Proto-oncogenes

Conversion of proto-oncogene

Proto-oncogenes code for proteins involved in signal transduction, cell cycle control, or apoptosis promotion.

They transform into oncogenes when their sequences are altered by mutations (e.g., deletions) or when regulatory changes cause overexpression, leading to excessive production of their gene products.

Overexpression may occur due to gene amplification (production of many functional gene copies) or if the gene is influenced by an overactive promoter.

If, at the same time, there is a failure in the regulation of oncogene expression due to defects in tumor suppressor gene products, this can lead to malignant transformation and uncontrolled cell proliferation.

Usually, a single proto-oncogene mutation is not sufficient to cause a loss of growth control. Transformation occurs when multiple mutations and regulatory defects accumulate in a single cell over time.

They were first discovered as viral oncogenes (v-oncogenes) in tumor retroviruses (oncoviruses). These viruses often incorporate host cell genes into their own genome. If such genes are later integrated into the DNA of another host cell during infection, they can, in rare cases, initiate tumor formation.

Classification

Gene names typically consist of three-letter abbreviations indicating the viral origin and are written in italics (e.g., myc for myelocytomatosis—a viral disease in birds).

Based on their function, proto-oncogene products are classified as follows:

1. Ligands of receptors, such as growth factors and cytokines, which activate cell proliferation.
2. Type I membrane receptors with tyrosine kinase activity (RTKs), which can bind growth factors and hormones.
3. GTP-binding proteins and adaptor proteins – including G-proteins and related proteins like Ras (the product of the oncogenic c-ras gene).
4. Receptors for lipophilic hormones, which mediate the effects of steroid hormones and similar signaling molecules. These also regulate the transcription of specific genes. Products of multiple proto-oncogenes (e.g., erbA) belong to the superfamily of ligand-activated transcription factors.
5. Nuclear tumor suppressors inhibit terminally differentiated cells from re-entering the cell cycle. Genes coding for these functions are referred to as anti-oncogenes.
6. DNA-binding proteins. Many proto-oncogenes encode transcription factors. Of special importance for regulating cell proliferation are myc, fos, and jun. The protein products of fos and jun form a heterodimeric transcription factor called AP-1.

Protein kinases

Protein kinases play a central role in intracellular signal transduction. They phosphorylate proteins, altering their biological activity, which can later be reversed by protein phosphatases.

The interaction between kinase-induced phosphorylation and phosphatase-induced dephosphorylation (interconversion) regulates the cell cycle and many other critical processes. For instance, Raf kinase is particularly involved in insulin signal transduction.

Sources

MATOUŠ, Bohuslav, et al. Základy lékařské chemie a biochemie. 1. vydání. Praha : Galén, 2010. 540 s.