Oncogenesis and Viral Proteins

Oncogenesis and Viral Proteins

• HTLV-1 oncogenesis involves a nonstructural viral regulatory protein, Tax, essential for viral replication.
• Tax interacts with cellular transcription factors and signaling molecules to enhance or repress cellular gene expression.

DNA Tumor Viruses

• DNA tumor viruses have diverse structures, genome organization, and replication strategies.
• They have two life forms: in permissive cells, viral replication causes cell lysis and cell death, while in non-permissive cells, viral DNA is mostly integrated into different sites of cellular chromosomes.
• Oncogenic mechanism in DNA tumor viruses involves the viral genome encoding proteins that interfere with cell-cycle regulating proteins such as p53, retinoblastoma, and others.

Oncogenic Viruses in Humans

• Examples of oncogenic viruses in humans include:
  • Epstein-Barr Virus (dsDNA) associated with Burkitt's lymphoma
  • Hepatitis B virus (dsDNA) associated with Hepatocellular carcinoma
  • Human T-lymphotropic virus-I (ss (+) RNA) associated with Adult T cell leukemia
  • Human Papillomavirus 16 and 18 (dsDNA) associated with Cervical cancer
  • Hepatitis C virus (ss (+) RNA) associated with Hepatocellular carcinoma
  • Human Herpesvirus 8 (dsDNA) associated with Kaposi's sarcoma
  • Merkel cell polyomavirus (dsDNA) associated with Merkel Cell carcinoma

Classification of Oncogenic Viruses

• Oncogenic viruses can be divided into two broad categories: direct carcinogens and indirect carcinogens.
• Direct carcinogens express viral oncogenes that directly contribute to cancer cell transformation.
• Indirect carcinogens cause cancer through chronic infection and inflammation, leading to carcinogenic mutations in host cells.
• Some viruses, such as HBV, HCV, and HTLV-I, do not fit neatly into either category.

RNA Tumor Viruses

• RNA tumor viruses can be divided into two groups based on their genetic material: DNA tumor viruses and RNA tumor viruses.
• Examples of RNA tumor viruses include retroviruses and hepatitis C virus.
• Retroviruses have 3 basic genes (gag, pol, and env), which are used for the synthesis of structural proteins, virion-associated enzymes, and envelope glycoproteins.

Mechanisms of Viral Transformation in Retroviruses

• Oncogene activation by retroviral insertion occurs through the integration of promoter sequences and viral enhancers near cellular growth-stimulating genes, initiating cell transformation.
• Retroviruses can cause oncogenesis by inserting near potential oncogenes, leading to cell transformation.
• Cell transformation is a rare event because insertion near potential oncogenes is infrequent.
• Monoclonal tumors result from proviral sequences integrated at the same chromosomal site.

Acute versus Slow Transforming Retroviruses

• The third group of RNA tumor viruses, including Human T cell Leukemia Virus type I (HTLV-I), constitutes an exception to the paradigm of retroviral oncogenesis.
• HTLV-I is responsible for Adult T cell leukemia and HTLV-I associated myelopathy neurodegenerative disease.
• HTLV-I is endemic in parts of Japan, South America, Africa, and the Caribbean, with an estimated 10-20 million people infected worldwide.

Retroviral Transduction of Oncogene

• Acute-transforming retrovirus can cause rapid tumor development by encoding oncogenic proteins, which stimulate cellular proliferation
• Oncogenic proteins are similar to cellular proteins in cellular growth control and are called viral oncogenes (v-onc)
• Overproduction or modification of these proteins can lead to cancer

Origin of v-onc Genes

• Acutely transforming viruses are generated when a cellular protooncogene is captured by insertion into the viral genome during viral replication
• This process usually causes genetic changes in the protooncogene, resulting in an oncogene

Outcome of Retroviral Transduction

• Single-hit carcinogenesis: one event can initiate tumor growth
• Polyclonal: tumor growth is initiated in every infected cell
• Tumors form within days
• Characteristic of animal retroviruses

Oncogenesis Mediated by Essential Retrovirus Proteins

• HTLV-1 oncogenesis involves a non-structural viral regulatory protein (tax) essential for viral replication
• Tax interacts with cellular transcription factors and signaling molecules to enhance or repress cellular gene expression

DNA Tumor Viruses

• Diverse group of viruses with different structures, genome organization, and replication strategies
• Oncogenic potential is linked to virus replication strategy
• Two life forms: permissive cells (viral replication causes cell lysis and death) and non-permissive cells (viral DNA integrates into cellular chromosomes)

Oncogenic Mechanism in DNA Tumor Viruses

• Integrated viral genome encodes proteins that interfere with cell-cycle regulating proteins (e.g., p53, retinoblastoma)
• Examples: HBV (HBx), HHV-4 (LMP-1), HPV (E6 and E7), HHV8 (vGPCR)

Conclusions

• Carcinogenesis is a multi-step process involving mutations of cellular proto-oncogenes and tumor suppressor genes
• Oncogenic viruses can cause cancer by activating cellular signal transduction pathways, interfering with cell cycle control, and impairing DNA repair

Classification of Oncogenic Viruses

• Divided into direct carcinogens (expressing viral oncogenes that directly contribute to cancer cell transformation) and indirect carcinogens (causing cancer through chronic infection and inflammation)
• Some agents (e.g., HBV, HCV, and HTLV-I) do not fit neatly into either category

Retroviruses

• Have 3 basic genes (gag, pol, and env) used for the synthesis of structural proteins, virion-associated enzymes, and envelope glycoproteins
• LTR-gag-pol-env-LTR structure

Retroviral Transduction of Oncogene

• Acute-transforming retrovirus can cause rapid tumor development by encoding oncogenic proteins, which stimulate cellular proliferation
• Oncogenic proteins are similar to cellular proteins in cellular growth control and are called viral oncogenes (v-onc)
• Overproduction or modification of these proteins can lead to cancer

Origin of v-onc Genes

• Acutely transforming viruses are generated when a cellular protooncogene is captured by insertion into the viral genome during viral replication
• This process usually causes genetic changes in the protooncogene, resulting in an oncogene

Outcome of Retroviral Transduction

• Single-hit carcinogenesis: one event can initiate tumor growth
• Polyclonal: tumor growth is initiated in every infected cell
• Tumors form within days
• Characteristic of animal retroviruses

Oncogenesis Mediated by Essential Retrovirus Proteins

• HTLV-1 oncogenesis involves a non-structural viral regulatory protein (tax) essential for viral replication
• Tax interacts with cellular transcription factors and signaling molecules to enhance or repress cellular gene expression

DNA Tumor Viruses

• Diverse group of viruses with different structures, genome organization, and replication strategies
• Oncogenic potential is linked to virus replication strategy
• Two life forms: permissive cells (viral replication causes cell lysis and death) and non-permissive cells (viral DNA integrates into cellular chromosomes)

Oncogenic Mechanism in DNA Tumor Viruses

• Integrated viral genome encodes proteins that interfere with cell-cycle regulating proteins (e.g., p53, retinoblastoma)
• Examples: HBV (HBx), HHV-4 (LMP-1), HPV (E6 and E7), HHV8 (vGPCR)

Conclusions

• Carcinogenesis is a multi-step process involving mutations of cellular proto-oncogenes and tumor suppressor genes
• Oncogenic viruses can cause cancer by activating cellular signal transduction pathways, interfering with cell cycle control, and impairing DNA repair

Classification of Oncogenic Viruses

• Divided into direct carcinogens (expressing viral oncogenes that directly contribute to cancer cell transformation) and indirect carcinogens (causing cancer through chronic infection and inflammation)
• Some agents (e.g., HBV, HCV, and HTLV-I) do not fit neatly into either category

Retroviruses

• Have 3 basic genes (gag, pol, and env) used for the synthesis of structural proteins, virion-associated enzymes, and envelope glycoproteins
• LTR-gag-pol-env-LTR structure

Retroviral Transduction of Oncogene

• Acute-transforming retrovirus can cause rapid tumor development by encoding oncogenic proteins, which stimulate cellular proliferation
• Oncogenic proteins are similar to cellular proteins in cellular growth control and are called viral oncogenes (v-onc)
• Overproduction or modification of these proteins can lead to cancer

Origin of v-onc Genes

• Acutely transforming viruses are generated when a cellular protooncogene is captured by insertion into the viral genome during viral replication
• This process usually causes genetic changes in the protooncogene, resulting in an oncogene

Outcome of Retroviral Transduction

• Single-hit carcinogenesis: one event can initiate tumor growth
• Polyclonal: tumor growth is initiated in every infected cell
• Tumors form within days
• Characteristic of animal retroviruses

Oncogenesis Mediated by Essential Retrovirus Proteins

• HTLV-1 oncogenesis involves a non-structural viral regulatory protein (tax) essential for viral replication
• Tax interacts with cellular transcription factors and signaling molecules to enhance or repress cellular gene expression

DNA Tumor Viruses

• Diverse group of viruses with different structures, genome organization, and replication strategies
• Oncogenic potential is linked to virus replication strategy
• Two life forms: permissive cells (viral replication causes cell lysis and death) and non-permissive cells (viral DNA integrates into cellular chromosomes)

Oncogenic Mechanism in DNA Tumor Viruses

• Integrated viral genome encodes proteins that interfere with cell-cycle regulating proteins (e.g., p53, retinoblastoma)
• Examples: HBV (HBx), HHV-4 (LMP-1), HPV (E6 and E7), HHV8 (vGPCR)

Conclusions

• Carcinogenesis is a multi-step process involving mutations of cellular proto-oncogenes and tumor suppressor genes
• Oncogenic viruses can cause cancer by activating cellular signal transduction pathways, interfering with cell cycle control, and impairing DNA repair

Classification of Oncogenic Viruses

• Divided into direct carcinogens (expressing viral oncogenes that directly contribute to cancer cell transformation) and indirect carcinogens (causing cancer through chronic infection and inflammation)
• Some agents (e.g., HBV, HCV, and HTLV-I) do not fit neatly into either category

Retroviruses

• Have 3 basic genes (gag, pol, and env) used for the synthesis of structural proteins, virion-associated enzymes, and envelope glycoproteins
• LTR-gag-pol-env-LTR structure