16 - Oncogenic Viruses Flashcards
Transformed cells
- Are immortal, grow indefinitely (e.g. Vero; HeLa)
- Loss of contact inhibition
- Loss of anchorage dependence
- Forms colonies in semi solid media
- Altered requirement for growth factors and nutrients
- Not necessarily oncogenic
Carcinogenesis
Complex multistage process by which cancer develops
Carcinoma
A malignancy that begins in skin or in tissues that line or cover internal organs
Sarcoma
Begins in bone, cartilage, fat, muscle or other connective tissue
% of human cancers that virla cancers account for
20%
T/F: Malignancy is required for viral replication
FALSE
T/F: Cancer is a side effect of host response or host-viral interaction
TRUE
RNA tumour viruses and their oncogenes
Can activate cellular growth signalling pathways
DNA tumour viruses and their tumour suppressor proteins
Can disrupt pathways that prevent cell proliferations
Proto-oncogenes
Normal cellular proteins involved in promoting regulation and proliferation of normal cells
Oncogenes
DNA sequence that has been altered via mutation from its original form (proto-oncogene), causing formation of cancerous tumour
Oncogene single gain of function mutation
Single activating mutation enables oncogene to stimulate cell proliferation
Tumour suppressor loss of function mutation
Two inactivating mutations eliminating the tumour suppressor gene, stimulating cell proliferation
Retroviral insertion into proto-oncogenes
Can convert proto-oncogene (integral to control of cell division), into an oncogene
Acutely transforming virus
- Produces tumours within weeks of infection
- Incorporates genetic material from a host cell into its own genome upon infection, forming a viral oncogene
- When the viral oncogene infects another cell vDNA which includes the oncogene is then integrated into the cellular genome
Slowly transforming virus
- Requires months to elicit tumour growth
- Does not disrupt cellular function through the insertion of a viral oncogene
- Rather, it carries a promoter gene that is integrated into the cellular genome of the host cell next to or within a proto-oncogene, allowing conversion of the proto-oncogene to an oncogene
Rous sarcoma virus
- Virus of chickens that contain oncogene viral(v)-src (an incorporated proto-oncogene cellular(c)-src)
- Altered form of avian leukosis virus that common infects chicken flocks
Src
Tyrosine kinase that is involved in regulation of cell growth and differentiation
c-Src
- Cytoplasmic signaling protein that can be phosphorylated at different sites.
- Responds to extracellular growth factors by binding to an activated growth factor receptor, becoming phosphorylated at certain positions, and subsequently sending a proliferation signal.
c-Src C terminal regulatory region
Can also be phosphorylated, but in that case phosphorylation is inhibitory event that turns signalling off when extracellular stimulus is withdrawn
RSV v-Src protein
Lacks C-terminal phosphorylation site so that v-Src is constitutively active, sending a constant proproliferation signal irrespective of the presence or absence of growth factors
Two groups oncogenic retroviruses are classified into
- Oncogene transducing retrovirus
- Oncogene deficient retrovirus
Oncogene transducing retrovirus
- Carry oncogene as part of their genome
- Rapidly leads to cancer in nearly 100% of susceptible animals
Oncogene deficient retrovirus
- Cause cancer when insertion of the LTR causes overexpression of a cellular proto-oncogene
- Leads to cancer only some of the time, and does so slowly in infected animals;
Human T cell lymphotropic virus type 1 (HTLV-1)
- Linked to adult cutaneous T-cell lymphoma and HTLV associated myelopathy
- Oncogenic properties caused by two proteins (Tax and HBZ) encoded in the provirus
- Neither protein has a known homolog among normal cellular genes.
HTLV-1 Tax
- Transcription regulator
- In addition to activating viral genes, also activates many host genes, including those that
promote host cell proliferation and resistance to apoptosis.
HBZ
- Can interact with pRB, therefore promoting cell cycling
- Tax may be essential for starting the process of oncogenesis, but HBZ may be responsible
for maintaining it - Active at different times over course of persistent oncogenic infections
Rb
- Tumour suppressor gene that shuts off cell proliferation by binding to E2F (transcription factor)
- If conditions are not right for cell division, cell cycle pauses at restriction point (no DNA synthesis)
- R point is controlled by cellular protein Rb
- Oncogenic DNA viruses (also HCV) put cells into S phase (so they can replicate DNA) by blocking Rb
HCV NS5B protein
- Interacts with Rb in the cytoplasm and recruits the E3-ubiquitin ligase E6AP to facilitate ubiquitinylation of Rb
- This targets Rb for degradation in proteasome
Loss of Rb
Results in dysregulation of many Rb controlled process including comprised cell cycle checkpoints that guard against p53 dependent apoptosis
How do viruses cause transformation
Via inactivation of tumour suppressor p53
p53
- Arrests cell cycle in presence of damaged DNA and leads to apoptosis of cells whose DNA is irreversibly damaged
- Virus infection causes DNA damage and hypoxia (activated p53)
- MAny viruses alter p53 activity
SV40 large T antigen
Stabilises p53 in inactive state
HPV E6
Triggers degradation of p53
Adeno E1B
Blocks transcriptional activation function of p53
