Week 3 - Microbiology Tumor Virology Flashcards
Cellular transformation
Poor or no control of cellular division
What do DNA tumor viruses do to permissive cells? To non-permissive cells?
Lyse permissive cells (kill)
Transform non-permissive cells
Permissive host cell
A host cell the virus can completely replicate in
What do RNA tumor viruses do to permissive cells?
RNA tumor viruses transform permissive and non-permissive cells
What do RNA tumor genes carry that are responsible for the transformation of permissive cells?
Oncogenes
Carcinogenesis
A multistep process involving multiple genetic changes
Cellular transofmration
A stable, heritable change, resulting in poor or no control of cellular growth
What does cellular transformation result in?
In the alteration of cellular processes and properties which can result in altered morphology, growth control, and cellular and biochemical properties
All tumor viruses are DNA viruses OR…
Generate a DNA provirus (retrovirus)
Know what virus family and virus causes human cancer
Use Association of Viruses with Human Cancers Table
Papovavirdae
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Herpesvirdae
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Hepadnavirdae
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Retroviridae
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What is P110rb?
P110 RB (retno blastoma) - protein that when is phosphorylated, it is master break in cell cycle - so when it is ACTIVE you will NOT have uncontrolled cell growth… It is a break in cell cycle on purpose.. WITHOUT the block you get uncontrolled growth
What is P53?
P53 - If active, turns on P21 when regulates cycling kinases (phosphorylates things). The kinases shut P110 RB down. This phosphorylates (inactivates) the P110rb and uncontrolled cell growth will occur
C - Oncogenes
Cellular oncogenes
Mutated forms of normal cell genes (proto-oncogenes)
Code for heterogeneous group of proteins that are involved in normal cell division or differention pathways
Abnormal expression or regulation lead to cellular transformation or cancerous growth
V-oncogenes
Only occurs from RNA viruses
Are copies of cellular oncogenes which have been acquired by viruses during replication
Present in viral genome
Responsible for cellular transforming activity of those viruses which contain them
Tumor suppressor genes
Negative regulators of cellular growth.
Anti-oncogenes or growth suppressor genes
Cause cellular transformation if functional activity of both alleles is lost
Are exemplified by P110rb and P53
Adenoviruses
affect rodent cells.. In human cells - can make early proteins but don’t have all enzymes needed. Early cells E1b binds to P53 and E1a binds to P110RB.. So break is eliminated and have uncontrolled growth…….
Do DNA and RNA viruses produce tumors in host cell?
No for DNA tumor viruses
Yes for RNA tumor viruses
What host cells do DNA tumor viruses transform?
ONLY non-permissive cells
Interaction of specific viral proteins with products of tumor suppressor genes directly lead to or contribute to the transformation process (P110rb, P53)
What viruses are associated with human cancers?
EBV, HBV, HSV, HPV
Types of adenoviruses
Types
Vary in their oncogenic potential from high to not at all
Types 12, 18 and 31 are highly oncogenic
Transformation characteristics
Transform rodent cells
No association with human neoplasms
Transforming proteins
E1a – binds to p110Rb (represses cell proliferation)
E1b – binds to p53 (represses cell proliferation)
Papillomaviruses
Types
60 different types have been described; types 16 and 18 have a strong association with cervical intraepithelial neoplasia (CIN)
Transformation characteristics
Majority of cervical, penile and vulvular cancers contain HPV DNA
Suspected cofactors include tobacco smoke and coinfection with HSV
Virus multiplies only in differentiating keratinocytes
Type 16 transforms rodent cells
Viral DNA is episomal in normal tissue, but integrated in cancers and CIN
Transforming proteins
E6 – binds to p53
E7 – binds to p110Rb
Polyomaviruses
Types
BK (renal transplant patient) and JC (PML patient) viruses can transform rodent cells and induce tumors in newborn hamsters
SV-40 replicates in monkey cells, transforms rodent cells and induces tumors in newborn hamsters
Polyoma virus replicates in mouse cells and transforms hamster’s cells
Transforming proteins
SV-40 – large tumor (T) antigen has domains that bind to p110Rb and p53
One or two of the three polyoma virus T antigens have transforming activity
EBV
Epstein-Bar virus
Episome
Extra chromosomal piece of DNA
Herpesviruses
Some are linked to human cancer
Data is most convincing for EBV
EBV
Linked to Burkitt’s lymphoma and nasopharyngeal carcinoma
EBV DNA in Burkitt’s cells
Viral genome is mostly multiple episomes, but some is integrated
Important viral proteins involved in transformation include: EBNA-2 (transcriptional transactivator), LMP 1 and LMP 2a and b (tyrosine kinases)
Possible cofactors involved are malaria and c-myc proto-oncogene translocation (chromosome 8 to 14)
HSV-2
Implicated in cervical cancer and CIN
DNA fragments, including those containing ribonucleotide reductase, can transform cells
CMV
Implicated in cervical cancer and CIN
Some DNA segments can transform cells
HHV-8
Cause of Kaposi’s sarcoma
Implicated in multiple myeloma
Contains 16 cellular genes including C-cyclin and cytokines
Pox viruses
Skip
Hepadnaviruses
75-85% of primary human hepatocellular carcinoma cells carry human hepatitis B virus (HBV) genes
Impaired immunity and alcohol-associated hepatic cirrhosis are co-factors
X protein interacts with p53 (X is synthesized by HepB virus)
Hep B virus can cause cancer**
Latency period between infection and primary hepatocellular carcinoma ranges from 9-35 years
What hep virus can cause cancer?
HEP B
RNA tumor virues
lk
***Viruses cuase transformations by:
– introduction of oncogenes
– insertional activation or promoter insertion
– transcriptional activation
Sub families of retroviurses
s
IMportant aspects of retroviridae
s
Oncovirus morphologica types.. retroviruses
l
Endogenout tyep c viruses
Lots of type C retroviruses in body**
Exogenous type C virses
Spread horizontally; behave as infectious agents
When oncogenic, mainly cause tumors of reticuloendothelial system and hematopoietic systems (leukemia, lymphomas) or connective tissue (sarcomas)
Endogenous Type C viruses
Found in all cells of all individuals of a species
Viral information – is a constant part of genetic constitution; not pathogenic for host; can be activated by radiation, chemical carcinogens or metabolic inhibitors
What are genes involved in replication of retroviruses?
GAG, POL, ENV
Replication is reverse transcription and the integration of DNA into host cell DNA
Watch movie on retrovirus replicaton.
IMportatn
reverse transcription occurs
get DNA copie of RNA
Stuck into host chromosome by integrate
then make mRNAs from chromosome and make positive sense copies of
Protease
Cuts polyprotein so make all diff proteins for formation of virus . that s why its a good drug target.
If virus was integrated next to oncogene in host
When the viral dna comes out of the host, it can accidentaly make copy of onco gene. it then goes to other cell.. and makes product of oncogene. Once onco gene is sitting with virogene it is called v-onc.
Viral Oncogenes
Viral conpies of cellular oncogenes involved in cellular division
What are non-defective viruses?
Infectious progeny virus formed
Include most leukemia viruses and Rous sarcoma virus, an acute tumor virus which contains virogenes and an oncogene
Defective Viurses
Have lost part or an entire virogene which has been replaced by an oncogene
Require a helper virus for replication
Are acute transforming viruses
In order for them to replicate… they need a helper virus (why? because their own replication genes was replaced with onco gene from host.. (it made a mistake))
Defective acute transfoming virus
Introduce oncogenes into cell. THe gene products are NOT turned off, they are turned on and
Mechanisms of Oncogenicity 1
Mechanism of transformation by acute transforming viruses utilized by both nondefective viruses (e.g., Rous sarcoma virus) and defective viruses (e.g., many sarcoma and acute leukemia viruses, like Abelson murine leukemia virus) to transform cells
Mechanisms of oncogenicity 2nd method
Insertional activation or promoter insertion (e.g., chronic leukemia viruses and mouse mammary tumor virus):
Involves viral promoters and transcriptional enhancer in LTR’s in activation of cellular oncogenes
A mechanism of transformation by chronic transforming viruses
This takes much longer for this cancer to appear.. the virus is randomly inserted.. The virus isnt replicating the cell replicates and happens to also make the virus (because it was inserted)
3rd mechanism.. Transcriptional activation
Involves transactivator proteins to activate cellular oncogenes - go sit on DNA sequences and say ‘make me’
The tax protein of HTLV-1 enhances transcription of viral genes and cellular genes like IL-2, IL-3, GMCSF and IL-2 receptor
Always activated in cells that are about ready to divide.
Tax protein
Enhances transcription of viral genes and cellular genes
