Metastasis is the process whereby cancer cells detach from the parent tumor and by entering the vascular or lymphatic system spread throughout the body and initiate new tumors at distant sites The new tumors are called metastatic tumors or metastases Tumor cells may enter the bloodstream directly by crossing the wall of a blood vessel or by crossing the wall of a lymphatic vessel that ultimately discharges its contents into the bloodstream Tumor cells that have entered a lymphatic vessel often become trapped in lymph nodes along the way giving rise to lymphnode metastases Less than one in every thousand malignant tumor cell that enters the bloodstream will survive to produce a tumor at a new site Metastatic cancer cells usually enter capillaries near or in the primary tumor and end up in the venous circulation They pass through the heart The first capillary bed they encounter after escaping the primary tumor is usually the lung Slower ow rates of blood in a capillary bed facilitates the exit of metastatic cells through the thin walls of these blood vessels and into the neighboring tissues where an escaped metastatic cell can proliferate to form a new tumor So the lung is a common site for metastatic tumor growth for many types of cancer melanoma breast cancer etc Exceptions O In the case of colorectal cancers the first capillary bed the metastatic cells encounter is the liver so colorectal cancer often spreads first to the liver 0 Sometimes cancer cells carry receptor molecules that are specific for some other cell type Prostatic cancer cells for example often express receptors for adhesion molecules on bone cells and therefore often metastasize to bone Summary of the process of metastasis 1 Cells grow as benign tumors 2 Break through basal lamina 3 Invade capillary and travel through bloodstream 4 Adhere to blood vessel wall in liver 5 Escape from blood vessel 6 Proliferate in different area Chapter 18 Control of Gene Expression in Eukaryotes Animal cells can be controlled on the level of PE JNH Chromatin remodeling Splicing of the primary RNA transcript mRNA stability Post translational modifications Transcriptional Control in Eukaryotes vs Prokaryotes Bacteria has a promoter that consists of the pribnow box 10 region and the 35 region In most bacterial genes the promoter is all that is necessary for RNA polymerase to sit down on the DNA and begin transcription Eukaryotic RNA polymerase does not bind to its promoter transcription does not occur without the assistance of other proteins Eukaryotic Promoters Eukaryotic promoters have a sequence that resembles the Pribnow box called a located 25 to 35 to the transcription start site RNA polymerase cannot directly bind to the promoter the TATA box instead a protein called TATA box binding protein binds at the promoter site 0 TBP induces a sharp bend in the DNA 0 TBP is a subunit of a protein complex called I TFIIID TBP 13 TAF proteins TBP Associated Factors After TFIID binds to the TATA box and bends the DNA a set of additional proteins TFIIA TFIIA TFIIE TFIIH are recruited to the promoter These proteins are called Once the general transcription factors have assembled on the promoter RNA polymerase can bind Activator Proteins The assembly of the general transcription factors on the promoter requires assistance of additional gene regulatory proteins called These proteins bind adjacent to the promoter or at more distant locations Activator proteins can assist in the assembly of general transcription factors on the promoter even though they are so far away due to the exibility of DNA The activator at enhancer sites binds comes in direct contact to help assemble transcription factors because the DNA can bend to make a loop to allow it to do so Most often the interaction between the activator proteins and the general transcription factors involves a protein complex called a and act to modify the nucleosome structure r activator protein n u 1 t enhancer TATA box start of transcription binding site for BINDING DF activator protein GENERAL TRANSCRIPTION FACTORS R NA POLYMERASE MEDIATOH CHROIMIATIN HIEMDDEILIHNG COMPLEXES AND HISTQNE ACETYILASES 1 il l chromatin r remodeling 39 complex mediator 39 k I i p 39 lhistone acetylases THAMSGHIP TWDN BEGINS Figure 649 Molecular Biology of the Cell lth Edition Chromatin 0 Eukaryotic DNA wraps around histone proteins to form The combination of DNA and histones is called chromatin 0 Chromatin can exist both in an extended beads on a string state and in more condensed forms most specifically a form called the 30nm fiber 0 The 30nm fiber is the basic state of most chromatin in the cells I Genes are inaccessible for transcription in a 30nm fiber 0 Accessible in the beads on a string form 0 Chromatin remodeling proteins and histone acetylases act to convert chromatin in the 30nm form to the more accessible beads on a string form which permits the binding of transcriptional activators and permits RNA polymerase to transcribe 0 Also Chromatin remodeling complexes 0 1 Reposition the nucleosome on the DNA often exposing enhancer sites 0 2 Loosen the DNA on the nucleosomes for RNA polymerase 0 Other chromatin remodeling complexes return the nucleosomes back to their standard state when gene expression is finished Histones and nucleosomes 0 Nucleosome core of 8 histone proteins 2 each of histones H2A H2B H3 and H4 0 Each of the 4 types of histone protein that form the octameric core of a nucleosome has it amino terminus aning free These free waving amino terminal segments are rich in the positively charged amino acid lysine These lysines in the amino terminal histone segments are what can become acetylated by the Acetylation of these lysines has several functions in gene activation including unpacking of the 30nm fiber and also recruiting general transcription factors such as TFIID once the fibers have been unpacked Acetylation of histone lysines by is associated with decondensing chromatin and making genes accessible for transcription 0 Acetylation activation Removing these acetyl groups from the histones by silence gene eXpression by repacking the nucleosomes back into 30 nm fibers Alternative RNA splicing Another aspect of regulation gene eXpression in eukaryotes Different proteins are encoded by a single gene but the primary RNA transcript is spliced differently in the two different cell types to produce 2 mRNAs 0 Different mRNAs I different but related proteins EX The eXpression of two different versions of the protein tropomysin in skeletal muscle versus smooth muscle RNA interference micro RNAs miRNA molecules act to target certain mRNA molecules to which they are complementary in sequence for rapid degradation There are several hundred genes that encode miRNA molecules that have evolved to target specific mRNAs in the cytosol thereby limiting the lifetime of these mRNAs and limiting expression of the protein encoded by the target mRNA These miRNAs initially form a hairpin structure which is trimmed in the nucleus then eXported to the cytosol where the loop at the end is cleaved yielding ultimately a 22 nucleotide long double stranded mature miRNA molecule In the cytosol the RISC compleX a set of proteins binds the double stranded miRNA removing one of the strands The remaining strand is complementary to a sequence on the target mRNA The miRNA RISC compleX then binds the target mRNA and a ribonuclease component of the RISC compleX cleaves the mRNA If there is an imperfect match between the miRNA and the mRNA the mRNA is not cleaved but the RISC miRNA compleX remains bound to the mRNA thereby inhibiting its translation Chemical Carcinogenesis What causes cancer 1 Environment a Radiation UV Xrays cosmic rays b Chemicals c Viruses d Bacteria Helicobacter pylori 2 Heredity a Loss of one copy of a tumor suppressor gene aka antioncogene recessive oncogene b Alterations in the levels or activity of certain detoxifying enzymes that act to chemically modify polycyclic aromatic hydrocarbons PAHs c Alteration in the levels or activity of the enzymes that repair DNA damage Chemical Carcinogenesis 0 Percival Pott British physician made the first connection between an occupational exposure to chemicals and the subsequent development of cancer 1775 0 High incidence of scrotal cancer in chimney sweeps hypothesized to be due to exposure to coal soot 0 Early 1900s epidemiological studies showed high skin cancer rates among men in the coal tar industry from exposure to extraction solvents 0 1915 Yamagiwa and Ichikawa applied possible carcinogens coal tar extract on mice At first no tumors developed After multiple applications for 23 months multiple tumors developed 0 It was subsequently shown that the active ingredients in coal tar were certain polycyclic aromatic hydrocarbons PAHs PAHs 0 The most basic cyclic hydrocarbons cyclohexane and Benzene are not very carcinogenic 0 Polycyclic aromatic hydrocarbons however are very carcinogenic especially Benzapyrene and dibenzahanthracene 0 They are made up of many unsaturated aromatic benzene rings The Two Stage model of chemical carcinogenesis 1 Initiation mutagenesis with a chemical carcinogen that causes mutations in the DNA 2 Promotion cell proliferation with a chemical promoter such as phorbol ester the active ingredient of croton oil 0 Exposure to the initiator must precede exposure to the promoter Exposure to multiple shortly spaced doses of the promoter is necessary Widely spaced doses are not effective Promotion is not necessary if multiple exposures of initiator occur The promoter causes proliferation of the mutant cell leading to more cells with the mutation Chemical carcinogens are generally electrophilic molecules that react well with proteins as well as RNA and DNA although the critical target is DNA 0 Determined by applying carcinogens to mice The potency of the carcinogen correlated with their propensity to bind DNA The role of mixed function oxidases MFOs detoxifying enzymes For many chemical carcinogens especially PAHs it is a metabolic derivative of the original molecule that is the actual carcinogen Cells contain enzymes called mixed function oxidases which act on large insoluble molecules to introduce hydroxyl groups into them thereby making them watersoluble so they can be excreted from the body These hydroxylation reactions proceed in a stepwise fashion and involve very reactive epoxide intermediates Ex Catalyzed by mixed function oxidases benzpyrene forms an epoxide then dihydroxylates repeatedly to form BPDE benzpyrene diol epoxide the ultimate carcinogen The carcinogen is capable of reacting with guanine in DNA that leads to a massive distortion of the DNA molecule Benzpyrene therefore is a mutagen for any cell that has the enzymes that produce this intermediate If the enzymes that stabilize the intermediate are less abundant there will be more of the mutagen Benzpyrene reaction In some tissues Enzyme 3 might be more active or abundant than enzyme 4 causing a higher concentration of BPDE III in the cell and therefore a higher rate of mutation Similar variations might occur between different species of animals thus accounting for the difference in sensitivity to a given carcinogen among different animals Ex one PAH may cause mostly liver cancer in one species leukemia in another species etc Relatedly different individuals within on species can have different sensitivities to various carcinogens Ex Your grandmother drank and smoke all her life but lived to be 93 whereas if you do the same you may die of lung cancer at 48 Ames test Since the early sixties they were introducing chemicals into bacteria to see if they cause mutations The realization that many PAHs are not directly mutagenic but are instead converted to mutagenic molecules by the MFOs in the animal lead to a modification of the mutagenicity screen called the Ames Test The chemical is incubated with rat liver extract provides MFOs before being added to the bacterial culture If reactive intermediates of the test chemical are produced they can then be detected by the mutations they induce in the bacterial culture EX In one Ames test they showed that the bacteria was mutated because histidine requiring bacteria acquired the ability to make histidine from glucose Not all reactive intermediates react With DNA Not all DNA modifications lead to cancer DNA repair enzymes fix most Oncogenes cancer genes genes that induce infected cells to proliferate How do retroviruses acquire an oncogene and thereby become an acute oncogenic retrovirus 1 Acutely transforming retroviruses contain oncogenes Oncogenes are part of growth hormone signal transduction pathways These genes were acquired by the virus through a rare recombination event with a host cell mRNA For each of the many viral oncogenes ex vsrc that have been identified there is a gene present in all cells called a cellular oncogene or protooncogene ex csrc encoding a protein involved in normal growth regulation Several hundred oncogenes have been discovered 2 Slow chronic leukemia retroviruses activate cellular oncogenes ex cmyc by promoter insertion viral LTR 3 Chromosomal translocations sometimes move cellular oncogenes to active sites strong promotersenhancers located on other chromosomes ex cmyc in Burkitts lymphoma 0 Characteristic translocations occur in many human cancers not just Burkitts lymphoma 0 Ex Philadelphia chromosome 922 translocation is characteristic of chronic Myelogenous Leukemia CML The translocation event results in the production of a mutant cAbl protein that causes unregulated growth 4 Many tumors have mutated cellular oncogenes ex cras that can transform recipient normal cells in DNA transfection assays 0 Transfection assay put human tumor cells or chemically transformed rodent cells in dish Take DNA add to calciumphosphate buffer Apply prepared DNA to cells and culture Cells transformed 0 The mutant forms of the ras gene identified in DNA from a variety of cancer cells all encode altered version of the ras protein ex RasD that are unable to hydrolyze bound GTP to GDP ie they have lost their GTPase activity This means that these mutant ras proteins are constitutively turned on 0 Ras is a Gprotein Active Ras GTP bound is able to bind to a downstream target enzyme and activate it Inactive Ras GDP bound is unable to bind to a downstream target 0 The mutated Ras in cancer cells cannot be shut off by GAP Ex Src oncogene 0 Src is a growth regulatory gene 0 The acute virus acquires the src gene by a rare event where a slow leukemia virus comes into a cell and acquires the src gene from the host cell at the level of src mRNA and is now an acute cancer virus like RSV 0 The src oncogene is spliced from the host cell mRNA converted to DNA via reverse transcriptase and added between the end of the env gene and the 3 LTR in the acute sarcoma virus 0 RSV is a nondefective virus RNA tumor virus In almost all other cases the recombination process that caused acquisition of the oncogene results in a simultaneous loss of viral genes gag pol env Specific Oncogenes Oncogene Protooncogene Function erbB Protein kinase tyrosine Epidermal growth factor EGF receptor myc Gene regulatory protein transcription factor of the HLH family ras Gprotein GTPbinding protein sis Plateletderived growth factor B chain src Protein Kinase tyrosine fos Transcription factor Products associate to form APl gene regulate protein Summary of Oncogenes 1 Environment a Viruses 0 Oncogenic retroviruses like RSV led to the discovery of genes that acutely transforming retroviruses have called viral oncogenes 0 It was discovered that viral oncogenes are cellular genes that slow chronic retroviruses have captured thereby becoming converted into acutely transforming retroviruses 0 The host cell genes that were captured by the retrovirus are called protooncogenes b These protooncogenes are present in all normal cells They are basically the genes that encode the proteins that function in the signal transduction pathways that are activated in the response of cells to growth stimuli such as the binding of a growth hormone to its cellular receptor These signal transduction proteins are under tight control in normal cells they are normally inactive and become activated only transiently in response to a growth signal The captured oncogenes of acutely transforming retroviruses express mutated versions of these proteins that are constitutively active thus when the virus infects the cell the oncogene protein encoded by the virus gives the cell a continuous growth signal causing dysregulated growth of the infected cell Chemicals Carcinogenic chemicals cause cancer by mutating the protooncogenes in cells such that the gene is now an oncogene and encodes a constitutively active component of a growth hormone signal transduction pathway Ames test biological assay used to determine the mutagenic potential of chemical compounds Radiation Radiation causes mutation of the same protooncogenes Chemical carcinogens and radiation also act on another class of genes involved in carcinogenesis anticancer genes called tumorsuppressor genes 2 Heredity a b Tumor suppressor genes Class of genes whose loss via mutation can convert a cell to a cancer cell like one or more oncogenes Function normally to regulate and inhibit growth Discovered by an investigation of the hereditary component of cancer studying cancers that run in the family In the case of a hereditary predisposition to a particular cancer or set of cancers the individual inherits one good and one defective allele of one of these tumor suppressor genes Cancer is initiated when the remaining good allele of the gene is lost in one of that individual s cells Even individuals with two good alleles of all the tumor suppressor genes can get cancer when both alleles are lost or become defective EX Rb and p53 Telomeres The highly shortened telomeres that arise in the dysregulated growth of premalignant cells initiate a stopgrowt signal that arrests the growth of many premalignant tumors Apoptosis Cells normally die off under programmed cell death called apoptosis which is initiated by a set of enzymes called caspases Certain genes such as Bel2 encode proteins that inhibit apoptosis Activation of these antiapoptosis genes is common in human cancers The Role of Viruses in Cancer DNA Tumor Viruses 0 Viruses play a role in about 15 of human cancers worldwide 0 These viruses have genes that induce infected cells to proliferate viral oncogenes 0 Mere proliferation of infected cells though is not enough to make the cells fully cancerous Infection with one of these viruses just increases the probability that you might develop a particular kind of cancer 0 The virus is a kind of cocarcinogen which acts together with other cofactors like chemical carcinogens in the environment to result in cancer Virus Associated Tumors Cofactors DNA Viruses Papillomavirus Ex HPV Responsible for most genital and cervical cancer Warts benign and carcinoma of the uterine cervix Smoking herpes Simplex virus infection HepatitisB responsible for most liver cancer in SE Asia Liver cancer A otoxin alcohol smoking EpsteinBarr Virus EBV Causes mononucleosis Burkitt s lymphoma Cancer of B lymphocytes Malaria infection RNA Viruses Human Tcell leukemia virus typel an oncovirus Adult Tcell leukemialymphoma Associated with Japan West Indies and South US Unknown HIV a lentivirus Kaposi s sarcoma Certain type of herpesvirus EBVBurkitt s Lymphoma 0 EBV infects B cells antibodyproducing cells infection by EBV immortalizes these cells 0 Chronic malarial infections cause continuous proliferation of B cells to produce antibody to fight off malarial infection The large number of B cells increases the probability of a mutant B cell arising in the population Immortal B cells accumulate 0 Eventually a mutation involving the exchange of chromosomal segments between chromosome 8 and 14 occurs The translocation occurs at the site of the gene encoding the myc protein on chromosome 8 and the strong promoter for immunoglobulin H chains on chromosome 14 This results in the overproduction of myc mRNA and therefore the myc protein 0 The myc protein activates the transcription of genes that cause cell proliferation independent of any antigenic stimulation This results in an even larger pool of B cells and further mutations leading to leukemia 0 An 814 chromosomal translocation is characteristic of the leukemic cells in all Burkitt s lymphoma patients as is EBV infection Experimental Tumor Viruses DNA Tumor Viruses Provirus Polyoma Virus normally grows in mice harmless put into monkey cells cause cancer Simian Virus 40 SV40 normally grows in monkeys harmless put into mouse cells cause cancer The viral oncogenes of DNA tumor viruses evolved together with the rest of the viral genes they encode proteins which bind to and neutralize growth inhibitory host cell proteins such as p53 and Rb tumor suppressors Neutralization of p53 or Rb releases the brakes and causes cells to initiate DNA synthesis The tumor virus uses the host cell DNA replicating machinery to replicate viral DNA Ex SV40 is put in both monkey cells and rodent cells In monkey cells the viral DNA replicates forms virions in the nucleus the cells lyses and the virions are released In a rodent cell the viral DNA does not replicate the cell continues to grow and divide Either the cell loses the viral genome and reverts to normal growth abortive transformation or the viral genome becomes integrated into the cell DNA and the cell progeny are permanently transformed RNA Tumor Viruses Retrovirus Ex Chronic Murine Leukemia Virus MuLV parent virus and Avian Leukosis Virus ALV Acute Various isolates of acute MuLV avian leukemia and sarcoma viruses mutant version of parent virus Eg Rous Sarcoma Virus mutant gene src Myelocytomatosis Virus aka MC29 mutant gene myc etc Acute RNA tumor viruses have oncogenes that are mutated versions of cellular growth genes that the parent chronic virus acquired via a rare recombination event Most retroviruses do not lyse the infected cell or even make it sick They just use the host cell RNA polymerase to replicate themselves and continuously release virus from the infected cell The viral oncogenes of acute RNA tumor viruses are captured cellular genes involved in normal cell growth regulation Expression of the proteins encoded by these genes usually in mutated constitutively active forms causes the infected cells to proliferate This proliferation of the infected cell is irrelevant to the virus life cycle Structure of a retrovirus The genome of a retrovirus is single stranded RNA 3 genes of chronic leukemia retroviruses are gag pol and env O gag encodes the capsid protein 0 pol encodes the reverse transcriptase O env encodes the envelope protein How retroviruses enter the cell HIV specifically 0 HIV envelope protein gp120 bind the CD4 protein on T cells other retroviruses bind other proteins on other cells 0 After attachment the virus membrane fuses With the cell membrane 0 Capsid structure releases viral genome into cell Life Cycle of the retrovirus Details on Steps of the Retrovirus Life Cycle 0 Reverse transcriptase has 2 enzymatic activities 0 1 It is a special DNA polymerase that can synthesize DNA on either an RNA or DNA template 0 2 It has RNase H activity H hybrid meaning if it encounters a hybrid RNADNA molecules it Will digest away the RNA molecule 0 LTR Sequences Long Terminal Repeats sequences at the end of the RNA molecule that have the sequence U3 R US LTR sequences function in the late phase of a retrovirus in mRNA synthesis off proviral DNA 0 The LTR sequences that ank the viral genes function as enhancers and promoters at the 5 end and terminators Poly A site at the 3 end for the synthesis of the viral primary RNA transcript 0 Processing of retroviral RNA including splicing occurs just as in host cells mRNAs O 1 3 cleavage and addition of poly A tail 0 2 Intron excision exon ligation
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