Myc is a family of proteins that functions as a master regulator of gene expression. These proteins are a type of transcription factor, meaning they control the rate at which genetic information is transcribed from DNA into messenger RNA, effectively turning genes on or off. This regulatory capability places Myc at the center of many fundamental cellular activities. Its role is so widespread that it is estimated to influence the expression of approximately 15% of all human genes.
Proper Myc function is necessary for normal development and the maintenance of healthy tissues. When tightly controlled, Myc drives processes for life. However, if this control is lost, Myc can become a potent force in the development of diseases, most notably cancer.
The Role of Myc in Normal Cell Function
In a healthy state, the Myc protein is a proto-oncogene, a normal gene that can contribute to cancer if mutated or overexpressed. Its primary function is to accelerate cellular growth and division. When a cell receives signals to proliferate, Myc is activated to orchestrate the gene expression program that prepares the cell for division.
One of Myc’s responsibilities is to drive an increase in cell mass. It achieves this by boosting the production of proteins and lipids, the building blocks of the cell. This process involves stimulating the creation of ribosomes, the cellular machinery for protein synthesis. By ensuring a plentiful supply of these components, Myc enables the cell to double in size before it divides.
Myc also directly pushes the cell cycle forward by regulating genes involved in the progression through its different phases. This ensures a timely and orderly replication of the cell’s DNA and its subsequent split into two new cells. This function is tightly regulated so that cells only divide when needed, such as during development or tissue repair.
To fuel these energy-intensive processes, Myc also alters cellular metabolism. It shifts the cell’s metabolic pathways to favor the rapid production of energy and the molecular precursors required for synthesizing new cellular components. This metabolic reprogramming ensures that the cell has the resources to support proliferation.
The Myc Signaling Pathway
The activity of the Myc protein is tightly controlled through a sequence of events known as a signaling pathway. This pathway begins with external cues, such as the presence of growth factors in the cellular environment. These growth factors bind to specific receptors on the cell surface, initiating a cascade of chemical reactions inside the cell. This intracellular signaling chain culminates in the activation of genes that lead to the production of the Myc protein itself.
Once synthesized, the Myc protein partners with another protein called MAX to perform its function. The formation of a Myc-MAX heterodimer allows the complex to bind to DNA. This structure recognizes and attaches to specific DNA sequences known as E-boxes, found in the promoter regions of genes that Myc regulates. The level of Myc within the cell is kept low, with the protein being rapidly degraded to ensure its activity is brief.
After the Myc-MAX complex binds to an E-box, it acts as a transcriptional amplifier. It recruits other proteins to the site, including co-activators that help unwind the local chromatin structure, making the DNA more accessible to the cell’s transcription machinery. This action enhances the rate at which target genes are transcribed into RNA. This leads to an increased production of the proteins those genes encode, turning on genes involved in cell growth, proliferation, and metabolism.
Myc can also be involved in gene repression. In some contexts, Myc interacts with different sets of proteins to turn genes off. For example, by associating with a protein called MIZ-1, Myc can suppress the expression of genes that inhibit cell cycle progression. This dual ability to both activate and repress genes allows Myc to orchestrate the changes required for proliferation.
Myc Dysregulation in Cancer Development
When the Myc signaling pathway becomes dysregulated, it transforms from a controlled proto-oncogene into a cancer-driving oncogene. In cancer, the mechanisms that keep Myc levels in check are broken, leading to constant and excessive activity. This sustained “on” state provides a relentless drive for cell proliferation, a defining characteristic of cancer.
One of the most well-known mechanisms of Myc dysregulation is chromosomal translocation. This occurs when a piece of one chromosome breaks off and attaches to another. In Burkitt’s lymphoma, a translocation moves the MYC gene from its normal location on chromosome 8 to a position near a highly active gene region on chromosome 14. This new location places MYC under the control of powerful genetic elements that drive its continuous expression, leading to abnormally high levels of the Myc protein.
Another common mechanism is gene amplification. In this scenario, a segment of a chromosome containing the MYC gene is duplicated multiple times, resulting in many extra copies of the gene within the cancer cell. This amplification is frequently observed in neuroblastomas and certain types of lung and breast cancers. With more copies of the gene available, the cell produces a correspondingly larger amount of Myc protein, fueling uncontrolled growth.
Mutations within the MYC gene itself can also lead to its dysregulation. Certain mutations can alter the structure of the Myc protein, making it more stable and resistant to normal cellular degradation. This increased stability means the protein persists in the cell for longer, continuously promoting proliferation even without normal growth signals.
Therapeutic Strategies Targeting Myc
For many years, Myc was considered an “undruggable” target in cancer therapy. This is due to its structure, which lacks the defined pockets that traditional small-molecule drugs are designed to inhibit. The Myc protein functions through protein-protein interactions and by binding to DNA, which are challenging interfaces to disrupt with drugs.
Given the difficulties of targeting Myc directly, research has focused on indirect strategies. One approach is to disrupt the partnership between Myc and its binding partner, MAX. Since the Myc-MAX dimer is the functional unit that binds to DNA, preventing this interaction could neutralize Myc’s ability to regulate genes. Researchers are developing small molecules that interfere with the formation of this complex.
Another strategy involves targeting the cellular machinery that Myc relies on to function. For instance, BET bromodomain inhibitors are a class of drugs that inhibit proteins that help “read” the genes that Myc turns on. By blocking these reader proteins, BET inhibitors can prevent the downstream effects of Myc activation. This works even when the Myc protein itself is overexpressed.
Scientists are also exploring ways to inhibit cellular processes that are uniquely stressed by high Myc activity. Cancer cells with overactive Myc are often under significant metabolic and replicative stress, making them more vulnerable to drugs that target these pathways. By exploiting these vulnerabilities, it may be possible to selectively eliminate Myc-driven cancer cells while sparing healthy tissues.