The acronym “APC” in biology can be a source of confusion, as it refers to two different cellular components: the Adenomatous Polyposis Coli (APC) protein and the Anaphase-Promoting Complex/Cyclosome (APC/C). The first is a large protein that acts as a tumor suppressor, while the second is a complex of many proteins that regulates the cell division cycle. Understanding the distinction between these two is fundamental to appreciating their specific functions and implications for human health.
The Adenomatous Polyposis Coli (APC) Protein: A Cellular Guardian
The Adenomatous Polyposis Coli (APC) protein was identified through research into Familial Adenomatous Polyposis (FAP), a hereditary condition causing numerous colon polyps with a high cancer risk. Scientists discovered that individuals with FAP have inherited mutations in the APC gene, located on chromosome 5. This gene provides instructions for making the APC protein, which is classified as a tumor suppressor that prevents uncontrolled cell growth.
The APC protein performs its tumor suppressor role primarily as a negative regulator in the Wnt signaling pathway. It is a core component of a “destruction complex” that targets another protein, β-catenin, for degradation. By controlling β-catenin levels, the APC protein prevents the over-activation of genes that stimulate cell division. When the APC gene is mutated, this regulation is lost, leading to an accumulation of β-catenin and uncontrolled cell growth.
Beyond its role in the Wnt pathway, the APC protein is involved in other cellular processes, including:
- Contributing to cell adhesion, the process by which cells attach to one another.
- Influencing cell migration.
- Maintaining the cell’s internal scaffolding, the cytoskeleton.
- Ensuring the correct number of chromosomes is distributed to daughter cells during division.
The Anaphase-Promoting Complex/Cyclosome (APC/C): Master of Cell Cycle Timing
The Anaphase-Promoting Complex/Cyclosome (APC/C) is a large assembly of 11 to 13 protein subunits. It functions as an E3 ubiquitin ligase, an enzyme that attaches a small protein tag called ubiquitin to other proteins. This process marks the target proteins for destruction by the cell’s waste disposal system, the 26S proteasome. Targeted protein degradation is a major mechanism for regulating cellular processes.
The primary responsibility of the APC/C is to control the progression of the cell cycle, particularly the transitions through mitosis. It ensures that events in cell division occur in the correct order and at the proper time. The APC/C’s activity is not constant; it is turned on and off at specific stages by associating with one of two activator subunits, Cdc20 or Cdh1, which guide it to its targets.
A main function of the APC/C is initiating the transition from metaphase to anaphase, where duplicated chromosomes are pulled apart. With its Cdc20 activator, the APC/C targets a protein called securin for destruction. The degradation of securin releases separase, which cleaves the cohesin complexes holding sister chromatids together. The APC/C also targets mitotic cyclins for degradation, which inactivates key enzymes and promotes the cell’s exit from mitosis.
Consequences of APC Protein Dysregulation
Adenomatous Polyposis Coli (APC) Protein
When the APC protein malfunctions, the consequences are most prominent in cancer development. Inherited APC gene mutations cause Familial Adenomatous Polyposis (FAP), where the resulting protein is often nonfunctional. This prevents β-catenin regulation, leading to numerous colon polyps and a nearly 100% risk of colorectal cancer if untreated.
APC gene mutations are also common in sporadic colorectal cancers and are considered an early event in tumor development. Beyond the colon, these mutations are associated with other cancers, including those of the stomach and breast. The loss of a functional APC protein can also affect the immune system’s ability to control colon inflammation, creating an environment that favors cancer.
Anaphase-Promoting Complex/Cyclosome (APC/C)
Dysregulation of the APC/C also has severe consequences for the cell. Because the APC/C is responsible for the proper separation of chromosomes during mitosis, defects in its function can lead to errors in this process. This can result in aneuploidy, a condition where cells have an abnormal number of chromosomes. Aneuploidy is a characteristic of many cancers and is thought to contribute to tumor development.
Improper APC/C activity can cause cell cycle regulators to accumulate when they should be destroyed. The failure to degrade proteins like cyclins can prevent cells from exiting mitosis properly, leading to genomic instability. Mutations in APC/C subunits have been identified in various cancers, and an imbalance between its activators, Cdc20 and Cdh1, can also contribute to cancer.
Scientific Exploration and Therapeutic Avenues for APC-Related Conditions
Adenomatous Polyposis Coli (APC) Protein
Current research explores ways to address problems from a faulty APC protein. For individuals with FAP, genetic testing can identify risk, allowing for early screenings. Scientists are investigating therapies for cancers with APC mutations, such as small molecules to help restore Wnt pathway regulation. Other strategies include using drugs like certain NSAIDs to reduce the number of polyps in FAP patients.
Researchers are also exploring gene therapy to deliver functional APC gene copies or use gene-editing technologies like CRISPR-Cas9 to correct mutations. There is also interest in how natural compounds in foods might influence APC function. For existing cancers, research focuses on targeting the downstream effects of the mutation, such as inhibiting overactive pathways.
Anaphase-Promoting Complex/Cyclosome (APC/C)
The APC/C is also being investigated as a potential target for cancer therapies. Since it regulates the cell cycle, modulating its activity could selectively target rapidly dividing cancer cells. Drugs that either inhibit or activate the APC/C are being explored for their potential to halt cancer cell proliferation or induce cell death.
Scientists are working to map how the different subunits and activators interact and how the complex chooses its substrates. This detailed knowledge could reveal new binding sites for future drugs to more specifically target the APC/C in cancer cells. The goal is to develop therapies that are effective against tumors while minimizing harm to healthy cells.