In the complex world of genetics and cellular biology, proto-oncogenes hold a prominent position. These genes, integral to the normal growth and division of cells, also have the potential for mutation and transformation into oncogenes – culprits behind the uncontrolled cell growth that characterizes cancer. This article aims to delve into the intricacies of proto-oncogenes, elucidating their role, importance, and implications for human health.

What are Proto-oncogenes?

Proto-oncogenes are normal genes present in all cells. They contain the codes for proteins that stimulate normal cell growth and division. These proteins also aid in the transmission of signals within cells, regulating cell death, or apoptosis. Essentially, proto-oncogenes are the body’s inbuilt system for managing cell growth and maintaining a healthy balance in the body.

However, these beneficial proto-oncogenes can convert into harmful oncogenes due to mutations or changes in their genetic structure. These changes can be triggered by various factors, including exposure to specific chemicals or radiation, viruses, or certain inherited mutations. 

The conversion from a proto-oncogene to an oncogene often involves an increase in the amount of protein produced or a change in the protein structure that makes it perpetually active. This heightened activity can push cells into an uncontrolled growth phase, leading to the formation of a tumor.

Role of Proto-oncogenes in Cancer

The link between oncogenes and cancer is well established. However, it’s important to understand that the transformation of a proto-oncogene into an oncogene alone may not directly result in cancer. Usually, a series of several mutations in different genes across a cell is required before it transforms into a cancer cell.

Some of the common proto-oncogenes implicated in human cancers include RAS, MYC, and HER2/neu. RAS mutations are commonly found in pancreatic, colorectal, and lung cancers. MYC mutations are often associated with Burkitt lymphoma, while the overexpression of the HER2/neu gene is observed in some aggressive forms of breast cancer.

Importance and Therapeutic Implications

Understanding proto-oncogenes and the processes involved in their mutation to oncogenes presents a pathway for potential therapeutic interventions. Targeted therapies aimed at specific oncogenes have already shown promise in cancer treatment. For example, drugs like Trastuzumab (Herceptin) are used to target the HER2/neu receptor in breast cancer patients, inhibiting the signal that stimulates cell growth.

However, further research is needed to identify more proto-oncogenes, understand the mechanisms by which they convert into oncogenes, and develop effective strategies to intervene at various stages of this process.

Understanding the Background

As early as the 1910s, the German biologist touched upon the possible existance of oncogenes in his book Zur Frage der Entstehung Maligner Tumoren (Concerning the Origin of Malignant Tumors), published in 1914. He predicted the existance of Teilungsfoerdernde Chromosomen (oncogenes) that would become amplified (“im permanenten Übergewicht“) during the development of a tumour.

The first confirmation of an oncogene came in 1970, after the interest in oncogenes had been revived thanks to George Todaro and Robert Huebner at the The National Cancer Institute (NCI)  in the United States. This oncogene, which was discovered in a chicken retrovirus, was named SRC, which is pronounced sarc. Later experiments at Berkeley, led by G. Steve Martin, showed that SRC was the gene of the virus that acted as an oncogene.

In 1976,  Dominique Stéhelin, J. Michael Bishop, and Harold E. Varmus of the University of California, San Francisco demonstrated that oncogenes were activated proto-oncogenes; the ones found naturally in many organisms, including humans. There research would later result in Bishop and Varmus being awarded the 1989 Nobel Prize in Physiology or Medicine.

The first human oncogene was identified in a human bladder cancer cell line by Robert Weinberg, and the first nucleotide sequence of  v-Src was sequenced by A.P. Czernilofsky et al.

In 1982, the Spanish biochemist Mariano Barbacid published an article in Nature, showing how he had managed to isolate and characterize the molecular nature of the mutation leading to oncogenesis. After continuing with his research, Barbacid also discovered that the oncogene was a mutated allele of HRAS (GTPase HRas, from “Harvey Rat sarcoma virus”). Barbacid also managed to characterize its activation mechanism.

Final Thougts

Proto-oncogenes, while essential for normal cell functioning, hold a precarious position due to their potential to mutate into oncogenes. A better understanding of these genes and their role in cancer can pave the way for improved therapies and potential cures. As scientific research continues to evolve, so does the hope for more efficient and targeted treatments for various forms of cancer.

This article was last updated on: June 6, 2024