Mechanism of Ribosomes Biogenesis in TSC
[Technical Report, Final Report]
The Regents of the University of Michigan
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Tuberous Sclerosis Complex TSC is a genetic disorder caused by mutations in either TSC1 or TSC2 gene. TSC is characterizedby widespread benign tumor formation in a variety of organs. Mutations in either TSC1 or TSC2 tumor suppressor gene areresponsible for TSC. The gene products of TSC1 and TSC2, also known as hamartin and tuberin, respectively, form a physical andfunctional complex. We have found that TSC complex functions as a tumor suppressor to inhibit mammalian target of rapamycincomplex1 mTORC1 signaling. mTORC1 is an important protein kinase complex that stimulates cell growth and proliferation.Hyper-activation of mTORC1 contributes to the development of TSC diseases as well as many cancers. mTORC1 dominantlystimulates translation of an essential class of mRNAs such as ribosome protein subunits thereby increasing cellular ribosomes andenhancing the capacity of protein synthesis in cells. The number of ribosomes in the cell determines how fast they can makeproteins. Increased ribosome biogenesis is thus important in rapidly dividing cells such as cancer cells or for cell growth in postmitoticcells. However, the mechanisms by which mTORC1 stimulates these mRNA translations remain elusive. Our main goal isto understand how mTORC1 preferentially stimulates ribosome biogenesis through a novel mTORC1 substrate LARP1 and itsfunctional importance in cell growth and proliferation in TSC diseases.
- Medicine and Medical Research