Protooncogene

Proto-oncogenes are normal genes that promote cell growth, division, and survival. When these genes are mutated or misregulated, they can become oncogenes that drive cancer development. The concept emerged from studies of viral oncogenes and their cellular counterparts, which revealed that alterations in normal growth-promoting genes can lead to malignant transformation.

Proto-oncogenes encode key components of growth factor signaling pathways. They include extracellular ligands and their receptors, such as receptor tyrosine kinases in the ERBB family and other growth factor receptors; intracellular signaling molecules like the RAS family GTPases and RAF kinases; lipid and protein kinases such as PI3K, AKT, and mTOR; and transcription factors including MYC, JUN, and FOS. In normal cells, these genes are tightly regulated to coordinate growth and differentiation.

Activation of proto-oncogenes can occur through several mechanisms. Point mutations may lock a protein in an active state, gene amplification can increase gene dosage and expression, and chromosomal rearrangements can create fusion proteins or place a gene under a more active promoter, leading to overexpression. In many cancers, a single activating mutation in one allele can be sufficient to drive the oncogenic process, illustrating the dominant effect of oncogenes at the cellular level.

Notable examples of proto-oncogenes include KRAS, HRAS, and NRAS; BRAF; ERBB2 (HER2); MYC family members; and CTNNB1 among others. These genes represent major classes of cancer drivers and are targets for therapeutic intervention, with inhibitors developed to block aberrant signaling in tumors that harbor activating alterations.