The SKI gene is a proto-oncogene, a class of genes that holds the potential to promote cancer if it undergoes certain changes, such as mutations or increased expression. In the human body, this gene is involved in a variety of normal cellular functions. It provides the necessary instructions for producing a protein that is integral to cell regulation.
The Normal Function of the SKI Gene
The SKI gene provides instructions for creating a protein that regulates cell activities, including their growth, division, and differentiation into specialized cells. This protein is found in many cell types and is involved in the development of tissues like the skull, bones, skin, and brain. Its primary role is to act as a regulator within the Transforming Growth Factor-beta (TGF-β) signaling pathway. This pathway transmits chemical signals from outside the cell directly to the nucleus, influencing which genes are turned on or off.
The TGF-β pathway is instrumental in controlling cell growth and can prevent the formation of tumors. The SKI protein functions as a brake on this system. It achieves this by interacting with proteins called SMADs, which are activated by TGF-β signals. When the SMAD proteins form a complex, they travel to the cell’s nucleus to activate specific genes. The SKI protein can intercept this process by binding to the SMAD proteins, preventing them from entering the nucleus or blocking their ability to activate genes once they are in the nucleus.
The Link Between the SKI Gene and Cancer
When a proto-oncogene like SKI functions abnormally, it can become an oncogene, a gene that drives cancer development. This transformation is often linked to its overexpression, which means the cell produces too much of the SKI protein. High levels of the SKI protein disrupt the TGF-β pathway, a system that helps to suppress tumors, and this interference can lead to uncontrolled cell growth.
By binding excessively to SMAD proteins, the overabundant SKI protein prevents them from activating genes that would typically halt cell division or initiate cell self-destruction. Many human cancer cell lines that are resistant to the growth-inhibiting signals of TGF-β show high levels of SKI protein. Reducing the expression of SKI in these cancer cells can restore the pathway’s normal function and make the cells sensitive to growth inhibition once again.
This mechanism has been observed in several types of human cancers. Overexpression of the SKI gene is frequently noted in cases of melanoma, where it is believed to prevent the cancer cells from responding to TGF-β levels. It is also implicated in esophageal squamous cell carcinoma and certain leukemias. In these contexts, the elevated SKI protein allows cancer cells to bypass normal growth controls.
Shprintzen-Goldberg Syndrome
Distinct from its role in cancer through overexpression, the SKI gene is also associated with a rare congenital disorder known as Shprintzen-Goldberg syndrome (SGS). This condition is not caused by an excess of the SKI protein but by mutations within the SKI gene itself. These mutations are present from birth and disrupt the normal development of various body systems.
Shprintzen-Goldberg syndrome arises from “gain-of-function” mutations. These genetic changes alter the SKI protein in a way that enhances its activity, leading to an uncontrolled TGF-β signaling pathway. Many of these mutations affect the specific region of the SKI protein that is responsible for binding to SMAD proteins. The altered SKI protein is unable to properly attach to the SMADs, which allows the signaling pathway to proceed without its usual regulatory brake.
This unchecked signaling disrupts the normal development of bones, the brain, and other tissues. Individuals with SGS often present with physical traits, including distinctive craniofacial features, skeletal abnormalities such as elongated limbs and curvature of the spine (scoliosis), and sometimes cardiovascular complications.
Therapeutic and Research Implications
The involvement of the SKI gene in both cancer and a rare developmental syndrome makes it a subject of scientific inquiry. Researchers are exploring targeting the SKI protein or its associated pathways as a therapeutic strategy for cancer treatment. The goal is to counteract the effects of SKI overexpression and restore the tumor-suppressing capabilities of the TGF-β pathway. One approach involves using RNA interference to inhibit the gene, which has been shown to decrease tumor growth in laboratory settings.
Developing drugs that can specifically inhibit the SKI protein presents challenges. A primary concern is the potential for side effects, as the SKI protein and the TGF-β pathway are involved in numerous normal cellular processes throughout the body. A successful therapy must be able to target the cancerous cells without causing widespread disruption to healthy tissues. Researchers are investigating ways to make cancer cells that overexpress SKI more sensitive to the growth-inhibitory effects of TGF-β.
Scientists are working to uncover the precise mechanisms by which SKI contributes to tumor progression in different types of cancer, such as pancreatic cancer and melanoma. This work is important for developing novel therapies for both the cancers linked to SKI overexpression and congenital disorders like Shprintzen-Goldberg syndrome that result from its mutation.