Molecular mechanism by which IkBa regulates NF-kB activity
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: All of the information necessary for the functions of every cell in our body is encoded in the DNA stored within the nucleus of the cell. This information is translated into the amino acid sequences of the proteins that carry out all of the tasks necessary for the growth and functions of the cell. At any given time only a small fraction of the genes that make up the DNA are translated into active proteins. The cell has a number of signaling molecules that sense changes in the environment and help the cell to respond by controlling which tasks are performed and when. Transcription factors are one type of signaling molecules that bind to highly specific recognition sequences within the DNA and promote transcription of the gene that corresponds to the protein required for a given task. One of these regulatory molecules, nuclear factor kappa B (NF-kappa-B) is pivotal in controlling the transcription of more than 150 genes. Consequently, when NF-kappa-B functions incorrectly, it causes a wide variety of undesired symptoms. This is highlighted by the many disease states in which NF-kappa-B has been implicated as the dysfunctional element. The diseases include AIDS, many cancers, such as breast cancer, thyroid cancer, leukemia, melanoma, colon cancer, and bladder cancer, and many other diseases, including asthma, multiple sclerosis, heart disease, and Alzheimer’s disease. Understanding how NF-kappa-B works in healthy cells is vital for developing new treatments for the many diseases that involve improper control of NF-kappa-B function. In healthy cells, an inhibitor known as I-kappa-B-alpha tightly regulates NF-kappa-B activity so that the hundreds of proteins it manages are only made when the cell requires their specific tasks. This stringent regulation prevents the production of too many proteins or proteins performing tasks that are undesirable for the cell at a given time, which is frequently the case for diseased cells. In my proposed research, I will investigate the interaction between NF-kappa-B and I-kappa-B-alpha, using not only individual, purified proteins, but also in living cells. I-kappa-B-alpha is a protein that, unlike traditional proteins, has a very flexible structure. I will characterize its flexibility, how this property influences its interactions with NF-kappa-B, and ultimately how I-kappa-B-alpha’s flexibility affects NF-kappa-B activity and the biological response of the cell. I will also investigate a short region in NF-kappa-B that appears to enable I-kappa-B-alpha to peel NF-kappa-B from the DNA. Again, I will study this interaction using individual, purified proteins and also in living cells. Understanding the detailed mechanism by which I-kappa-B-alpha regulates NF-kappa-B activity in healthy cells will help with the development of new therapies to restore proper NF-kappa-B activity in the many diseases characterized by aberrant NF-kappa-B regulation.