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Block 2 Cancer > Viral Oncogenesis > Flashcards

Viral Oncogenesis Flashcards

1
Q

Are viruses a major cause of cancer

A
  • FLV

- BLV (bovine leukemia virus) responsible for most leukemia and lymosarcoma in older cows

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2
Q

Viruses that aren known to be oncogenic

A
  1. Retroviruses
    - feline, bovine, avian
  2. Herpes viruses
    - Leukemia/ lymphoma in chickens
    - Merits dx
  3. Adenovirus
    - cause cancer in model
  4. Polyoma, SV40
    - cause cancer in model
  5. Papiloma viruses
    - horses and people
  6. Poxviruses
    - ungulates
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3
Q

what do oncogenic viruses have in common

A
  1. DNA viruses
  2. Non-lytic when associated with tumors
  3. most replicate in nucleus
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4
Q

Direct carcinogens

A

Permanent heritable change, like a DNA mutation

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5
Q

Indirect carcinogen

A

temporary alteration in expression of a protein the causes cell proliferation ex. cytokine or growth factor (viruses kind of fit in this category as well)

  • antigen -> amplification B and T cell growth -> oprotunity for mistakes -> leukemias and lymphomas
  • injection site sarcomas
  • get wound, higher chance of getting sarcoma bc cell division can get ball rolling
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6
Q

Viral oncogenes

A
  • there is no such think as virus that causes cancer
  • cancers associated with viral infections are mistakes or byproducts viral replication or gene expressoin
  • cancer arises bc failures in host defenses, viruses are unwitting collaborators
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7
Q

Structure of simple retrovirus

A
  • basal building block
  • have LTR-gag-pol-env-LTR
  • LTR important part in terms of cancer bc promotor
  • retrovirus has copies of RNA plus tRNA bc went from DNA to RNA (went backwards)
  • we were infected throughout evolution and eded up with viral sequences in our genome; some of these are beneficial
  • modify anyone on the provirus and can end up with cancer but primary motivator in terms causing cancer is LTR
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8
Q

LTR

A

promotor

- have largest effect on cancer in simple retrovirus (retroviruses have powerful promotors LTRs)

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9
Q

gag

A

codes for matrix, capsid, nucleocapsid

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10
Q

pol

A

integrase, reverse transcirptase

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11
Q

env

A

surface glycoprotein, transmembrane proteins

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12
Q

Marian leukemia virus

A

basically FLV cats got this from mice

  • LTR separated intone U3 R and U5 regions
  • TATA box where initiation starts off
  • enhancer region where transcriptional activators and repressors bind (400 enhancer regions sequences discovered so far)
  • enhancer region and Tata box play important role in controlling level of transcription
  • GRE1 and NFkapaB also play a role
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13
Q

Retrovirus life cycle

A
  1. Retorvirus has envelope moieties that are recognized by certain receptors on the cell
  2. Retrovirus enters cell by endocytosis
  3. Once endocytosed uncoats nucleocapsid
  4. 2x stranded DNA goes into nucleus have cell division and nuclear membrane breaks down so it can integrate via reverse transcriptase (will be integrated in random location in host DNA)
  5. Transcription
  6. Transcript to cytoplasm
  7. mRNAs made into viral proteins which go to cell membrane
  8. Assembly takes place at interface and viral envelope proteins be formed from host cell which prevents zoonosis
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14
Q

simple vs complex retroviruses

A
  • complex retroviruses also have REX and TAX (RNA processor) so they can control replication at much higher level; this is highly regulated around cell cycle
  • complex like simple also have gag, pol, and env
  • all complex retroviruses have accessory chains
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15
Q

Hubner and Todaro

A

hypothesized that cancer is caused by activation of normal cellular gene (port-oncogene) and activated cellular gene now called oncogene

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16
Q

Retrovirus replication and cancer

A
  • retroviruses that cause cancer aren’t lytic
  • integration is random
  • in tumors retrovirus integration is in specific chormosmal site (clonal integration); every cell in tumor has provirus integrating at same site
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17
Q

what does tumor provirus always being at same site indicate

A

that tumor arose from one cell (clonal) and something important about this integration site for oncogenic transformation

18
Q

C-myc

A

example of oncogenesis by promotor insertion
- C-myc was protogene; myc transcriptional regulator tightly controlled in normal cells (only one copy per cell express too much is bad)
- C-myc activated by retroviral insertion/ promotor insertion
so have gene for tumor next to this get tumor (myelocytoma tumor in birds)

19
Q

How can retroviruses lead to cancer

A
  1. Activated by integrated provirus (insertion activation)

2. Transduced by retrovirus

20
Q

Consequence of integration

A

put retorvirus next to oncogene and have consequences (end up with higher replications of it)

21
Q

Retroviral DNA insertion activation

A

Promotor inset on and enhancer insertion

22
Q

promotor insertion

A

Viral and cellular transcripts fuse and viral promotor overrides cellular promotor so cellular protooncogene can be mutated or simply over or mis expressed

23
Q

Enhancer insertion

A

viral and cellular transcripts are not fused; strong viral enhancers increase transcription from cell promotor
- this acts on normal cellular transcription start site; have over expression of host because of enhancer and overexpression can lead to complimenting cascade that leads to cancer

24
Q

retrovirus transducing cellular genes

A
  • can transduce (capture) cellular genes (oncogenes)
  • recombine and retrovirus picks up host protogene can be replication competent (helper) or replication incompetent (defective) where it needs a helper virus to spread
  • recombination at RNA level
    ex. FLV= replication competent; feline sarcoma virus (replication incompetent)
25
Q

viral acquisition of cellular oncogenes

A

virus has to give up gene because of size constrain to pick up cellular oncogene; if give up critical gene enormous consequences
- if give up a critical gene then oncogenes can be found and reduced by wild type virus that will provide the missing gene and this wt will carry defective virus along with it as defective virus and then it will be able to replicate

26
Q

Genomes of transducing retroviruses

A
  • viral coding sequences are replaced by cell-derided oncogene sequence and these retroviruses are defective in replication
  • in some cases retrovirus may transduce 2 oncogenes
27
Q

Efficacy of tumor formation transducing retroviruses, nontransducing retroviruses , and nontransducing long laterncy retroviruses

A
  • transducing retroviruses: High efficacy (almost 100% infected animals)
  • nontransducing retroviruses high to intermediate efficacy
  • nontransducing long latency retroviruses very low efficacy (<5%)
28
Q

Tumor latency transducing retroviruses, nontransducing retroviruses , and nontransducing long laterncy retroviruses

A
  • transducing retroviruses: short (days)
  • nontransducing retroviruses: intermediate (weeks, months)
  • nontransducing long latency retroviruses: long (months, years)
29
Q

infecting viral genome transducing retroviruses, nontransducing retroviruses , and nontransducing long laterncy retroviruses

A
  • transducing retroviruses: viruses-cell recombinant; normally replication defective
  • nontransducing retroviruses; intact replication- competent
  • nontransducing long latency retroviruses; intact replication-competent
30
Q

oncogenic element transducing retroviruses, nontransducing retroviruses , and nontransducing long laterncy retroviruses

A
  • transducing retroviruses: cell derived oncogene carried in viral genome
  • nontransducing retroviruses: cellular oncogene activated in situ by a provirus
  • nontransducing long latency retroviruses: virus-encoded regulatory protein controlling transcription
31
Q

mechanism transducing retroviruses, nontransducing retroviruses , and nontransducing long laterncy retroviruses

A
  • transducing retroviruses: oncogenic transduction
  • nontransducing retroviruses: cis-acting provirus
  • nontransducing long latency retroviruses: trans-acting protein?
32
Q

ability to transform cells in culture transducing retroviruses, nontransducing retroviruses , and nontransducing long laterncy retroviruses

A
  • transducing retroviruses: Yes
  • nontransducing retroviruses: No
  • nontransducing long latency retroviruses: No
33
Q

Are protooncogenes conserved?

A
  • avian feline and murine cell-derived oncogenes are same genes (homologues) found in human cancers that arise from mutations?
  • mutations we get form diet show there are favorite oncogenic sweeps in different cancers
34
Q

Complex retroviral associated canacers

A

ex. Bovine leukemia virus
1. No cellular oncogene activated by BLV insertion
2. No viral gene expression in tumor
- BLV causes tumors bc deregulate host genes involved in proliferation like cytokines

35
Q

BLV and HDL1

A

identical viruses one causes T cell cancer 1 causes B cell cancer

36
Q

BLV

A

30% persistant lymphocytosis in 1yr of infection
5% get bovine lymphosarcoma in 8 years of infection (but we usually kill them before then so doesn’t really matter)
- BLV encodes TAX

37
Q

TAX

A
  • TAX is viral transcriptional trans-activator and fxs to make lots of viral RNA
  • TAX is cellular transcriptional transactivator fxs to increase transcription of select cellular genes many of which are tumor promotors (transcriptionally activates cytokines, growth factors, receptors, and survival factors)
  • inactivates TGFB, p53
  • ultimately TAX -> genomic instability and clonal proliferation in infected cell
38
Q

oncogenes originate from

A

normal cellular genes that have been transcriptionally activated, altered, or mutated

39
Q

retroviruses like FeLV

A

occasionally activate or transduce cellular genes -> cancer

40
Q

retroviruses like BLV

A

Trans-activate cellular genes that are proliferative in function and increase susceptibility of infected cell to secondary mutation that leads to cancer (causes rapid proliferation so makes you more susceptible to cancer)

41
Q

Walleye dermal sarcoma

A
  • fish get these tumors then they go away and never see them again
  • this is complex retrovirus with several accessory chains
  • in young walleye without developed immune system causes metastatic invasive cancer and kills them but doesn’t happen in nature (if you change anything about virus and its relationship to the host there are consequences)

Block 2 Cancer (10 decks)

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