Within human and animal cells exists a protein known as C-terminal binding protein 2, or CtBP2. This protein functions as a transcriptional corepressor, a term that describes its role in managing which genes in a cell are active or inactive. By regulating gene expression, CtBP2 contributes to the operation of various cellular activities. It is one of two such proteins in mammals, alongside the closely related CtBP1, both of which are important for normal development and cellular function.
The Core Function of the CtBP2 Protein
As a transcriptional corepressor, CtBP2 does not attach directly to DNA to control genes. Instead, it is recruited by other proteins already bound to DNA. Once in position, CtBP2 acts as a scaffold, assembling a complex of other proteins that work together to silence, or “repress,” specific genes. This process involves modifying the histone proteins that package DNA, making the genetic code less accessible for activation.
A distinct feature of CtBP2 is its function as a metabolic sensor. The protein’s ability to repress genes is influenced by the cell’s energy state, specifically the ratio of the molecules NADH and NAD+. This sensory capability is tied to its structure, which includes a domain that can bind to NADH. This binding alters the protein’s shape and its interactions with other molecules, allowing CtBP2 to coordinate metabolic pathways based on the cell’s energy supply.
Involvement in Hearing and Vision
CtBP2 has a specialized job in the sensory systems for hearing and vision. In the inner ear, a specific version of the protein, known as RIBEYE, is a main component of structures called synaptic ribbons. These ribbons are located in the cochlear inner hair cells, which convert sound vibrations into neural signals for the brain. The RIBEYE isoform helps to organize and sustain the rapid release of neurotransmitters required for this process.
Impaired CtBP2 function in the cochlea can result in a condition called auditory neuropathy. This form of hearing loss is characterized by the ear’s ability to detect sound but an impaired ability to transmit that auditory information to the brain. The problem lies with the synaptic communication that follows sound detection.
A parallel function for CtBP2 exists in the retina of the eye. Photoreceptor cells, which detect light, also utilize synaptic ribbons to transmit visual information. The RIBEYE protein is important here, ensuring that visual signals are relayed efficiently from the photoreceptors to retinal neurons. The structural integrity of these ribbons, in both the ear and the eye, depends on the proper function of the CtBP2 protein.
The Link Between CtBP2 and Cancer
The connection between CtBP2 and cancer is caused by its overproduction, not by a defect in the protein itself. In many types of cancer, including gastric, breast, and lung cancer, tumor cells produce an excessive amount of CtBP2. This high level contributes to cancer’s progression by altering the normal balance of gene expression within the cells.
This overexpression helps cancer cells to survive and multiply. CtBP2 achieves this by repressing the genes that would normally cause a damaged cell to undergo programmed cell death, a process called apoptosis. It can also suppress genes that act as brakes on cell division. By silencing these protective genes, elevated CtBP2 allows tumor cells to grow without the usual checks.
Consequently, higher levels of CtBP2 are linked to more aggressive forms of cancer and a greater likelihood of metastasis, where cancer spreads to other parts of the body. CtBP2 can promote cell migration and invasion by activating other genes, like Tiam1. This makes the amount of CtBP2 in tumor tissue a potential indicator of a patient’s prognosis.
Disorders from CTBP2 Gene Mutations
Separate from its role in cancer, mutations in the gene that codes for CtBP2 can lead to rare congenital disorders. When a person inherits a faulty version of the CTBP2 gene, the protein’s structure and function are altered from birth. This is different from the overexpression seen in cancer, as the issue here is a defective protein, not an excess of a normal one.
While disorders related to the similar CTBP1 gene are more documented, mutations in CTBP2 are also a recognized cause of health issues. A condition known as HADDTS syndrome has been linked to the CTBP1 gene, and similar neurodevelopmental outcomes can be expected from CTBP2 mutations. These may include low muscle tone (hypotonia), developmental delays, and intellectual disability.
Because the CtBP2 protein is active throughout the body, a genetic mutation can have widespread effects. The early lethality of inheriting two faulty copies in animal models suggests the protein is necessary for normal development. The resulting disorders are systemic, affecting an individual’s growth and neurological function from the beginning of life.