lecture 7 - viral transformation of cells

viral transformation is...

change in growth, phenotype, or indefinite reproduction of cells caused by introduction of viral genes

what is special about transformed cells

immortal - can grow indefinitely

reduced reqs. for growth factors

loss of ability to arrest growth with nutrient deprivation

high growth density

loss of contact inhibition

anchorage independence

altered morphology

tumorigenic

describe the altered morphology aspect of transformed cells

appear rounded and refractile

what is the leading cause of death in developed countries

cancer

viruses are the causal factor in what percent of human cancers

20%

viruses are the principal cause of what type of cancers

human liver and cervical

in order list the events of immortalization, oncogenesis, and transformation

immortalization, transformation, and oncogenesis

most cancers result from the accumulation of

sequential mutations in cells over a long period

what are the 2 types of RNA viruses that are oncogenic

flaviviridae and retroviridae

which type of virus more commonly causes cancer, RNA or DNA viruses

DNA viruses

do oncogenic viruses cause cancer in every infected person/animal they infect

no

what are the 3 ways viruses can cause cancer

1. introduction of oncogene into cell and expression of viral oncogene proteins

2. disrupting reg. cell division with aberrant expression of cell proteins post retroviral integration or expression of viral proteins with DNA viruses

3. stimulating uncontrolled growth and inflammation of tissue and damaging DNA

how do retroviruses cause cancer

either encode oncogenes or integrate into cell genome and dereg. expression of cellular proto-oncogenes

how do small transforming DNA viruses cause cancer

encode proteins that inhibit specific proteins like Rb/p53 to promote cell cycle progression

what can proteins encoded by transforming viruses do

prevent cell death, block immune recognition, and promote blood vessel formation

how can Hep C cause cancer

induction of chronic immune response resulting in tissue damage and the emergence of malignant cells causes cancer

what are proto-oncogenes

cell genes that express proteins that cause cell to undergo cell cycle

normal accelerator for cell growth

what are tumor suppressor genes

keep cell from unnecessary division

normal break for cell growth

what are 2 important tumor suppressor genes

Rb and p53

viral transformation can be the result of expression of proteins that either

1. constitutively activate cytoplasmic transduction pathways

2. disrupt nuclear pathways that negatively regulate cell cycle progression

what forms of cell transformation can DNA viruses do

both forms

what is the only type of virus associated with activation of proto-oncogenes/adding new genes

retroviruses

what can only retroviruses do for transforming cells

permanently activate proto-oncogenes and add new genes

what normally regulates the cell cycle

progressive accumulation of cyclins and CDKs

what regulates cyclins

MAPK signal transduction pathway

oncogenic DNA viral proteins can do what

alter activities of products of cellular progenitors

transforming proteins of DNA viruses are mostly

nuclear proteins that are involved in disrupting normal controls to cell cycle progression

DNA viruses mostly require the cell to be doing what

synthesizing DNA for replication of viral genome

especially needed for small DNA viruses that dont encode own machinery

what is p53

critical cellular protein for regulating response of cells to DNA damage

tumor suppression gene

describe normal p53 concentrations in nucleus

low concentrations in nucleus

when does the concentration of p53 rise

following DNA damage

what is the function of p53

transcriptional activator of certain genes involved in cell cycle arrest and apoptosis

what is the most frequently mutated gene in human tumors

p53

what can happen when DNA viruses inactivate p53

cell is driven into S phase leading to replication of viral genome

more p53 deactivated =

better transforming abilities

what are a few ways that DNA viruses can inactivate p53

bind to it and mark it for degradation in proteasome

sequester it

bind and block it

what does Rb phosphorylation accomplish

makes restriction point to prevent cell progression

what do viral proteins affecting Rb do

prevent formation of Rb-E2F complexes enabling transcription of E2F-dependent genes and entry to S phase

How can DNA viruses affect cell signal transduction

they can place proteins in the mems. that interact with cell signal transduction proteins to constitutively activate transduction pathway

EBV uses what protein to interfere with signal transduction

LMP-1 protein

LMP-1 is implicated with what in EBV

immortalization of B cells

LMP-1 induces the expression of

Bcl-1 family of proteins that inhibit apoptosis

why do cytotoxic lymphocytes not recognize LMP-1

a sequence of this protein inhibits the proteasome

define transducing retrovirus

viral genome encodes an oncogene

define nontransducing retrovirus

insertion activation of cellular proto-oncogenes

compare the aspect between non/transducing retroviruses: efficiency of tumor

transducing - high, 100% of infected get tumor

nontransducing - low to intermediate % chance

compare the aspect between non/transducing retroviruses: tumor latency

transducing - short, tumor in days

nontransducing - months to years

compare the aspect between non/transducing retroviruses: infecting viral genome

transducing - viral-cellular recombinant, normal replication defective

nontransducing - intact: replication competent

compare the aspect between non/transducing retroviruses: oncogenic element

transducing - cell derive oncogene carried in viral genome

nontransducing - cellular oncogene activated in situ by provirus (no gene in retrovirus but activates another oncogene)

compare the aspect between non/transducing retroviruses: ability to transform in cell culture

transducing - yes

nontransducing - no

what are the 2 mechanisms of insertional activation by nontransducing oncogenic retroviruses

1. promoter insertion

2. enhancer insertion

describe the promoter insertion mechanism by nontransducing retroviruses

viral LTR takes over and removes other parts of genome and drives expression of cellular oncogene

describe the enhancr insertion mechanism by nontransducing retroviruses

viral LTR of provirus to stimulate transcription from natural promoter of cellular oncogene

can be up or downstream of oncogene, can operate over long distances, can be in either orientation

do nontransducing retroviruses need other C-onocogene mutations for invasion

yes

what type of expansion do nontransducing retrovirus infected cells do

clonal expansion

describe the genome of transducing retroviruses

they have replaced a part of viral genome with c-onc sequences via recombination

all transducing retroviruses are

replication incompetent and require helper virus

except Rous Sarcoma virus

what is the minimum needed to be called a transforming retrovirus

proviral sequences are LTR

what is sacrificed in transducing retroviruses for c-onc gene

some ability for replication is sacrificed

what do oncogenes encode for

every step in control of the cell cycle

what are some types of proteins that oncogenes encode for

growth factors

tyrosine kinase growth factor receptors

hormone receptors

G proteins

adapter proteins

nonreceptor tyrosine kinases

serine/threonine kinases

nuclear proteins

do transducing retroviruses need addition mutations in other c-onc to invade

no

what type of expansion do transducing retrovirus infected cells do

oligoclonal expansion (many cells growing and dividing to form tumor)

what kind of infection can Hep B cause

acute to persistent infections

how is liver damage caused by Hep B

sustained immune mediated damage to liver resulting in sustained proliferation of liver cells and exposure to free radicals causing DNA damage

what are the effects of Hep B on the immune system

continuous tissue damage due to immune responses driving abnormal liver cell proliferation

what type of infection does Hep C cause

persistent infection

with Hep C infection what do some people develop

hepatocellular carcinoma and cirrhosis

what are the effects of Hep C on the immune system

immune system kills infected cells eventually leading to proliferation of hepatocytes and tumor formation