question

How do viral infections cause harm?

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Their ability to multiply inside infected cells and releasing their progeny

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Tumor viruses

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Certain viruses that force their host to live and proliferate uncontrollably Notion was rejected but led to insights on the pathogenesis of human cancer

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Properties of transformed cells

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Altered morphology Loss of contact inhibition Ability to grow without attachment to solid substrate Ability to proliferate indefinitely Reduced requirement for mitogenic growth factors High saturation density Inability to halt proliferation in response to deprivation of growth factors Increased transport of glucose Tumorigenicity

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Tumorigenicity

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The ability to form tumors if injected into an animal model.

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How are normal cells different from cells transformed by tumor viruses in regards to proliferation?

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Normal cells in a culture will not proliferate unless they are provided with serum and serum-associated growth-stimulating factors; cells transformed by a variety of tumor viruses have reduced requirements for these factors. Also normal cells have a limited proliferative potential (they stop multiplying after a certain number of cell divisions) while cancer cells seem to be able to proliferate indefinitely (immortalization)

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Anchorage independence

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Ability to multiply without attachment to a solid substrate

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What is the benefit in using nude mice in tests of tumorigenicity?

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Lacking a thymus, they are highly immunocompromised and therefore relatively receptive to engrafted cells from genetically unrelated sources, including those from foreign species. In addition, because these mice are hairless, it is easy to monitor closely the progress of tumor formation afer transformed cells have been injected under their skin.

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Rous's protocol for inducing sarcomas in chickens

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Remove sarcoma from breast muscle of chicken Grind sarcoma with sand Pass sarcoma/sand mixture through a fine-pore filter Inject this filtrate into the wing web of a young chicken Observe development of a sarcoma weeks later Repeat process

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Why did Rous's protocol prove that the sarcoma was caused by a virus?

answer

The carcinogenic agent was clearly very small, since it could pass through a filter, thus it was a virus

question

Why was Fibiger's Nobel Prize winning work debunked?

answer

He had reported that stomach cancer in rats was caused by spiroptera worms they harbored, but it was later found that the rats actually had metaplastic epithelia because of vitamin deficiencies (they lived off sugar in sugar cane refineries)

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What did Rous's finding of sarcoma virus reinforce?

answer

The belief that virtually all human diseases were caused by infectious agents

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What was the outcome of Fibiger's embarrassment?

answer

It led to a shift in studying chemically induced cancers

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Dulbecco's Research

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*Harry Rubin found that when stocks of RSV were introduced into Petri dishes carrying cultures of chicken embryo fibroblasts, the RSV-infected cells survived *RSV parasitized the cells, forcing them to produce a steady stream of progeny virus particles *RSV-infected cells displayed many of the traits associated with cancer cells *Foci of cells appeared after infection *Demonstrated that cancer formation could be studied at the cell level under a microscope

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Temin and Rubin's experimental model

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*They would expose cells to a solution of virus particles and place a layer of agar about the cell layer, preventing free virus particles from spreading from initially infected cells to uninfected cells *RSV-infected cell would induce a focus, in which cells lost contact inhibition and piled on top of each other *They learned that it could be shown that all cells within a given focus were descendants of a single progenitor cell; this is now termed a whole clonal outgrowth

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What did Temin and Rubin's model demonstrate?

answer

Tumor masses arising in human and animals also are clonal out growth from a single progenitor cell

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Berkeley experiments

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*Mutant RSV developed that was capable of transforming chicken cells at 37 degrees but not 41 degrees *Cells acted like cancer cells at the lower temperature but when raised weeks later, cells would lose their transformed shape and revert to the shape and growth pattern of cells that hadn't experienced an RSV infection *Showed that copies of the genome of the infecting virus persisted in cells for weeks after the initial infection *The viral transforming gene was required to both initiate and maintain the transformed phenotype of the virus-infected cells

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Retrovirus life cycle features

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*Single stranded RNA genome *Use DNA intermediates to replicate *Reverse transcriptase (a viral enzyme that comes from the virus itself) converts the viral RNA into a complementary strand of DNA *Complementary DNA is copied to produce a double-stranded molecule of viral DNA *After this DNA is integrated into the host genome using integrase

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What was Temin's solution to how RSV succeeded in transmitting its genome?

answer

*After RSV particles infected a cell, they made double-stranded DNA copies of their RNA genomes *These sDNA version of the viral genome became established in the chromosomal DNA of the host cell *DNA version of this viral genome (the provirus) assumed the configuration of a cellular gene and would be replicated each time the cell replicated its chromosomal DNA *Proviral DNA could also serve as a template for transcription

question

Discovery of rabbit fibroma virus/Shope papilloma virus

answer

*Discovered by making a filtered extra of a tumor from a wild rabbit, and by injecting the filtrate into another wild rabbit=benign growth *When this filtrate was injected into a domestic rabbit, there was a malignant growth *Could not isolate infectious growth from this domestic rabbit because the virus was integrated into chromosomes

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SV40 virus

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Launches a lytic cycle, involves formation of large vacuoles prior to cell death and releases thousands of progeny virus particles from these vacuoles

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Adenovirus

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*Larger than polyoma and pappiloma viruses, originally found in upper respiratory tract infections in humans, highly oncogenic in animals *Only a portion of the viral genome is integrated into the host genome

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Why are nude mice advantageous for in vivo studies of tumorigenicity?

answer

Lack of thymus=little to no immune response Hairlessness=ability to monitor tumor formation

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Transformed cell growth in in vitro systems

answer

Anchorage independent, can grow in significantly less serum than normal cells, expression of virus coded antigen

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NIH 3T3 cells

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Mouse fibroblast monolayer, highly sensitive compared to other assays for focus formation

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How do we know the tumor virus genome becomes part of DNA transfected cells?

answer

If this was not the case, transformed cells would revert to normal state after a few generations of growth DNA tumor viruses induce tumor associated proteins (t antigens) Additional info: t-antigens are virus specific

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gag gene

answer

Encodes proteins and nucleoprotein core

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pole gene

answer

encodes reverse transcriptase and integrase

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env gene

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encodes glycoprotein spikes of the viron

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src gene

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encodes the src protein, causes cell transformation

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oncogene

answer

a gene capable of transforming normal cell into tumor cells

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One main theory of how most human cancers arise and other main points

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Carcinogens acts as mutagens and function by mutating normal growth-controlling genes into oncogenes Most human cancer does not spread from one individual to another Cancer is a disease of the genes and is susceptible to the tools of molecular biology and genetics

question

Insertional mutagenesis

answer

Insertion of viral genome adjacent to cellular genes in cellular chromosomes, insertion of ALV at the c-myc locus causes slow activation of proto-oncogenes

question

Three ideas originated from the proto-oncogene concept

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1. Viruses could activate proto-oncogenes into potent oncogenes 2. All transforming powers of oncogenic viruses are derived from the presence of an oncogene in the viral genome; this single gene leads to change in shape, metabolism, and growth and behavior in transfected cell 3. RSV and v-src oncogene represent a model for behavior of other types of retroviruses

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c-src vs. v-src

answer

c-src is normal in normal cells, v-src acts as an oncogene and transforms infected cells

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Protooncogenes

answer

Precursors to active oncogenes

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Formation of RSV

answer

ALV captures c-src to form RSV, RSV exploits the kidnapped cellular gene to transform cells, lends to v-src

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Simple life cycle of viruses

answer

Genome of RNA virus encodes its own RNA dependent RNA-polymerase to replicate its viral genome, and capsized and lipid membrane

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Interaction of virus with host cell

answer

Host cell dies--virulent host cell survives--temporate

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Two major classes of mechanisms of transformation by tumor viruses

answer

Permanent activation of mitotic signal transduction cascades Disruption of the circuits that regulate cell cycle progression

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Transfection

answer

DNA is extracted from cancer cells growing in Petri dish DNA is introduced in a phosphate buffer, calcium ions are added and precipitate formed Crystals added to monolayer culture of normal cells, calcium phosphate crystals facilitate the uptake of DNA fragments by cells If transforming gene is present, it may be incorporated into the genome of one of the recipient cells and transform it

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Myc

answer

Acts as a transcription factor and controls the expression of several genes; may become activated by gene rearrangement or amplification

question

Src

answer

Tyrosine kinase, transfers phosphate groups onto target molecules Phosphate addition/removal process acts like an on/off switch to control the activity of target molecules

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Two classes of tumor viruses

answer

DNA tumor viruses and RNA tumor viruses (retroviruses)

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What do DNA and RNA tumor virus life cycles have in common?

answer

The ability to integrate their own genome into the genome of the host cell (this is not a prerequisite of tumor formation)

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Two ways a virus can cause cancer

answer

Carry an oncogene into a cell or activating a cellular proto oncogene

question

EMT

answer

Epithelial mesenchymal transformation, epithelial cells undergo this because viral genome integrates into host cell's genome

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Tumor suppressor genes

answer

Limits growth of cells, protective gene; when mutated it fails to keep cancer cells from growing; anti-oncogene

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Is the mutation in tumor suppressor genes recessive or dominant?

answer

Recessive

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Integrase

answer

Encoded by retroviral DNA, integrates newly synthesized viral DNA into the host cell genome

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Reverse transcriptase

answer

Copies viral DNA into double stranded DNA

question

What shows that oncogenes are genetically dominant over proto-oncogenes?

answer

Only one copy of an oncogene is sufficient to cause a change in behavior

question

Could activation of endogenous retroviruses lead to cancer in humans?

answer

Most likely no, no retroviral particles in human tumors could be verified

question

How was the presence of nonverbal oncogenes proved?

answer

DNA transfection studies

question

DNA transfection studies

answer

Involved introducing DNA from cancer cells into normal cells then determining if recipient cells became transformed 1. DNA from cancer cells extracted 2. Mixed with phosphate buffer 3. Calcium ions added to facilitate uptake of DNA by cells 4. If DNA is incorporated into the genome of one of the recipient cells and transforms it, proves that cells were transformed by oncogenes

question

Advantages of tumor DNA transfection assay

answer

Easier to screen a lot of samples Results obtained more quickly and procedure is simpler than in vivo test NIH-3T3 cells good at taking up and expressing foreign DNA

question

Disadvantages of DNA transfection assay

answer

If oncogenes are specific for particular cell types, this may not be detected with mouse fibroblasts Large genes may be missed (less likely to be transfected intact) NIH-3T3 cells are a permanent cell in, genes involved in early stages of carcinogenesis may be missed Will not detect tumor suppressor genes

question

Oncogenes

answer

Associated with the stimulation of cell division, is dominant (cancers result from only one mutant allele), those detected in human tumor cell lines are related to those that are carried by transforming retroviruses A common set of cellular photo oncogenes might be activated by retroviruses of animals OR nonviral mutational mechanisms during the formation of cancers (particularly in humans) Structurally and functionally heterogeneous group of genes, whose protein products act pleiotropically and affect multiple complex regulatory cascades within the cell Products regulate cell proliferation, growth, differentiation, and control of cell cycle and apoptosis

question

What was the critical difference between H-ras in bladder carcinoma and H-ras in normal human DNA?

answer

There was a point mutation in the oncogene G-->T, causing GGC-->GTC, glycine-->valine

question

Quantitative difference between proto oncogene and oncogene

answer

Coding function not altered, but gene under control of a promoter/enhancer or translocated to a new site (and gene product is transcribed at a higher rate Bottom line: Overproduction of a normal gene product

question

Qualitative difference between proto oncogene and oncogene

answer

Coding sequence is altered, so protein product is functionally different (usually hyperactive)

question

Categories of oncogenes

answer

Growth factors, transcription factors, membrane receptors, signal molecules

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