10 - Viral Oncogenesis Flashcards
Current estimate is the ~12% of human cancers are caused by __ of __ viruses?
1 of 7
What are common traits associated with viral oncogenesis?
Oncoviruses are necessary byt not sufficient for cancer development, and many who have the virus do not get the cancer.
Viral cancers appear in contexrt of persistent infections and occur many years to decades after acute infection.
What is the role of the immune system in viral oncogenesis?
Can play a deleterious role or a protective role.
How can viruses cause cancer indirectly? What infections is this seen with?
Hep B and C
Chronic infection can cause high levels of cell division.
This increases the probability that hepatocytes will develop mutations and chromosomal aberrations that derail their growth control.
How can viruses cause cancer directly? What infections is this seen with?
Papillomavirus
Some DNA viruses stimulate cells to enter S phase and ready themselves for DNA synthesis.
If the virus doesn’t complete its lifecycle and kill the cell, the same viral proteins can continue to override the normal controls on cell growth and divide inappropriately.
What are the structural characteristics of papillomavirus (HPV)? What human disease is it associated with?
Icosahedral capsid, naked virus.
Small 8 kbp dsDNA circular genome.
Associated with cervical cancer, penile cancer, head and neck cancer (~5.2%)
Describe the strong association of merkel cell polyoma virus and merkel cell carcinoma? What are characteristics of this virus
- common deletion in the viral genome renders it unable to replicate
- persistent infection
- Immunosuppressed
dsDNA, icosahedral capsid, naked virus
What does papillomavirus infect and what does replication depend on?
Infects cutaneous and mucosal epithelia hands, feet, and anogenital tract.
Replication depends on life cycle of keratinocyles and epithelial cells of the skin and mucosa.
What are the functions of E1 and E2 genes encoded by the papillomavirus?
Early 1 and 2 proteins mediate the replication and transcription of viral DNA
What are the functions of E3 and E5 genes encoded by the papillomavirus?
Early genes.
E3: disrupts keratin to facilitate virus egress (leaving)
E5: stimulates constitutive cellular growth factor receptor signaling
What are the functions of E6 and E7 genes encoded by the papillomavirus?
Early genes.
E6 and E7 neutralice the major “breaks” that regulate the cell cycle - p53 and Rb-uncoupling cell division from key regulatory controls.
What are the functions of L1 and L2 genes encoded by the papillomavirus?
Late genes.
Compose the self-assembling capsid and bind cell surface integrins.
E5, E6, and E7 intersect with key elements of ______ _______ _______ and are associated with __________.
E5, E6, and E7 intersect with key elements of cellular growth control and are associated with oncogenesis.
How many subtypes of papillomavirus are there? How do they differ?
Over 200, based on DNA sequence homology, tissue tropism, and disease penetration.
There’s cutaneous HPB and mucosal HPV.
There’s high rick and low risk HPV.
Where does HPV infect and replicate? What is a common location of these infections?
In squamous epithelium, and viral infection remains local in skin (warts) and mucous membranes (genital, oral, and conjunctival papillomas).
1/3 infect the genital tract and are sexually transmitted.
Which subtypes of HPV cause anogenital warts and are associated with condyloma acuminatum (genital warts)? What is the risk associated with these subtypes?
Types 6 and 11
Low risk
Which subtypes of HPV cause anogenital warts and are associated with cervical intraepithelial neoplasia and cancer? What is the risk associated with these subtypes?
Types 16 and 18
High risk
What is the life cycle of papillomavirus? What arethe potential outcomes of papilloma replication?
Normally only basal cells of the skin divide but HPV stimulates the cell cycle and causes cells in the stratum spinosum to divide instead of differentiate.
Altered keratinocyte division and differentiation are required for HPV replication.
Potential outcomes: maintain papilloma (wart-like growth) or regress
Describe the regulation of the cell cycle?
- Cylin-dependent kinases (CDKs) are the engine of the cycle that move it ahead via phosphorylating key substrates
- Enzymes also regulated to make sure the cell is ready
What are the major checkpoints of the cell cycle?
G1 (before entry to S): Is the environment favorable?
G2 (before entry into M): Is all DNA replicated? Is the environment favorable?
Metaphase checkpoint: Are all chromosomes attached to the spindle?
What is the Rb protein and what is its role in the cell cycle?
It’s the brake that blocks progression into S phase.
When sufficient Cdk/cyclin has accumulated in the G1 phase, Rb is inactivated by phosphorylation and the cell can then more into S phase.
What does E7 do to alter the cell cycle? What else does E7 make?
Binds Rb and targets it for proteasomal degradation, which prevents it from blocking progression into S phase. (Ie E7 removes a key regulator of cell cycle progression and allows S phase entry)
E7 also causes production of p16, which is a diagnostic marker of cervical cancer.
What is the function of p53?
“gaurdian of the genome” that is mutated in >50% of all human cancers.
It induces inhibitors of CDKs to stop the cell cycle. Also a major inducer of apoptosis.
What effect does HPV E6 protein have on the cell cycle?
It recruits ligase to target p53 for degradation to prevent it from blocking the cell cycle or inducing apoptosis.
It also induces expression of telomerase to maintain the chromosomal telomeres, leading to immortalization.
