7: Oncogenes and Tumor Suppressor Genes Lecture Notes

Oncogenes and Tumor Suppressor Genes Overview

• Oncogenes are genes that have the potential to cause cancer.
• Tumor suppressor genes are responsible for regulating cell growth and suppressing tumor formation.

Historical Context by Peyton Rous

• In 1909, Francis Peyton Rous discovered a tumor in chickens, leading to Nobel Prize recognition in 1966.
• Observed that a cell-free filtrate from the tumor could induce tumors in other chickens, suggesting a transmissible agent.

Discovery of Rous Sarcoma Virus (RSV)

• Identified as an RNA retrovirus responsible for tumor induction.
• Derived from Avian Leukosis Virus (ALV) when it acquired a cancer-causing gene named v-src.
• Mutant RSV strains lacking functional v-src do not cause cancer.

Proto-oncogenes

• The cellular counterpart of v-src is c-src, a proto-oncogene found in normal chicken cells.
• Proto-oncogenes are crucial the organisms and tend to be highly conserved across species.

Mechanism of Oncogenesis

• Oncogenes can cause phenotypic changes characteristic of cancer; consequently, a single oncogene can trigger transformation.
• Examples of cancer-causing viruses are identified, carrying oncogenes from the host.

Retroviruses and Cancer Induction

• "Acutely transforming" retroviruses can induce cancer quickly (days to weeks).
• "Slowly transforming" retroviruses (e.g., ALV) manipulate the host genome over a longer time via insertional mutagenesis.
• Example: In avian leukemias, ALV inserts into the c-myc proto-oncogene, causing excessive expression and leukemia.

Viral Theory of Human Carcinogenesis

• By 1970, it was hypothesized that many human cancers might stem from viral infections.
• Evidence showed otherwise: cancers do not appear in contagious patterns nor can many cancer-causing viruses be isolated from human cancers (exceptions: HPV, HBV).

Non-viral Oncogenes

• Studies confirmed that non-viral carcinogens could induce proto-oncogenes to become oncogenes.
• Oncogene Transformation Experiments:
• 1979: Chemically altered mouse cells exhibited potential to transform non-malignant cells into malignant ones.
• 1981: Human bladder tumor DNA was also shown to transform mouse fibroblasts into cancerous cells.

Cross-Species Oncogenes

• Observations indicate that oncogenes may act similarly across species, affecting both human and animal cancers.
• Identified animal retroviral oncogenes were homologous with transforming human oncogenes.

Myc Proto-oncogene Amplifications and Translocations

• The Myc proto-oncogene is implicated in various cancers.
• Amplification seen in neuroblastoma, and translocation in Burkitt lymphoma, where the MYC gene is paired with the immunoglobulin gene, activating its transcription.

Tumor Suppressor Genes

• These genes may prevent tumor formation and are critical in the genetic explanation of cancer.
• Cell fusion experiments suggest a recessive nature of cancer in some cases.
• Retinoblastoma serves as a model showing that one allele mutation could be inherited and another acquired, leading to cancer.

Knudson's Two-Hit Hypothesis

• The genetic model posits that one germline mutation plus one somatic mutation results in cancer, particularly in retinoblastoma.
• Challenges include understanding the low likelihood of random second hits causing malignancy.

Loss of Heterozygosity (LOH)

• Contributes to tumor development when both alleles of tumor suppressor genes lose function, often through recombination during mitosis.

Known Tumor Suppressor Genes and Their Functions

• p53: Responds to cellular stress, promotes DNA repair.
• Rb: Regulates cell cycle.
• PTEN: Opposes growth signaling.
• BRCA1/2: Involved in DNA repair, mutation might elevate cancer risks.

Conclusions

• Loss of tumor suppressor genes can increase cellular susceptibility to cancer by allowing oncogenic processes to proceed.
• The second allele's loss (through various mechanisms) can lead to tumorigenesis.
• Future discussions will explore more about tumor suppressor genes' functions further, confirming their paramount role in cell regulation and cancer prevention.