8_Tumor Viruses

Question 1

progression of cancer

Answer 1

starts w/ one modified tumor cell

*mutation of proto-oncogene creates an oncogene

Several mutations may cause inactivation of tumor suppressor genes

Question 2

common feature(s) of tumor viruses?

Answer 2

• only common feature is to cause/promote tumors
• various taxonomic groups; and viruses may not be closely related

Question 3

structure of retroviral particle

Answer 3

Question 4

general structure of retroviral genome

Answer 4

• contains several coding sequences, in variable positions:
  
  • Gag: processed to matrix & other core and structural proteins that determine retroviral core
  • Pol: reverse transcriptase; RNase H and integrase functions
  • Env: envelope protein, resides in lipid layer, determines viral tropism
  • Some regulatory sequences, only included in some strains
• Many variations of the retroviral genome possible

Question 5

retroviral life cycle

(REVIEW IN DETAIL), 1:13 in April 16 lecture

Answer 5

1. binding
2. fusion
3. reverse transcription
4. nuclear localization/uncoating
5. integration/transcription/ splicing
6. genomic RNA –> mRNA –> translation –> modification
7. assembly binding
8. maturation

Question 6

retroviruses may have an extra gene, what is this?

Answer 6

SRC gene

*NOT needed for lifecycle of retrovirus

• Rous Sarcoma Virus was discovered 100 years ago. It was the first oncogenic virus discovered. This discovery became the basis for the theories of immune surveillance and viral origin of cancer.
• Src, a protein tyrosine kinase, became the first oncogene discovered.

Question 7

SRC,

if taken out of original retrovirus and put in other artificial cell systems, can do what?

Answer 7

gene can transform various cell lines and is therefore called

“oncogene”

Question 8

retroviral oncogenes:

define, found where?

Answer 8

• mutated (activated, deregulated) versions of cellular genes that encode for various normal proteins
  
  • play key roles in the regulation of cell signaling and responses.
  • Thus, v-src is an oncogene, while c-src is a normal gene. Such normal genes are called proto-oncogenes.
• Many elements of cell signaling and transcription factors have been discovered following the discovery of their oncogenic forms
• *FOUND IN CYTOPLASM

Question 9

do viruses need to have oncogenes to produce tumor?

Answer 9

• Not necessarily, can cause tumor by other mechanisms
• “oncogenesis by promotor insertion” –> overexpression of proto-oncogene (c-Myc) may exert an effect similar to the effect of oncogene expression

Question 10

HTLV:

1. define
2. epidemiology
3. transmission
4. function

Answer 10

1. retrovirus somewhat similar to HIV
2. endemic to Japan, Africa, S. America, Caribbean
   
   • ~25M individuals are carriers
3. Transmission: mother-to-child, but sexual transmission exists
4. Fxn: diff’t functional regions incl.
   
   • gene expression/cell proliferation, transformation
   • cell cucle progression
   • aneuploidy
   • nuclear-cytoplasm shuttling

Question 11

HTLV-1:

disease/ symptoms

Answer 11

• HTLV-1-induced acute adult T-cell leukemia: cutaneous form (typically T-cell-related cancers)
  
  • Most carriers of HTLV-I remain asymptomatic
  • ~2-3% develop cancer after a 20-40 year period of latency (but can stay latent til death)
• The prevalent type of cancer in this case is Acute T-cell Leukemia, but other cancers may also develop (B-cell chronic lymphocytic leukemia, T-cell non-Hodgkin lymphoma, etc.)

Question 12

Papillomavirus

Answer 12

causes cancer in a different way, and has different structure than other retroviruses

Question 13

Polyomavirus

Answer 13

Not very important for human cancers

Question 14

describe the life cycle for:

papilloma/polyomavirus life cycle

(productive vs/ transforming cycles)

Answer 14

Question 15

Describe the progression of HPV-mediated oncogenesis?

Answer 15

• p53 degradation
• pRB interference

They’re doing what they’re supposed to be doing, but IN THE WRONG CONTEXT

Question 16

What is the relationship between E6 and p53?

Answer 16

• p53 protein (“tumor suppressor gene”): under normal conditions, up-regulates expression of cell-cycle down-regulators, including p21CIP1, which inhibits CDK2, thus suppressing G1-S transition.
  
  • Blocks this transition or induces apoptosis when DNA damage occurs
• E6 binds to p53 –> inducing ubiquitylation and degradation –> then viral DNA in in the host DNA

Question 17

How does HPV E7 affect the behavior of E2F?

Answer 17

Even in absence of the growth signal, E7 can sequester Rb –>allowing for E2F to progress in the cell cycle

Question 18

what are the effects of E6 on the host genome, in addition to promoting cell proliferation?

Answer 18

• E6- multiple effects to promote cell cycle
  
  • can also influence host chromosomal integrity (making less stable)

Question 19

effects of E7 in addition to promoting proliferation?

Answer 19

destabilizing chormosomal integrity of host

Question 20

HPV doesn’t necessarily cause cancer. What does it actually do?

Answer 20

• Renders cells integrating its DNA predisposed to developing cancer –> causing a pre-cancerous state –> due to additional mutations can become cancerous
• Moreover, E6 increases genomic instability of host cells (and E7 as well, but less actively so)
• can cause:
  
  • epidermodysplasia verruciformis (precancerous)–> squamous carcinoma
  • condyloma acuminatum (genital warts) –> cervical carcinoma

Question 21

Look at way the polyomavirus causes cancer

(early and late genes);

life cycle

Answer 21

• small T antigen
• middle T antigen
• Large T antigen: promote DNA replication & cell cycle

Question 22

Burkitt’s lymphoma assoc. w/ EBV:

consists of what type of cells?

Answer 22

• consists of differentiation-impaired B lymphocytes.
• This is but one of many types of cancer associated with EBV, a herpesvirus

Question 23

EBV is not a retrovirus, and typically does not integrate in host genome. Usually goes into latency.

Review Burkitt’s lymphoma mechanism

Answer 23

different modes of latency

Question 24

which viruses are associated w/ Hepatocellular carcinoma?

Answer 24

• HBV and HCV
• There’s a link between chronic infection with HBV (ds-DNA) and hepatocellular carcinoma (typically appears after 30-50 yrs of chronic liver damage)
  
  • Chronic carriers of HBV have a 300x greater risk of eventually developing liver cancer. 1M chronic carriers of HBV in the US.
• Hepatitis C virus (HCV) is a ss-RNA virus also causes chronic hepatitis.
• As it is for HBV, there is a link between chronic infection with HCV and liver cancer, typically appearing after 30-50 years of chronic liver damage. There are about four million chronic carriers of HCV in the US.

Question 25

What is the theory of the mechanism/link between HCC and HBV/HCV?

Answer 25

Chronic inflammation or direct; in favor of a link mediated by chronic inflammation:

1. There is a general rule of thumb related to the link between chronic inflammation and cancer of an organ.
2. Cirrhosis caused by chronic viral infection is the major risk factor for HCC (especially true for HCV).

In favor of the presence of specific oncogenic viral factors:

1. There is a detectable minority of HCV-related HCC cases that lack cirrhosis; even less link between HCC and cirrhosis is seen for HBV.
2. Both viruses exert multiple tumorigenic effects.

Question 26

what are the tumorigenic factors of HBV and HCV?

Answer 26

HBV

1. Integrates into host DNA (not a normal life-cycle stage; unclear whether cause or consequences; specificity of integration is not shown)
2. Viral proteins, especially HBx. However, HBx exerts multiple effects on signaling, transcription, apoptosis, cell-cycle progression, and viral replication, so their role remains unclear.

HCV

1. Multiple viral proteins, including structural, exert apparent oncogenic effects.