Medical Genetics - V. M. Zaporozhan 2005

Basics of Oncogenetics
Targets of Gene Action Involved in Carcinogenesis
Proto-oncogenes

Proto-oncogenes are normal cellular genes that promote Cell proliferation, thereby activating mitosis.

Mutations in proto-oncogenes or changes in their expression leading to increased activity convert them into cellular oncogenes, which drive unregulated Cell Division and tumor formation. Sometimes proto-oncogenes are simply called cellular oncogenes, and their activated copies are referred to as active oncogenes. However, it is preferable to designate normal genes as proto-oncogenes and their activated copies as cellular oncogenes.

The Discovery of the first proto-oncogenes and cellular oncogenes was linked to The Study of Oncogenic Viruses. Investigations of cellular genomes using DNA probes based on v-onc genes have demonstrated that all normal Eukaryotic Cells contain genes highly homologous in Structure to known Viral Oncogenes. However, under normal conditions, they do not cause malignant transformation. These genes were named proto-oncogenes, or cellular oncogenes — c-onc (derived from cellulae oncogenes).

Table 8.1. Examples of viral oncogenes (letters forming the oncogene designation are underlined)

As a rule, proto-oncogene names are derived from corresponding viral oncogenes. Sometimes they are named after Protein Functions. Genes are typically denoted in italicized Latin letters (human genes are written in all uppercase letters, while animal genes are in lowercase), whereas Gene-product Proteins are written in standard Roman font with an initial capital letter. For instance, the Rous sarcoma virus oncogene is designated as v-src, its animal proto-oncogene counterpart as c-src, and the human counterpart as SRC. The protein encoded by the SRC gene (a Tyrosine kinase enzyme and integrin signaling protein) is designated as Src.

To date, approximately 100 different proto-oncogenes have been identified. They control numerous cellular processes related to The regulation of mitosis, apoptosis, and others. The targets of proto-oncogene action include:

1. Various signaling pathways originating from growth factors, Integrins, cadherins, and other structures.

They encode:

— growth factors, such as epidermal growth factor (EGF), fibroblast, neuronal, platelet-derived, Insulin-like Growth Factors, and others;

— growth factor receptors and other membrane structures;

— a group of signaling (adapter) proteins that transmit signals from receptors or other membrane structures to MAP kinase cascades (Ras, Src, c-Abl proteins, etc.);

— Components of the MAP kinase cascade (Raf, PAK, JNK, etc.);

— METABOLISM/31.html">Transcription factors which, by influencing target Gene Expression, increase the levels or activity of cyclin-Cdk complexes — ß-catenin, Fos, Jun, Myc, and others;

— cyclin D;

— cyclin-dependent Kinases (Cdks).

Thus, proto-oncogenes stimulate cell proliferation. Their overactivity prevents cells from entering the G₀ phase and drives active cell division.

2. Suppression of apoptotic responses. Typically, the apoptotic program is triggered in cells with damaged DNA. Suppression of apoptosis increases the likelihood of preserving genetic mutations. Examples of such proto-oncogenes include the BCL2 and MDM2 genes.

3. The Development of malignant solid tumors (such as carcinomas and sarcomas) requires additional cellular alterations that disrupt cell interactions with neighboring cells and the Extracellular matrix (loss of anchorage dependence and contact Inhibition of Growth). Enhanced locomotive activity is necessary to enable invasion into surrounding Tissues. Neoplastic cells stimulate Blood vessel ingrowth (angiogenesis) into the tumor tissue to ensure its supply of nutrients. Many proto-oncogenes are also responsible for these and other processes. The number of mutations across various genes in solid tumor cells can occasionally reach several dozen.

Examples of certain proto-oncogenes and their functions are presented in Table 8.2.

Mechanisms of Proto-oncogene Conversion into Oncogenes

Mutations that activate proto-oncogenes and transform them into oncogenes are dominant. This means that a mutation in a single gene is sufficient to stimulate cell proliferation. Such mutations are generally not inherited because they are lethal (disrupting cell division during embryonic development). In most cases, proto-oncogene mutations occur in somatic cells. An exception is the Inheritance of the RET oncogene, which leads to multiple endocrine neoplasia and familial medullary thyroid carcinoma.

Mutations that decrease proto-oncogene activity can be inherited and cause various hereditary disorders, but such mutant genes are not oncogenes. For example, mutations in the RET gene lead to Hirschsprung's disease (an Autosomal dominant inheritance pattern with very low penetrance).

Thus, oncogene activation occurs more frequently As a result of somatic mutations. The following mechanisms of proto-oncogene activation and conversion into active oncogenes are possible (see Table 8.2):

1. Activation via Amplification (multiple gene reduplication). Tumor cells may contain numerous copies of a normal gene, resulting in elevated Synthesis of the corresponding protein. For instance, malignant breast Cancer is frequently driven by amplification of the ERBB2 gene (17q), and occasionally the MYC gene (8q24). Additional gene copies may exist as minute Chromosomes or be inserted into normal chromosomes.

2. Activation via point mutation (nucleotide substitution, deletion, or duplication). Such mutations in the RAS gene family are found in an average of 30% of all malignancies.

Table 8.2. Examples of proto-oncogenes and their functions (B. P. Kopnin, 2000)

3. Various types of Chromosomal aberrations (translocations, deletions, inversions, etc.). Chromosomal translocations can lead to The formation of chimeric genes or the activation of proto-oncogenes, converting them into oncogenes. For instance, in Burkitt lymphoma, 75–85% of patients exhibit a specific translocation between chromosomes 8 and 14, while the remaining patients show a translocation between chromosomes 2 and 8, or 8 and 22. Chromosome 8 harbors the MYC oncogen. In any of these translocations, this oncogene is relocated to a locus encoding IMMUNOGLOBULINS. Immunoglobulin genes are located on chromosomes 14, 9, and 22. The translocation moves the oncogene into a region of actively transcribed genes in antibody-producing B cells. Chromosomal rearrangements are typically characteristic of leukemias and lymphomas, and are less common in solid tumors.

4. Activation by oncogenic viruses. For example, Epstein-Barr virus DNA integrates directly into or near the cellular MYC proto-oncogene. The viral DNA acts as a gene promoter, driving its overexpression and converting the proto-oncogene into an oncogene, which leads to the development of Burkitt lymphoma in humans.