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57 Cards in this Set
- Front
- Back
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How have viruses been implicated in cellular transformation? |
Both as tumor promoters and tumor initiating agents (observations further suggest that many oncogenes implicated in tumorigenesis have an evolutionary relatedness with viruses) |
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How do viruses transform cells? |
Transforming viruses do now lyse host cells, they either integrate or exist as episomes (non-essential genetic element) within cells |
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How is an oncogenic virus released from the host cell?
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by the process of budding |
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Oncogenic DNA viruses when do they integrate? Do they often produce progeny? |
randomly integrate rarely produce progeny (unless host cell's immune response is compromised) |
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Oncogenic RNA viruses: Integration? Progeny? |
mostly productive, with integrative events occurring during life cycle |
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If a virus is oncogenic, it should ____ it's host cells and the host cells should demonstrate certain key ____ traits. |
transform, neoplastic |
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What properties do transformed cells exhibit? |
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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How is the morphology altered in transformed cells? |
Rounded shape, refractive in phase-contrast microscope |
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What does it mean to say that transformed cells have lost contact inhibition? |
They've developed the ability to grow over one another |
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What is anchorage independence? |
ability to grow without attachment to solid substrate |
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What is immortalization?
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ability to proliferate indefinitely |
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What does it mean when transformed cells have high saturation density? |
ability to accumulate large numbers of cells in culture dish |
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What does tumorigenicity mean for a transformed cell? |
can produce tumors in an "in vivo" model |
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What is the ultimate proof of neoplastic potential in an "in vitro" model of neoplasia? |
Tumorigenicity of those cells in-vivo |
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Why is the hairless or NUDE mouse a good "in vivo" model of tumorigenicity but not immogenicity (antigenicity)? |
NUDE mouse has no thymus and therefore no immune system (no graft rejection, no antibody formation, no cell-mediated immune responses, no delayed-type hypersensitivity response, no killing of virus-infected or malignant cells) |
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In order to assess the role of the immune system in antigenicity (immunogenicity), what type of model is needed? |
A syngeneic model (syngeneic means genetically similar or identical and hence immunologically compatible, especially so closely related that transplantation does not provoke an immune response) |
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What does it mean to say that the NUDE mouse is a good "in vivo" model of tumorigenicity? |
In general, degree of differentiation and phenotypic characteristics of human tumorsgrowing in Nude mice reflects that of original tumor taken from patient |
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T/F: Aside from two human viruses (HCV which doesn't integrate and HTLV1 which does), most RNA viruses initiate transformation in animal cells; butthese can be used to investigate mechanisms of oncogenic action of viruses in general. |
True |
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What are the transforming RNA viruses we're learned? (5) |
Avian Leukosis Virus (ALV) Rous Sarcoma Virus (RSV) Murine Leukemia Virus (MLV) Human T-cell Leukemic Virus (HTLV) Hepatitis C Virus (HCV) |
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Name the 3 Animal Transforming Retroviruses |
Avian Leukosis Virus (ALV) Rous Sarcoma Virus (RSV) Murine Leukemia Virus (MLV) |
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Name the Human Transforming Retrovirus |
Human T-cell Leukemic Virus (HTLV) |
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Name the Human Non-Integrative Transforming RNA virus |
Hepatitis C Virus (HCV) |
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While each also has further characteristic transforming sequences in its genome, all transforming retroviruses have a common structure. What are the 3 main viral proteins that the retroviral genome codes for? What are each parts of the structure used for? |
1. Envelope protein (env gene) for recognition and attachment 2. core protein (gag gene) that forms a complex protein coat (capsid) and encloses two DD RNA copies 3. Reverse transcriptase (encoded by pol gene) - each virus carries several copies of RT protein in it's genome |
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What is reverse transcriptase? |
It is an RNA-dependent DNA-polymerase |
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What happens to a transforming retrovirus as it buds from the cell? |
It becomes enveloped |
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What does it mean to say that atransforming retrovirus buds (no lysis) from an infected cell? |
as RNA virion leaves cell, it wraps itself with a patch of lipid bilayer taken from the plasma membrane of the infected host cell, forming a lipid envelope |
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Rous Sarcoma Virus (RSV) and Avian Leukosis Virus (ALV) are related. RSV and ALV are homologous avian retroviruses, with what one main difference? |
the presence of src in the RSV genome |
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ALV is a ___-acting retrovirus that causes.... |
SLOW acting retrovirus causes lymphoid leukosis, fibrosarcoma, various myeloid diseases in chickens |
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RSV is a ____-acting retrovirus that carries in its genome an additional ____ |
FAST acting retrovirus v-src |
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What is the importance of the additional v-src in the genome of RSV? |
v-src codes for an oncoprotein (an unregulated tyrosine kinase) v-src converts ALV into RSV which now rampantly produces various types of sarcoma |
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As cells transform, they show ______ properties. |
neoplastic |
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Chick embryo fibroblasts can be transformed "in-vitro" by _____. |
RSV |
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What do temperature sensitive RSV mutants demonstrate regarding transformation? |
Temperature sensitive (Ts) RSV mutants demonstrate that expression of v-src (genome integration plus src) is required to maintain transformation (to initiate the transformed phenotype) (Ts mutant produces v-src protein ONLY at permissive temp, 37C) |
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What are the two methods in which ALV can initiate host cell transformation? |
1. ALV evolves into RSV and RAPID transformation of cells (proviral insertion and capture of host c-src into viral genome - evolves a new viral species (RSV), that can spread to other cells and produce RAPIDtransformation) 2. Insertional mutagenesis and SLOW transformation of cells (provirus insertion near host cell c-myc - initiation of host cell genomic instability, mutational events and cellulartransformation) |
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Method 1 of ALV transformation: ALV evolves into rapidly transforming RSV ALV infects what type of cells? Provirus integrates next to host ____. Transcription using host cell polymerase produces new viral RNA now containing ____. Viral RNA is packed into a new virion called ___. |
ALV infects chicken cells c-src v-src RSV |
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What is an orthologue? Give an example. |
An orthologue is a gene that is found in different species but probably evolved from a common ancestral pool by speciation ex. the human gene BRCA2 and the mouse gene Brca2 |
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Other animal viruses have evolved into rapidly transforming viruses by capturing ____. |
c-oncs |
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Insertional mutagenesis is a ___ probability event. |
Low probability (it is a hit or miss process) |
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For ALV, what is the evidence of insertional mutagenesis? |
in transformed chicken cells infected with ALV, proviruses were found integrated into host chromosomal DNA segments carrying c-myc (majority found between first non-coding region and the second exon in which the normal c-myc reading frame occurs) |
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What does it mean to say that insertional mutagenesis is a low probability event? What effect does this have on rate of transformation? |
Many weeks and many millions of ransom infectious events are required before insertion in the correct place and malignancies are triggered this explains the slow transforming effects of ALV and other slow-acting retroviruses (e.g. MLV) |
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T/F: In some cases, insertional mutagenesis involves the increased expression and regulation of a growth promoting gene sequence. |
True |
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T/F: In some cases, insertional mutagenesis involves the inactivation of a tumor suppressor gene. |
True |
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Whether insertional mutagenesis involves the increased expression and regulation of a growth promoting gene sequence OR the inactivation of a tumor suppressor gene, this simple depends on what? |
the insertional dynamics |
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How do transforming animal viruses usually up regulate host cellular genes? |
by insertional mutagenesis |
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How else can insertional mutagenesis lead to genetic instability of host cell? |
can lead to genetic instability of host cell if insertion results in: Point mutations Frameshifts Deletions, insertions DNA breaks, inversions DNA expression mutations |
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What is the only human infective retrovirus that has been found definitively to induce tumors in its host (after insertional mutagenesis)? |
T-cell Leukemic/lymphoma Virus (HTLV) |
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Who does HTLV infect? |
T-cell Leukemic/lymphoma Virus (HTLV) Infects~1% inhabitants of Kyushu (Japan), andendemic in some islands of Caribbean |
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How is HTLV transmitted? |
virus transmitted mother to baby, via sexual promiscuity, and through bloodtransfusion and drug users |
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20-40 yr after infection, a small # of proviral carriers develop ATLL. Life long HTLV infection (20-40 yr) produces 3-4% risk of developing adult T-cell leukemiclymphoma (ATLL) due to _________. |
retroviral integration |
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What is adult T-cell leukemic lymphoma (ATLL)? |
Highly aggressive non-Hodgkin’s lymphoma involving proliferation of mature T-cellsand pre-granulocytes |
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What is needed to maintain infection of ATLL? |
To maintain infection gag, pol, env (the 3 main ones) plus expression of two other viral genes tax and rex are needed |
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In a few individuals infected with HTLV infection, the provirus integrates into the T-cell genomes and granuloblast genomes. What does this integration lead to? |
Integration leads to up-regulation of viral v-tax, stimulating host cell IL2 and IL2Rexpression and T-cell autostimulation (excessive host T-cell proliferation) - increased production of host cell GMCSexpression also leads to production of pre-granulocytes (granuloblasts) |
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The other prominent tumor virus in humans is Human Hepatitis C Virus (HCV). Is it a retrovirus or a provirus? |
NO, it is NEITHER a retrovirus or a provirus. It is EPISOMAL - enveloped single stranded RNA virus with no known DNA intermediate or host integration |
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What has been observed about the mutation rate for the viral RNA-dependent RNA polymerase of Hepatitis C virus (HCV)? |
High mutation rate for viral RNA-dependent RNA polymerase (needed for replication, since it's a single stranded RNA virus with no DNA intermediate) |
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How is Hepatitis C virus (HCV) spread? |
Spread via blood to blood contact maintaining persistent, subliminal infection |
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In HCV, what do viral proteins induce in their host? |
Viral proteins induce host chronic inflammation |
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Individuals with HCV are predisposed to ____. In which part(s) of the world is this implicated? |
Individuals predisposed to HCC Implicated worldwide (>33m Chinese carry particle) |
