Transforming acidic coiled-coil containing protein 3, or TACC3, is a protein that manages processes within our cells. It is found in different cellular locations, including the nucleus, centrosomes, and spindles. TACC3 is part of a protein family that interacts with microtubules, the tube-like structures forming the cell’s internal skeleton. Its roles change depending on its location within the cell and the stage of the cell’s life cycle.
This protein is fundamental for normal cell function and organismal growth. When TACC3 is overexpressed or altered, it can contribute to the development and progression of various cancers. This dual nature makes TACC3 a subject of scientific investigation, as understanding its normal functions provides insight into how its malfunction can lead to disease.
The Fundamental Role of TACC3 in Cell Division
The process of cell division, or mitosis, requires a precise and orderly distribution of genetic material into two new daughter cells. TACC3 helps orchestrate this event by building and maintaining the mitotic spindle, a complex apparatus made of microtubules responsible for segregating chromosomes. TACC3 accomplishes this as a component of a larger protein complex that includes clathrin and another protein called ch-TOG.
This TACC3/ch-TOG/clathrin complex functions as an inter-microtubule bridge, linking and stabilizing the fibers that make up the spindle. This stabilization is important for creating tension on the chromosomes, ensuring they are properly aligned at the cell’s equator before they are pulled apart. The interaction is initiated when another protein, Aurora A kinase, phosphorylates TACC3 at a specific site, Serine-558, which allows it to recruit ch-TOG to the spindle.
This recruitment promotes the growth and stability of the spindle microtubules. By managing the assembly and integrity of the mitotic spindle, TACC3 ensures that each new cell receives an identical and complete set of chromosomes. This precise regulation prevents genetic errors that could otherwise be harmful to the cell.
TACC3’s Involvement in Development
The regulated cell division guided by TACC3 is important during embryonic development. The formation of tissues and organs requires rapid and accurate cell proliferation. Studies in mouse models have shown that TACC3 is necessary for proper development, and its absence leads to embryonic lethality in the middle to late stages of gestation. This is often due to widespread apoptosis, or programmed cell death, affecting systems like the hematopoietic (blood-forming) system.
TACC3’s role is pronounced in the development of the nervous system. It is involved in a process called interkinetic nuclear migration, which is the movement of the nucleus within neural progenitor cells. This movement is coupled to the cell cycle and is a defining characteristic of the developing neocortex. TACC3’s interaction with microtubules helps ensure this process occurs correctly for the maintenance and self-renewal of the neural progenitor cells that build the brain.
The protein’s expression is tightly regulated during these developmental stages, appearing at high levels in proliferating tissues. Its function in ensuring accurate chromosome segregation is magnified in importance when building a complex organism from a single cell. Any errors during this process could lead to significant defects in the resulting tissues and organs.
The Link Between TACC3 and Cancer
The same machinery that TACC3 regulates for normal cell division can be hijacked in cancer. Many types of cancer are characterized by uncontrolled cell proliferation, and TACC3 is often found at high levels in tumor cells. This overexpression contributes to cancer’s aggressiveness by promoting rapid division and helping cancer cells survive. High TACC3 expression has been linked to a worse prognosis in multiple cancers, including primary central nervous system lymphomas and liver cancer.
In some cases, the gene for TACC3 becomes physically fused to another gene, such as the one for Fibroblast Growth Factor Receptor 3 (FGFR3). This FGFR3-TACC3 gene fusion creates an oncogenic driver, a hybrid protein that continuously signals for the cell to grow and divide. These fusions are found in a variety of cancers, including glioblastoma, bladder cancer, and lung cancer, and are a direct cause of tumor development.
TACC3 also helps cancer cells manage a common abnormality known as centrosome amplification, where cells have more than the normal two centrosomes. In healthy cells, extra centrosomes would lead to chaotic cell division and death. TACC3 helps cancer cells cluster these extra centrosomes, allowing the cell to divide in a bipolar fashion and survive, a trait that makes these cancers particularly aggressive and difficult to treat.
Targeting TACC3 for Medical Treatment
Because of its direct involvement in tumor growth and survival, TACC3 is an attractive target for new cancer therapies. The high levels of TACC3 protein in certain tumors make it a useful biomarker. A biomarker is a measurable substance in the body that indicates a particular disease state. Detecting elevated TACC3 levels could help doctors diagnose specific cancers or predict how aggressive a tumor might be, guiding treatment decisions.
Researchers are working to develop drugs that can inhibit the function of TACC3. The strategy is that blocking TACC3 in cancer cells, particularly those with centrosome amplification, would disrupt spindle formation and lead to fatal errors in cell division. This would cause the cancer cells to die while having a minimal effect on healthy cells, which are less reliant on TACC3 for survival.
This approach has shown promise in preclinical studies. Pharmacological inhibition of TACC3 has been shown to cause the formation of multipolar spindles in cancer cells with extra centrosomes, leading to cell death. Targeting the TACC3 protein represents a promising strategy in the effort to find more effective treatments for aggressive cancers.