Principles of viral oncogenesis (Lecture 10A)
Background
What is oncogenesis?
Process that leads to development of cancer
Mutations that affect pathways that control cell proliferation
Mutations may be inherited or caused by DNA damage, environmental
carcinogens or infectious agents
Human oncogenic viruses:
Contribute to 20% of all cancer (⅕)
7 human viruses that cause cancer:
DNA viruses:
- HHV8 (Kaposi’s sarcoma virus)- causes lymphoma
- HHV4 (Epstein Barr virus)- causes lymphoma
- Polyoma virus – causes Merkel cell lymphoma
- Hep B – causes hepatocellular carcinoma
RNA Viruses:
- Hep C – causes hepatocellular carcinoma
- HTLV – causes Leukaemeia/ Lymphomas
Viral transformation of cells:
Transformed cells are not infectious (non-productive, proliferative state)
Virally transformed cells become immortalized (grow forever)
Viral transformation is not a requirement (is accidental)
Properties: altered morphology, lose contact inhibition, grow without attachment
to substrate, proliferate indefinitely, reduced requirement for mitogenic growth
factors, high saturation density, increased glucose transport.
Viral transformation mechanisms:
- Carry modified cellular genes (v-onc) (RSV)
- Activate cellular protooncogenes (RSV)
- Express proteins that interfere with tumour suppressors (p53)
- Indirect methods, e.g. inducing chronic inflammation (HTLV-1, HBV and HCV)
Overview of the cell cycle:
Phases: G1, S, G2, M
Mitosis: prophase, metaphase, anaphase, telophase
Cyclins and CDKs control cell cycle
CKI’s (CDK inhibitors):
Cip/Kip family: Inhibit the ATP binding site of CDK
INK4 family: Inhibit the cyclin binding site
Regulation of CDK activity: Association with cyclin, activating and inhibitory phosphorylation,
CDK inhibitors
The restriction point:
pRb controls the G1/S restriction
Hypophosphorylated Rb binds to E2F and DP transcription factors
Hyperphosphorylated Rb releases E2F and DP: leads to cell proliferation
Transducing oncogenic retroviruses
(1) Rous sarcoma virus
Experiment 1: 1911, Rous extracted a filterable agent that could transduce tumours
from one chicken to another chicken
- The viral oncogene was shown to be V-Src
- V-Src has a SH2, SH1 and SH3 domain
Background
What is oncogenesis?
Process that leads to development of cancer
Mutations that affect pathways that control cell proliferation
Mutations may be inherited or caused by DNA damage, environmental
carcinogens or infectious agents
Human oncogenic viruses:
Contribute to 20% of all cancer (⅕)
7 human viruses that cause cancer:
DNA viruses:
- HHV8 (Kaposi’s sarcoma virus)- causes lymphoma
- HHV4 (Epstein Barr virus)- causes lymphoma
- Polyoma virus – causes Merkel cell lymphoma
- Hep B – causes hepatocellular carcinoma
RNA Viruses:
- Hep C – causes hepatocellular carcinoma
- HTLV – causes Leukaemeia/ Lymphomas
Viral transformation of cells:
Transformed cells are not infectious (non-productive, proliferative state)
Virally transformed cells become immortalized (grow forever)
Viral transformation is not a requirement (is accidental)
Properties: altered morphology, lose contact inhibition, grow without attachment
to substrate, proliferate indefinitely, reduced requirement for mitogenic growth
factors, high saturation density, increased glucose transport.
Viral transformation mechanisms:
- Carry modified cellular genes (v-onc) (RSV)
- Activate cellular protooncogenes (RSV)
- Express proteins that interfere with tumour suppressors (p53)
- Indirect methods, e.g. inducing chronic inflammation (HTLV-1, HBV and HCV)
Overview of the cell cycle:
Phases: G1, S, G2, M
Mitosis: prophase, metaphase, anaphase, telophase
Cyclins and CDKs control cell cycle
CKI’s (CDK inhibitors):
Cip/Kip family: Inhibit the ATP binding site of CDK
INK4 family: Inhibit the cyclin binding site
Regulation of CDK activity: Association with cyclin, activating and inhibitory phosphorylation,
CDK inhibitors
The restriction point:
pRb controls the G1/S restriction
Hypophosphorylated Rb binds to E2F and DP transcription factors
Hyperphosphorylated Rb releases E2F and DP: leads to cell proliferation
Transducing oncogenic retroviruses
(1) Rous sarcoma virus
Experiment 1: 1911, Rous extracted a filterable agent that could transduce tumours
from one chicken to another chicken
- The viral oncogene was shown to be V-Src
- V-Src has a SH2, SH1 and SH3 domain
