Mechanism of Ribosomes Biogenesis in TSC
Technical Report,01 Jul 2017,30 Jun 2018
The Regents of the University of Michigan Ann Arbor United States
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This project is aimed to investigate the molecular mechanisms underlying mTORC1-LARP1-mediated ribosome biogenesis and cellgrowth, and the roles of LARP1 in the development of TSC tumors. During the last funding period, we further investigated the molecularmechanisms by which LARP1 scaffolds mTORC1 to LARP1-interacting mRNAs. Upon LARP1 phosphorylation by Akt and mTORC1,LARP1 dissociates from the 5UTR of RP mRNAs and strongly interacts with the 3UTR of these mRNAs with mTORC1 related toAim1. We have also initiated the characterizations of podocyte-specific LARP1 knockout mice and the generation of LARP1TSC1 doubleknockout mice related to Aim2. It has been well documented that both hyper- and lack of mTORC1 activation in podocytes cause theirinjury and glomerular dysfunctions. Our preliminary data suggest that LARP1 is required for normal podocyte and glomerular functions asseem in podocyte-specific Raptor knockout mice. Although the pathological phenotypes in the podo-LARP1 KO mice is weaker than thosein podo-Raptor KO mice, the results are consistent with our proposed model that LARP1 is a downstream effector of mTORC1 to stimulateor maintain podocyte growth and function. We will continue to study whether LARP1 plays an important role in aberrant activation ofmTORC1-induced podocyte growth and dysfunctions.
- Anatomy and Physiology