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 biology. The mammalian target of rapamycin (mTOR) pathway is a cellular pathway that controls cell proliferation and this pathway is commonly dysregulated in many cancers. Therefore, understanding the role of mTOR pathway in cell proliferation is important. 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 are consisted 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 activiy 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. Based on this, we hypothesize that the same phenomena happen when cancer cells are activated to proliferate by mTOR. We searched cancer databases and found numerous candidate mRNAs for truncation in cancer, which was not recognized previously. Our goals in this proposal are to find them and understand their function in cancer cell proliferation using a series of experiments employing high profiling technologies including next generation sequencing and multi-dimensional LC-MS/MS. More importantly, we will narrow down the list of cancer-specific truncated mRNAs and finalize the critical truncated mRNAs by validating their existence in cancer patient database. The identified cancer-specific truncated mRNAs will be new targets in cancer research and provide novel platforms for the development of multiple biomarkers at both protein and RNA levels.

Public Health Relevance

The mTOR pathway is crucial in cell proliferation/growth and is central in the development of numerous human diseases including cancer. Therefore, investigating the role of this pathway in cellular mechanisms at a molecular level is fundamental to understand cancer development. The proposed study will investigate the function of brand new molecules produced by mTOR activation during mRNA processing and profile them in cancer cells and apply the list of these molecules to cancer patient datasets.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM113952-01A1
Application #
9027407
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Gaillard, Shawn R
Project Start
2015-09-17
Project End
2020-08-31
Budget Start
2015-09-17
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$291,467
Indirect Cost
$93,967
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Chang, Jae Woong; Yeh, Hsin Sung; Yong, Jeongsik (2017) Alternative Polyadenylation in Human Diseases. Endocrinol Metab (Seoul) 32:413-421
Yeh, Hsin-Sung; Yong, Jeongsik (2016) Alternative Polyadenylation of mRNAs: 3'-Untranslated Region Matters in Gene Expression. Mol Cells 39:281-5