1. Several viruses can cause cancer by inserting oncogenes into host cell DNA or expressing viral proteins that disrupt normal cell cycle regulation. This includes hepatitis B and C viruses, papillomaviruses like HPV16/18, and herpesviruses like EBV.
2. Retroviruses like HTLV-1 and oncogenic genes they carry, like src, can also cause cancerous transformation when expressed in host cells. Proto-oncogenes normally involved in cell signaling can become oncogenes when mutated or abnormally expressed.
3. Common oncogenic mutations involve genes in the Ras, Myc, and Bcr-Abl pathways, disrupting normal cell cycle controls and
1. Tumor virusesTumor viruses
1.1. Hepatitis B virusHepatitis B virus
-It an animal DNA virus-It an animal DNA virus
- 3kb genome3kb genome
- Acute infection, in not resolved, followed by chronic infection.Acute infection, in not resolved, followed by chronic infection.
- Chronic tissue damage and inflammation…….cell proliferation.Chronic tissue damage and inflammation…….cell proliferation.
- Cell transformation by viral X-gene…..continual proliferation of the cells.Cell transformation by viral X-gene…..continual proliferation of the cells.
2. Hepatitis C virus2. Hepatitis C virus
- It is RNA virusIt is RNA virus
- 10 kb genome10 kb genome
- Induces chronic infection….inflammation…..cancer development.Induces chronic infection….inflammation…..cancer development.
- Some viral proteins may be contributing to proliferation of the non-infectedSome viral proteins may be contributing to proliferation of the non-infected
cells.cells.
3. 3. SV 40 & Polyomavirus3. SV 40 & Polyomavirus
- Simian virus 40 & polyomaviruses– natural host monkeys and mice,Simian virus 40 & polyomaviruses– natural host monkeys and mice,
respectively.respectively.
- In the cells of permissive host no transformation, but in non permissive host.In the cells of permissive host no transformation, but in non permissive host.
- Early region genes…expressed immediately after infection, while late regionEarly region genes…expressed immediately after infection, while late region
genes code for viral structural proteins.genes code for viral structural proteins.
- SV-40 …….small and large T-antigens (17 & 94 kd, respectively) bySV-40 …….small and large T-antigens (17 & 94 kd, respectively) by
alternative splicing.alternative splicing.
- Polyoma virus…early region….small, large and intermediate antigen (55 kd).Polyoma virus…early region….small, large and intermediate antigen (55 kd).
- Becoz these proteins help in replication…..promote the cells for division ofBecoz these proteins help in replication…..promote the cells for division of
host cells, so that enzymes needed for DNA replication can be produced.host cells, so that enzymes needed for DNA replication can be produced.
- Viral DNA integration with genome……transformation….cancer.Viral DNA integration with genome……transformation….cancer.
- These proteins interact with the host proteins regulating the cell growth suchThese proteins interact with the host proteins regulating the cell growth such
as inactivation of Rb and p53.as inactivation of Rb and p53.
4. 4. Papiloma viruses4. Papiloma viruses
-DNA virus.-DNA virus.
-Early region genes E6 &E7.induces transformation.-Early region genes E6 &E7.induces transformation.
-E7 binds with Rb and E6 with p53 …….degradation by ubiquitin-mediated-E7 binds with Rb and E6 with p53 …….degradation by ubiquitin-mediated
proteolysis.proteolysis.
-Responsible for cervical and anogenital cancers.-Responsible for cervical and anogenital cancers.
-HPV-16 & 18 are mainly responsible for cancers.-HPV-16 & 18 are mainly responsible for cancers.
5. 5. Adenovirus5. Adenovirus
-DNA virus.-DNA virus.
-35 kb genome.-35 kb genome.
-lytic cycle in host.-lytic cycle in host.
-No transformation in permissive host, but in non-permissive host.-No transformation in permissive host, but in non-permissive host.
-Early regions E1A and E1B degrade the Rb and p53, respectively.-Early regions E1A and E1B degrade the Rb and p53, respectively.
6. 6. Herpes viruses6. Herpes viruses
-100 to 200 kb-100 to 200 kb DNA genome.DNA genome.
-Kaposi’s sarcoma-associated herpesvirus.-Kaposi’s sarcoma-associated herpesvirus.
-Epstein-Barr virus- Burkitt’s lymphoma and B-cell lymphoma in AIDS patients.-Epstein-Barr virus- Burkitt’s lymphoma and B-cell lymphoma in AIDS patients.
-These have many early genes affecting cell proliferation and survival by using-These have many early genes affecting cell proliferation and survival by using
different proteins.different proteins.
eg. Epstein barr virus protein LMP1………enhance the action of cell surfaceeg. Epstein barr virus protein LMP1………enhance the action of cell surface
protein B on lymphocytes……signals cell proliferation.protein B on lymphocytes……signals cell proliferation.
Transforming protein of Kaposi’s sarcoma…….interacts with Rb & p52.Transforming protein of Kaposi’s sarcoma…….interacts with Rb & p52.
7. 7. Retroviruses7. Retroviruses
-Human T-cell lymphotopic virus type-1 (HTLV-1)……..adult T-cell leukemia.-Human T-cell lymphotopic virus type-1 (HTLV-1)……..adult T-cell leukemia.
-tax gene….encodes protein affecting the expression of several cellular growth-tax gene….encodes protein affecting the expression of several cellular growth
controlling genes.controlling genes.
-HIV-not directly, but causing cancer as secondary events to immuno--HIV-not directly, but causing cancer as secondary events to immuno-
suppression.suppression.
8. Retroviral oncogenesRetroviral oncogenes
-Rous sarcoma virus….src oncogene….protein-tyrosine kinase.-Rous sarcoma virus….src oncogene….protein-tyrosine kinase.
-These viral oncogenes incorporated into viral genomes from their-These viral oncogenes incorporated into viral genomes from their
host….having proto-oncogenes.host….having proto-oncogenes.
-Viral oncogene:-Viral oncogene:
Work under strong viral promoter……transcribe even in inappropriate cells,Work under strong viral promoter……transcribe even in inappropriate cells,
cellular transformation.cellular transformation.
Raf proto-oncogene protein converts into oncogene by fusion with viral proteinRaf proto-oncogene protein converts into oncogene by fusion with viral protein
at N-terminal……replacement of regulatory domain…..induced constitutiveat N-terminal……replacement of regulatory domain…..induced constitutive
activity of this kinase…cell transformation or cancer.activity of this kinase…cell transformation or cancer.
9. Ras-family (ras K, ras H and ras N):Ras-family (ras K, ras H and ras N):
-These genes are involved in more than 20 % of all human malignencies.-These genes are involved in more than 20 % of all human malignencies.
-Point mutation-substitution of valine for glycine at 12 position.-Point mutation-substitution of valine for glycine at 12 position.
Ras gene………encode..guanine-nucleotide bindingRas gene………encode..guanine-nucleotide binding
proteins…………..tranduce the mitogenic signals from variety of growthproteins…………..tranduce the mitogenic signals from variety of growth
factors.factors.
GTP-bound state of Ras……active & GDP-bound inactive.GTP-bound state of Ras……active & GDP-bound inactive.
Hydrolysis of GTP into GDP by GAP (GTPase activating protein).Hydrolysis of GTP into GDP by GAP (GTPase activating protein).
Mutation in Ras…….can not allow GAP……constitutively activeMutation in Ras…….can not allow GAP……constitutively active
Ras……..unregulated cell proliferation.Ras……..unregulated cell proliferation.
10. C-mycC-myc
-Human Burkitt’s lymphoma.-Human Burkitt’s lymphoma.
-Translocation of c-myc from chromosome 8 to 14 (IgH/c-myc fusion protein).-Translocation of c-myc from chromosome 8 to 14 (IgH/c-myc fusion protein).
ablabl
-Chronic myeloid leukemias.-Chronic myeloid leukemias.
Translocation of chromosome 9 to 22.Translocation of chromosome 9 to 22.
Recombinant Bcr /Abl fusion protein…………….unregulated protein-tyrosineRecombinant Bcr /Abl fusion protein…………….unregulated protein-tyrosine
kinase activity of Abl protein...cancer.kinase activity of Abl protein...cancer.
11. Gene amplificationGene amplification
Repeated rounds of DNA replication yield multiple copies of a particularRepeated rounds of DNA replication yield multiple copies of a particular
chromosomal region or gene.chromosomal region or gene.
eg. N-myc…….in neuroblastoma and erB-2 (receptor protein tyrosine kinase) ineg. N-myc…….in neuroblastoma and erB-2 (receptor protein tyrosine kinase) in
brest and ovarion cancers.brest and ovarion cancers.
13. Growth factors + receptors…Ras activation…..interaction with Raf proteinGrowth factors + receptors…Ras activation…..interaction with Raf protein
kinase…….p (phosphorylation) of MEK…………activation………ERKkinase…….p (phosphorylation) of MEK…………activation………ERK
activation………p various nuclear & cytoplasmic targets (proteins)..includingactivation………p various nuclear & cytoplasmic targets (proteins)..including
Fos (oncogenic potential) protein.Fos (oncogenic potential) protein.
14. PDGFPDGF
PDGF receptor translocation….amino terminus replaced by the N-terminus ofPDGF receptor translocation….amino terminus replaced by the N-terminus of
transcription factor ‘Tel’transcription factor ‘Tel’
Inclusion of helix-loop-helix structure of Tel in the fusion protein leads to theInclusion of helix-loop-helix structure of Tel in the fusion protein leads to the
constitutive activation of the receptor.constitutive activation of the receptor.
AP-1: transcription factorAP-1: transcription factor
Fos and Jun are the components……dimerize………….transcriptionalFos and Jun are the components……dimerize………….transcriptional
activation of variety of growth factor inducible genes.activation of variety of growth factor inducible genes.
15. G-protein coupled receptors and G-proteinsG-protein coupled receptors and G-proteins
Thyrotropin +receptor (g-protein coupled receptor)…..stimulation of adenylylThyrotropin +receptor (g-protein coupled receptor)…..stimulation of adenylyl
cyclase……..activation of c-AMP signling……..thyroid cancer.cyclase……..activation of c-AMP signling……..thyroid cancer.
D1 oncogeneD1 oncogene
Growth factors+ Ras/ Raf/ ERK…………stimulate D-type cyclin……..Cdk4, 6 /Growth factors+ Ras/ Raf/ ERK…………stimulate D-type cyclin……..Cdk4, 6 /
Cyc D……cell cycle progression through restriction point G1.Cyc D……cell cycle progression through restriction point G1.
Chromosome translocation or gene amplification of D…oncogene D1.Chromosome translocation or gene amplification of D…oncogene D1.
16. ErbA & PML /RARErbA & PML /RARαα
Chicken erythroleukemia and human acute promyelocytic leukemia,Chicken erythroleukemia and human acute promyelocytic leukemia,
respectively.respectively.
Thyroid hormone receptor and retinoic acid receptors, respectively.Thyroid hormone receptor and retinoic acid receptors, respectively.
Mutation (fusion proteins) ……..Blocking cell differentiation…….maintainingMutation (fusion proteins) ……..Blocking cell differentiation…….maintaining
cells in proliferation.cells in proliferation.
17. Related to cell survivalRelated to cell survival
Growth factors+ receptors………activation of PI-3kinase…….p ofGrowth factors+ receptors………activation of PI-3kinase…….p of
Akt…..activation of Bcl-2……………inhibition of mitochondrial cytochromeAkt…..activation of Bcl-2……………inhibition of mitochondrial cytochrome
release……..caspase activation…….cell death.release……..caspase activation…….cell death.