The document discusses viral oncogenesis, describing oncogenic viruses that can induce tumors in hosts and the mechanisms by which they cause cancer, including mutations in proto-oncogenes, activation of oncogenes, and inactivation of tumor suppressor genes. It highlights the characteristics of viral oncogenesis and distinguishes between different types of transforming viruses, as well as the role of oncogene activation through various means such as insertional mutagenesis and gene amplification. Additionally, the document provides examples of oncogenic viruses from both RNA and DNA families and their associated tumor types.

1. VIRAL ONCOGENESIS
Submitted by- Submitted to-
 Rekha Panwar  Prof S. Maherchandani

2. INTRODUCTION
 ONCOGENIC VIRUSES
Viruses that produce tumours in their natural host /
experimental animals
or
which induce malignant transformation of cells on culture.
 Features of viral oncogenesis
- cause cancer in humans & animals
- long latency between viral infection and tumorigenesis
- modulate growth control pathways in cells
- viral markers are present in tumor cells

3.  Oncogenesis -An abnormal growth of tissue resulting from
uncontrolled,
progressive multiplication of cells and serving no physiological
function. Result of genetic changes that alter the expression or
function of proteins that play critical roles in the control of cell
growth and division
 Proto-oncogenes - normal (pre-mutation) (pre-diseased) genes
- present in normal cells
- conserved in their genomes
- code for proteins which regulate cell growth
&differentiation
 Oncogenes - mutated versions of proto-oncogenes
- contribute to cancer development by disrupting a cell's
ability to control its own growth.

4.  TRANSFORMATION
alteration in a cell’s properties that leads to immortalization and
different growth patterns that result from alteration in cell cycle.
 Acute tranforming viruses
- retrovirus(alpha ,gamma)
- replication defective (does not produce viral infection)
- contain viral oncogene( transform cells in culture )
 Non acute transforming viruses
- retrovirus (alpha,beta,gamma)
- replication competent (cause viral disease)
- lack viral oncogene (high level of infection months before tumor )

5. TRANFORMATION

6. CELLULAR ONCOGENES
 Present in cancer cells
 Contains introns
characteristic of eukaryotic
cells
 Encodes proteins triggering
transformation of normal
cells
VIRAL ONCOGENES
 Present in viruses
 Host cell origin
 Do not possesss introns
 Also called ‘cancer genes’
 Encodes proteins triggering
transformation of normal
cells into cancer cells

7. Conversion of Proto-oncogene to Oncogene

8. Activation of cellular oncogenes-
c- onc gene is also responsible for some oncogenic transformation
Oncogene activation via insertional mutagenesis-the presence upstream
from a c-onc gene of an integrated provirus , with it’s strong promoter and
enhancer elements may enhance the expression of c-gene.
e.g. integrated avian leukosis provirus increase the synthesis of c-myc oncogene
product 30-100 fold.
Oncogene activation via transposition –
Transposition of c- onc may result in their enhanced expression by bringing them
under the control of strong promoter and enhancer elements.
E.g. Burkitt’s lymphoma
Oncogene activation via gene amplification-
Increase in gene copy number leads to corresponding amount of oncogene
products , thus producing cancer.
E.g. c- myc gene , c- ras gene
Oncogene activation via mutation-
Mutation alter the function of corresponding oncoprotein . it may be induced by
physical or chemical means or in course of recombination with integrated
retroviral DNA.

9.  Tumor suppressor genes
 Directly inhibit uncontrolled proliferation (RB,P53,)
 Maintain integrity of the genome
 House keeping genes
 P53 gene
 Retinoblastoma (Rb) gene

10. ONCOGENIC VIRUSES
TAXONOMIC
GROUPING
EXAMPLES PRIMARY TUMOR
TYPES
RNA VIRUSES
1.Flaviviridae Hepatitis C virus Hepatocellular carcinoma
2.Retroviridae
• Alpharetroviruses Rous sarcoma virus(RSV) Sarcoma
Rous associated virus(RAV) Bcell
lymphoma,erythroleukemia
Avian myeloblastosis virus (AMV) Myeloid/erythroid leukemia
Avian erythroblastosis virus (AEV) Erythroid leukemia
Myelocytoma virus (MC29) Myeloid leukemia
•Betaretroviruses Mouse mammary tumor virus(MMTV) Mammary carcinoma
Jaagsiekte sheep retrovirus Lung carcinoma

11. Gammaretroviruses Murine leukemia virus(MuLV) Leukemia, lymphoma
Murine sarcoma virus(MuSV) Sarcoma
Feline leukemia virus Leukemia,lymphosarcoma
Feline sarcoma virus Sarcoma
Simian sarcoma virus Sarcoma
Koala retrovirus T cell leukemia
Deltaretroviruses Human T lymphotropic virus(HTLV) Adult T cell leukemia
Bovine Leukemia virus B cell leukemia
•Epsilonretroviruses Walleye dermal sarcoma virus Sarcoma

12. DNA VIRUSES
1.Adenoviridae Types 2,5,12 Various solid tumors
2. Hepadnavirus Hepatitis B virus (HBV) Hepatocellular carcinoma
3.Herpesviridae Epstein-Barr virus(EBV)
(HHV4)
Burkitt’s lymphoma,
nasopharyngeal carcinoma
Kaposi sarcoma Herpes
virus(KSHV) (HHV8)
Kaposi sarcoma
4.Polyomaviridae SV40,polyoma virus Various solid tumors
5.Papillomaviridae HPV 6,11,16,18
Bovine papilloma virus
Papilloma,carcinoma
6.Poxviridae Shope fibromavirus Myxoma,fibroma

13. TUMOR VIRUSES
DNA VIRUSES RNA VIRUSES
VIRAL
ONCOPROTEIN
EXPRESSION
VIRAL
ONCOGENE
PROTO
ONCOGENE
CONVERSION
PROVIRAL
INSERTION NEAR
CELLULAR
ONCOGENE
TRANSFORMING NON
TRANSFORMING
INACTIVATION OF
TUMOR
SUPPRESSOR
GENES

14.  Viral Oncoproteins
- virus – encoded non structural proteins
- target tumor suppressor proteins of host cell
 Acquisition of proto-oncogene
- usually mutated in the process
- viral cellular genes are lost
- transformation of target cell
 Proviral Insertion
- activate cellular proto-oncogene
- replication intact
- induce tumors after long latent periods

15. How do oncogenes and tumor suppressors
work?
oncogene
Tumor
suppressor

16. MECHANISM OF ONCOGENECITY
Introduction of new Alteration of expression of
‘Transforming gene’ preexisting cellular gene
into the cell
Loss of normal growth regulation processes
Affection of DNA repair mechanisms
Genetic instability
Mutagenic phenotype
DIRECT ACTING
INDIRECT
ACTING

17. MECHANISM OF VIRAL ONCOGENESIS
 Impairment of the signal transduction pathway
- Growth factor expression
- Growth factor receptor activation
- Cytoplasmic or membrane-bound kinases
- Transcription factors
 Inactivation of Tumor-suppressor genes
- Uncontrolled proliferation (Rb gene & P53gene)
- Inhibition of Apoptosis (P53 gene)

18. Rb GENE MEDIATED ONCOGENESIS

19. 19
RNA Tumor
Viruses

21.  FLAVIVIRIDAE (HCV)
 RETROVIRIDAE (HTLV-1)
 XENOTROPIC MURINE LEUKEMIA VIRUS(XMRV)
 Viral oncogenes capture cellular oncogene(proto-oncogene)
(reverse transcriptase mediated in retrovirus)
proto-oncogene is mutated to cause cancer
 About 70 proto-oncogenes identified
code for key cell signaling proteins involved in the control of
cellular proliferation and apoptosis

22. Retrovirus oncogenes and oncoproteins-
Viral oncogene virus nature of oncoprotein /associated tumors
Retroviral oncogene that encode growth factor
v-sis feline leukemia virus platelet derived growth factor /leukemia
Retroviral oncogene that encode growth factor receptor and hormone
receptor
v- erbB Avian leukosis virus truncated epidermal growth factor receptor/
erythroblastosis
v- erbA Avian leukosis virus thyroxin receptor/ erythroblastosis
Retroviral oncogene that encode intracellular signal transducer
v-src Rous sarcoma virus tyrosine phosphokinase/sarcoma
V-mas murine leukemia virus serine/ threonine kinase / leukemia
V-Ha- ras murine sarcoma virus GTP-binding protein / sarcoma
V- crk avian leukemia virus signaling protein / leukemia
Retroviral oncogene that encode nuclear tanscription factor
V- myc feline leukemia virus bind to DNA regulate transcription /lymphoma

23.  Standard leukemia virus (alpha,gamma retrovirus) – no viral
oncogene
gag – encodes core proteins(group specific)
pro – encodes protease enzyme
pol – encodes reverse transcriptase
env – encodes envelope glycoproteins
 Influence proto-oncogene by insertional
mutagenesis
 Deltaretrovirus, Lentivirus
tax/tat – transactivating regulatory gene
 Transforming retrovirus
onc – encodes for oncogenetic potential

24. Oncogenic retroviruses are subdivided in two ways-
(a) Replication competent-it consists of two identical copies of a positive sense
ssRNA
each of which has 3 genes ; GAG , POL and ENV
(b) Replication defective – rapidly oncogenic exogenous retrovirus carries an
additional gene v- onc , responsible for malignant change in infected cells . This
oncogene is usually incorporated in viral RNA in place of or part of one or more
normal viral genes , such viruses are replication defective , as they depend on
nondefective helper viruses for their replication
However Rous sarcoma virus contains a viral gene v- src in addition to gag , pol and
env genes. Gag pol env
Gag onc env
Gag pol env src
( 1)

25. MECHANISM OF TUMORINDUCTION BY
RETROVIRUSES-
They produce tumor in one of three ways-
 Transducing retroviruses introduce a v-onc in to the chromosome
of the cell.
 Cis activating retroviruses which lack a v-onc gene , transform cell
by becoming integrated in host cell DNA close to c-onc and thus
usurping normal cellular regulation of this gene.
 Trans activating retroviruses contain a gene that codes for a
regulatory protein that may either increase transcription from viral
LTR or interfere with transcriptional control of cellular genes .