Let Ting Glucose Take Hold

RESEARCH HIGHLIGHTS

METABOLISM mTOR) suppressed glucose uptake. Next, they investigated the role of let‑7 in the insulin–PI3K–mTOR pathway. By transfecting a mature Letting glucose take hold let‑7f duplex (which cannot be suppressed by LIN28A) they found that AKT phosphorylation was partially reduced and that S6 and 4EBP1 phosphorylation was inhibited in insulin-stimulated myoblasts, indicating that let‑7f suppression at least partially mediates the induc- tion of the PI3K–mTOR pathway following LIN28A overexpression. Analyses of the quadricep muscles of Neil Smith transgenic mice showed that LIN28B and LIN28A induce the upregula- Cancer cells often reprogram by these mice indicate that LIN28A tion of insulin receptor (INSR) and metabolic pathways in favour of and LIN28B function in the same insulin-like growth factor 1 receptor glucose metabolism, glycolysis and pathway in order to regulate RNAs (IGF1R). Furthermore, using a anapleurotic pathways that promote that are associated with glucose bioinformatic screen of mRNAs growth and survival. Interestingly, metabolism. To investigate whether that exhibit increased stability when many genes that are associated let‑7 is a target in this pathway, the LIN28A was overexpressed in C2C12 with type 2 diabetes — which is a authors produced transgenic mice myoblasts, the authors found that 16 disorder of glucose metabolism — overexpressing a let‑7g mutant that is genes in the insulin–PI3K–mTOR are proto-oncogenes and regulators resistant to LIN28 regulation. These pathway have let‑7‑binding sites, of proliferation. Making further mice were glucose intolerant but several of which were confirmed connections between type 2 diabetes had normal insulin sensitivity, and in vitro and in vivo. Therefore, and cancer, George Daley and col- crossing with mice overexpressing LIN28A and LIN28B derepress leagues identify a role for LIN28 LIN28B prevented the increase in let‑7‑mediated suppression of the and the let‑7 microRNA family in glucose tolerance that is observed insulin–PI3K–mTOR pathway to glucose metabolism. in LIN28B‑transgenic mice. This increase glucose metabolism but also The let‑7 microRNAs inhibit the indicates that LIN28B‑mediated have let‑7‑independent targets. translation of various target genes suppression of let‑7g regulates glucose The authors found that genes regu- (including oncogenes and cell cycle metabolism in vivo, but that LIN28B lated by let‑7 and LIN28 are associated regulators), and so they are often sup- also targets other RNAs. with type 2 diabetes; this pathway may pressed in cancer cells. One way this To further investigate the also regulate glucose metabolism in occurs is through the RNA-binding mechanism of glucose metabolism cancer cells. Interestingly, LIN28A proteins LIN28A and LIN28B, which regulation by LIN28, the authors and LIN28B are expressed in embryo- LIN28A and bind and suppress the processing overexpressed LIN28A in C2C12 genesis (when energy demands also LIN28B derepress of let‑7 microRNAs; LIN28A and myoblasts that were cultured in favour glucose metabolism) and are let‑7‑mediated LIN28B can therefore be upregulated the presence of insulin. These cells then re-expressed in cancer, which suppression of in cancer. exhibited suppression of let‑7 expres- indicates that the further analysis of Daley and colleagues showed sion and increased glucose uptake, as embryonic metabolism could teach us the insulin–PI3K– that transgenic mice overexpressing well as phosphorylation of AKT, S6 more about metabolic reprogramming mTOR pathway to LIN28A or LIN28B exhibit enhanced ribosomal protein and 4EBP1, which in cancer cells. increase glucose glucose metabolism, having a are members of the PI3K–mTOR Gemma K. Alderton metabolism higher glucose tolerance and insulin pathway. Indeed, treatment with the ORIGINAL RESEARCH PAPER Zhu, H. et al. The sensitivity than wild-type mice. PI3K–mTOR inhibitor LY294002 Lin28/let‑7 axis regulates glucose metbolism. Cell The common phenotypes shared or rapamycin (which inhibits 147, 481–494 (2011)