| First Author | Ogórek B | Year | 2018 |
| Journal | Hum Mol Genet | Volume | 27 |
| Issue | 9 | Pages | 1654-1663 |
| PubMed ID | 29509898 | Mgi Jnum | J:261762 |
| Mgi Id | MGI:6155318 | Doi | 10.1093/hmg/ddy073 |
| Citation | Ogorek B, et al. (2018) TSC2 regulates microRNA biogenesis via mTORC1 and GSK3beta. Hum Mol Genet 27(9):1654-1663 |
| abstractText | Tuberous sclerosis complex (TSC) is an autosomal dominant disease caused by germline inactivating mutations of TSC1 or TSC2. In TSC-associated tumors of the brain, heart, skin, kidney and lung, inactivation of both alleles of TSC1 or TSC2 leads to hyperactivation of the mTORC1 pathway. The TSC/mTORC1 pathway is a key regulator of cellular processes related to growth, proliferation and autophagy. We and others have previously found that mTORC1 regulates microRNA biogenesis, but the mechanisms are not fully understood. Microprocessor, a multi-protein complex including the nuclease Drosha, processes the primary miR transcript. Using a dual-luciferase reporter, we found that inhibition of mTORC1 or downregulation of Raptor decreased Microprocessor activity, while loss of TSC2 led to a striking increase ( approximately 5-fold) in Microprocessor activity. To determine the global impact of TSC2 on microRNAs we quantitatively analyzed 752 microRNAs in Tsc2-expressing and Tsc2-deficient cells. Out of 259 microRNAs expressed in both cell lines, 137 were significantly upregulated and 24 were significantly downregulated in Tsc2-deficient cells, consistent with the increased Microprocessor activity. Microprocessor activity is known to be regulated in part by GSK3beta. We found that total GSK3beta levels were higher in Tsc2-deficient cells, and the increase in Microprocessor activity associated with Tsc2 loss was reversed by three different GSK3beta inhibitors. Furthermore, mTOR inhibition increased the levels of phospho-GSK3beta (S9), which negatively affects Microprocessor activity. Taken together these data reveal that TSC2 regulates microRNA biogenesis and Microprocessor activity via GSK3beta. |
