Characterization of mTOR-Responsive Truncated mRNAs in Cell Proliferation
Abstract
Most, if not all, cancer cells proliferate much faster than normal cells. Thus, studying how cancer cells proliferate faster than normal cells is a key in understanding cancer pathogenesis. The mammalian target of rapamycin (mTOR) pathway is a cellular pathway that controls cell proliferation, and this pathway is commonly deregulated in many cancers. In addition, tuberous sclerosis complex (TSC) negatively regulates the mTOR pathway. Therefore, studying the role of mTOR pathway in cell proliferation is important to understand the pathogenic mechanism by TSC. When cells are activated to proliferate, the first thing they do is producing a lot of proteins. To make more proteins in cells, they need to make more messenger RNAs (mRNAs) from DNA. The whole procedure is called gene expression, and mRNA is a key molecule in this procedure. Thus, the questions of how mRNAs are made and how they are regulated in cancer mechanisms are important questions to ask to understand cancer at a molecular level. Generally, mRNA undergoes very complicated process to make it competent for protein synthesis in cells. Recently, we discovered a pervasive production of truncated mRNAs when mTOR is activated in cells. The truncated mRNAs are produced by dysregulation of one of the steps during mRNA synthesis in cells. The cellular consequence of this phenomenon is the production of truncated proteins. Usually, fundamental elements of many proteins consist of catalytically active domains and regulatory domains. The active domain represents the function of a protein, and the regulatory domain is a platform for fine-tuning of the protein activity regulated by other cellular proteins. Interestingly, many truncated proteins produced by mTOR activation were lacking the regulatory or catalytic domain. This suggests that mTOR activation produces many deregulated "super isoform" proteins by truncation, and this could be a driver to fast cell proliferation and cancer initiation at a molecular level. Our goals in this proposal are to find them and understand their function in cell proliferation using a series of experiments employing high profiling technologies including next-generation sequencing and multi-dimensional targeted LC-MS/MS. More importantly, we will narrow down the list of truncated mRNAs that are crucial for cell proliferation. The identified truncated mRNAs will be new targets in cancer-related research and provide brand new molecules that function as a driver in TSC-related pathogenesis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610135
Entities
People
- Jeongsik Yong
Organizations
- United States Army
- University of Minnesota