Explain about oncogene and conversion of proto oncogenes to oncogenes in biochemistry
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Oncogenes and Conversion of Proto-Oncogenes to Oncogenes
(Source: Basic Medical Biochemistry - A Clinical Approach, 6e)
1. What is a Proto-Oncogene?
Proto-oncogenes are normal cellular genes that regulate cellular proliferation and differentiation. They encode proteins involved in:
- Growth factor signaling
- Signal transduction
- Transcription factor activity
- Cell cycle regulation
When a proto-oncogene undergoes a gain-of-function mutation, it becomes an oncogene - a mutated, overactive version that drives uncontrolled cell growth. The term "oncogene" comes from the Greek onkos, meaning "bulk" or "tumor."
"The genes that regulate cellular growth are called proto-oncogenes, and their mutated forms are called oncogenes."
- Basic Medical Biochemistry, p. 594
2. What is an Oncogene?
An oncogene is a mutated proto-oncogene that produces either:
- A more active protein (hyperactive/constitutively active), or
- An increased amount of the normal protein
Either way, the result is that growth-promoting signals are continuously "on," pushing the cell toward uncontrolled proliferation even in the absence of normal activating signals.
The first proof that oncogenes were mutant proto-oncogenes came from studies of human bladder carcinoma, where the ras oncogene sequence differed from the normal c-ras by just a single point mutation - yet this was enough to transform normal cells.
3. Mechanisms of Conversion: Proto-Oncogene → Oncogene
There are four major mechanisms:
A. Point Mutations / Chemical & Radiation Carcinogens
Radiation, UV light, and chemical carcinogens (e.g., nitrosamines) cause mutations in DNA in two ways:
- Mutation in the coding region - produces a protein with altered amino acid composition that is constitutively active (hyperactive), even without its normal activating signal
- Mutation in the promoter/regulatory region - increases the rate of transcription, resulting in overproduction of the normal proto-oncogene protein
Classic example: A single point mutation at codon 12 of ras (glycine → valine) locks the Ras G-protein in its active GTP-bound state permanently, continuously stimulating cell proliferation. This mutation is found in lung, colon, thyroid, pancreatic cancers, and many leukemias.
B. Gene Rearrangement (Translocation or Transposition)
The proto-oncogene (or a portion of it) is moved from its normal chromosomal location to a new position. This can cause:
- Strong promoter takeover - the relocated gene comes under control of a stronger, more active promoter, leading to overexpression in inappropriate tissues or at abnormally high levels
- Fusion protein formation - a portion of the proto-oncogene fuses with another gene, producing a chimeric protein that is hyperactive or loses its regulatory region
Classic examples:
-
Burkitt lymphoma: The proto-oncogene c-myc (chromosome 8) translocates to chromosome 14, placing it under the control of the immunoglobulin heavy-chain promoter - a very active promoter in B cells. This causes massive overexpression of Myc transcription factor → uncontrolled B-cell proliferation.
-
Chronic Myelogenous Leukemia (CML) - Philadelphia Chromosome: A reciprocal translocation between chromosomes 9 and 22 fuses the Bcr gene (chr 22) with the Abl proto-oncogene (chr 9). The resulting Bcr-Abl fusion protein has lost its regulatory region and is constitutively active as a tyrosine kinase, continuously activating the Ras pathway and driving leukemic cell proliferation. This is the molecular target of the drug imatinib (Gleevec).
C. Gene Amplification
Multiple copies of the proto-oncogene are produced in a single cell. More gene copies = more mRNA = more protein = accelerated cell growth.
Examples:
- N-myc amplification in some neuroblastomas (associated with poor prognosis)
- erb-B2 (HER2/neu) amplification in breast, ovarian, lung, and stomach cancers - this is the target of trastuzumab (Herceptin)
D. Viral Insertion
- Direct oncogene insertion: An oncogenic virus integrates its viral oncogene (v-onc) into the host cell genome
- Insertional mutagenesis: A virus inserts a strong viral promoter adjacent to a normal cellular proto-oncogene, driving its overexpression (e.g., retroviruses in animal models)
4. Classes of Oncogenes and Associated Tumors
Oncogenes can be classified by the normal function of their protein products:
| Class | Proto-oncogene | Activation Mechanism | Location | Associated Tumor |
|---|---|---|---|---|
| Growth factors | sis (PDGF-β) | Overexpression | Secreted | Glioma |
| int-2 (FGF) | Amplification | Secreted | Fibrosarcoma, Breast cancer, Melanoma | |
| Growth factor receptors | erb-B1 (EGFR) | Overexpression | Cell membrane | Squamous cell carcinoma (lung) |
| erb-B2 (HER2) | Amplification | Cell membrane | Breast, ovarian, lung, stomach cancers | |
| PDGFR | Translocation | Cell membrane | Chronic myelomonocytic leukemia | |
| SMO (Hedgehog) | Point mutation | Cell membrane | Basal cell carcinoma | |
| Signal transduction (G-protein) | ras | Point mutation | Cytoplasm | Lung, colon, thyroid, pancreas, leukemias |
| Tyrosine kinases | abl | Translocation | Cytoplasm | Chronic myeloid leukemia (Philadelphia chr) |
| src | Overexpression | Cytoplasm | Acute lymphoblastic leukemia, Colon carcinoma | |
| raf | Overexpression | Cytoplasm | Myeloid leukemia | |
| Serine-threonine kinase | akt2 | Amplification | Cytoplasm | Ovarian carcinoma |
| Hormone receptors | RARα (retinoid) | Translocation | Nucleus | Acute promyelocytic leukemia |
| Transcription factors | Myc | Translocation | Nucleus | Burkitt lymphoma |
5. The Multistep Nature of Carcinogenesis
A single mutation in a proto-oncogene is not sufficient to cause cancer. Full transformation requires the accumulation of 4 to 7 mutations in genes controlling:
- Cell proliferation/differentiation (proto-oncogenes)
- Growth suppression (tumor-suppressor genes like Rb, p53)
- DNA repair (BRCA1, BRCA2, mismatch repair genes)
- Apoptosis regulation
The process follows a pattern of clonal expansion: one cell acquires a mutation, proliferates to form a large population, then one cell in that population acquires a second mutation, and so on. Each expansion step increases the probability of acquiring the next transforming mutation.
Key Summary
| Feature | Proto-oncogene | Oncogene |
|---|---|---|
| Normal function | Promotes regulated growth | Drives uncontrolled growth |
| Mutation type | None | Gain-of-function |
| Activity | Active only when signaled | Constitutively active |
| Copies | Normal (2 alleles) | Amplified or overexpressed |
| Dominance | - | Dominant (one mutant allele suffices) |
The dominant nature of oncogenes means that even a single mutated allele can override the normal allele and drive transformation - unlike tumor-suppressor gene mutations, which require loss of both alleles (Knudson's "two-hit" hypothesis).
- Basic Medical Biochemistry - A Clinical Approach, 6e, pp. 594-597
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