NF1

Neurofibromin 1  (NF1)

NF1 is a tumor suppressor gene located on chromosome 17 with 61 exons that serves the role of producing a specific type of protein known as neurofibromin. The neurofibromin protein can be found in various cells, such as nerve cells and oligodendrocytes. This protein is tasked with the important job of regulating cell growth, and making sure cells are multiplying at a normal pace. It does this by directly regulating a different protein known as RAS, which accelerates and promotes cell division and growth when turned on.   

Related Diseases

Due to NF1’s important role as a tumor suppressor gene, a mutation can cause serious problems and allow several diseases to develop. One example of this is Neurofibromatosis Type 1, a disease that can be induced from over 1,000 different NF1 mutations. The majority of NF1 mutations originate from a missense mutation, and result in a malfunctioning, shortened form of neurofibromin that lacks the capabilities to fully suppress the pace of cell division. As a result, a non-cancerous tumor known as neurofibromas can develop. 

Mutations in NF1 have also been known to cause several cancers, one being juvenile myelomonocytic leukemia. This typically occurs in children younger than 2, and it causes the bone marrow to create far too many white blood cells that fail to fulfill their normal purpose of fighting infections. The only working treatments for this condition are chemotherapy and a bone marrow transplant, which attempts to replace the original stem cells.  

Discussion 

While in class, I learned several new facts about NF1 and how it functions as a tumor suppressor gene. Firstly, NF1 is located in the inner aspect of the plasma membrane, and primarily serves to inhibit RAS signal transduction along with the p21 cell cycle inhibitor in specific cells. However, in the instance this gene is mutated, it can cause neuroblastoma tumors, sarcomas, and neurofibromatosis type 1. Beyond the effects of a potential mutation, NF1’s role in controlling RAS and p21 in certain cells is essential in understanding how it truly operates. RAS proteins function as the link between RTK and the MAP kinase cascade. 

When GTP binds to RAS, the protein is “turned on”, and when GDP binds to RAS, the protein is “turned off”. On the other hand, p21 mainly serves to halt progression of the cell cycle through restraining the activity of cyclin-dependent kinases. NF1’s regulatory control over both RAS signal transduction and the cell cycle inhibitor p21 make it a very important tumor suppressor gene, also explaining why potential mutations can be so detrimental.   

Therapeutic Approaches for Treating NF1 Mutant Tumors

As of today, the majority of therapeutic approaches for treating NF1 mutations are redesigned ones used against cancer. However, research is being done to develop more specialized treatment for NF1 that would actually fix and replenish the malfunctioning neurofibromin protein, allowing it to properly regulate RAS. Some of these developing treatments include nonsense suppression therapy, gene therapy, and exon skipping. Other forms of therapy aim to regulate RAS directly, as opposed to NF1. This is done by targeting RAS effectors, where some treatments block the RAS binding domains to restrain it from becoming active.

Alexander Cesca

• https://medlineplus.gov/genetics/gene/nf1/#conditions
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017752/
• https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=NF1
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555610/