Mechanism of Ribosomes Biogenesis in TSC
Abstract
Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations in either TSC1 or TSC2 gene. TSC is characterized by widespread benign tumor formation in a variety of organs. Mutations in either TSC1 or TSC2 tumor suppressor gene are responsible for TSC. The gene products of TSC1 and TSC2, also known as hamartin and tuberin, respectively, form a physical and functional complex. We have found that TSC complex functions as a tumor suppressor to inhibit mammalian target of rapamycin complex1 (mTORC1) signaling. mTORC1 is an important protein kinase complex that stimulates cell growth and proliferation. Hyperactivation of mTORC1 contributes to the development of TSC diseases as well as many cancers. mTORC1 dominantly stimulates translation of an essential class of mRNAs such as ribosome protein subunits, thereby increasing cellular ribosomes and enhancing the capacity of protein synthesis in cells. The number of ribosomes in the cell determines how fast they can make proteins. Increased ribosome biogenesis is thus important in rapidly dividing cells such as cancer cells or for cell growth in post-mitotic cells. However, the mechanisms by which mTORC1 stimulates these mRNA translation remain elusive. Our main goal is to understand how mTORC1 preferentially stimulates ribosome biogenesis through a novel mTORC1 substrate LARP1 and its functional importance in cell growth and proliferation in TSC diseases. In this proposal, we will investigate the molecular mechanisms by which mTORC1 regulates LARP1 through its phosphorylation and how LARP1 contributes to aberrant proliferation or growth in cell lacking the functional TSC complex in both in vitro and in vivo. We believe that completion of this project will provide important and novel molecular insights into how LARP1 executes critical functions in ribosome biogenesis and tumorigenesis in response to aberrant mTORC1 activation. In addition, these studies will establish a new direction for future mechanistic studies in the regulation of mTORC1-mediated protein synthesis and provide a basis for new therapeutic approaches targeting specific translation downstream of mTORC1 for the TSC-related diseases and cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510222
Entities
People
- Ken Inoki
Organizations
- United States Army
- University of Michigan