Sandbox Reserved 718: Difference between revisions
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Lin28 is a conserved cytoplasmic protein with an unusual pairing of RNA binding motifs: a cold shock domain and a pair of retroviral type CCHC zinc fingers. It plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, Lin28 is known to repress maturation of let-7 microRNAs and enhance translation of certain mRNAs. Mammals have two homologs, Lin28a and Lin28b. These two homologs are found from worms to humans.<ref>Jun Cho, Hyeshik Chang, S. Chul Kwon, Baekgyu Kim, Yoosik Kim, Junho Choe, Minju Ha, Yoon Ki Kim, and V. Narry Kim: ''Lin28A Is a Suppressor of ER-Associated Translation in Embryonic Stem Cells.'' In: Cell 151, S.765–777, November 9, 2012</ref><ref>Erica Balzer and Eric G. Moss: ''Localization of the Developmental Timing Regulator Lin28 to mRNP Complexes, P-bodies and Stress Granules.'' In: RNA Biology 4:1, S.16-25, January/February/March 2007.</ref> Lin28a is highly expressed in embryonic stem cells (ESCs) and was shown as one of the four factors that convert fibroblasts into induced pluripotent stem cells.<ref>Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. In: ''Induced pluripotent stem cell lines derived from human somatic cells.'' Science 318, 1917–1920, 2007.</ref> | Lin28 is a conserved cytoplasmic protein with an unusual pairing of RNA binding motifs: a cold shock domain and a pair of retroviral type CCHC zinc fingers. It plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, Lin28 is known to repress maturation of let-7 microRNAs and enhance translation of certain mRNAs. Mammals have two homologs, Lin28a and Lin28b. These two homologs are found from worms to humans.<ref>Jun Cho, Hyeshik Chang, S. Chul Kwon, Baekgyu Kim, Yoosik Kim, Junho Choe, Minju Ha, Yoon Ki Kim, and V. Narry Kim: ''Lin28A Is a Suppressor of ER-Associated Translation in Embryonic Stem Cells.'' In: Cell 151, S.765–777, November 9, 2012</ref><ref>Erica Balzer and Eric G. Moss: ''Localization of the Developmental Timing Regulator Lin28 to mRNP Complexes, P-bodies and Stress Granules.'' In: RNA Biology 4:1, S.16-25, January/February/March 2007.</ref> Lin28a is highly expressed in embryonic stem cells (ESCs) and was shown as one of the four factors that convert fibroblasts into induced pluripotent stem cells.<ref>Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. In: ''Induced pluripotent stem cell lines derived from human somatic cells.'' Science 318, 1917–1920, 2007.</ref> | ||
At the molecular level, Lin28 acts as a suppressor of let-7 microRNA biogenesis.<ref>Heo, I., Joo, C., | At the molecular level, Lin28 acts as a suppressor of let-7 microRNA biogenesis.<ref>Heo, I., Joo, C., Cho, J., Ha, M., Han, J., and Kim, V.N. In: ''Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.'' Mol. Cell 32, S.276–284, 2008.</ref><ref>Newman, M.A., Thomson, J.M., and Hammond, S.M. In: ''Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing.'' RNA 14, 1539–1549, 2008.</ref><ref>Rybak, A., Fuchs, H., Smirnova, L., Brandt, C., Pohl, E.E., Nitsch, R., and Wulczyn, F.G. In: ''A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment.'' Nat. Cell Biol. 10, S.987–993, 2008.</ref><ref>Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. In: ''Selective blockade of microRNA processing by Lin28.'' Science 320, 97–100, 2008.</ref> In the nucleus, Lin28 binds to the primary transcript of let-7 (pri-let-7) and prevents its processing by RNase III DROSHA.<ref>Newman, M.A., Thomson, J.M., and Hammond, S.M. In: ''Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing.'' RNA 14, 1539–1549, 2008.</ref><ref>Viswanathan, S.R., Daley, G.Q., and Gregory, R.I. In: ''Selective blockade of microRNA processing by Lin28.'' Science 320, 97–100, 2008.</ref> In the cytoplasm, it interacts with the precursor form of let-7 (pre-let-7) and interferes with pre-let-7 processing. <ref>Heo, I., Joo, C., Cho, J., Ha, M., Han, J., and Kim, V.N. In: ''Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.'' Mol. Cell 32, S.276–284, 2008.</ref><ref>Rybak, A., Fuchs, H., Smirnova, L., Brandt, C., Pohl, E.E., Nitsch, R., and Wulczyn, F.G. In: ''A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment.'' Nat. Cell Biol. 10, S.987–993, 2008.</ref> Lin28 recruits TUTase 4 (ZCCHC11) to induce oligo-uridylation of pre-let-7, which effectively blocks DICER processing and facilitates degradation of the RNA. <ref>Hagan, J.P., Piskounova, E., and Gregory, R.I. In: ''Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells.'' Nat. Struct. Mol. Biol. 16, S.1021–1025, 2009.</ref><ref>Heo, I., Joo, C., Cho, J., Ha, M., Han, J., and Kim, V.N. In: ''Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA.'' Mol. Cell 32, S.276–284, 2008.</ref><ref>Heo, I., Joo, C., Kim, Y.K., Ha, M., Yoon, M.J., Cho, J., Yeom, K.H., Han, J., and Kim, V.N. In: ''TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation.'' Cell 138, S.696–708, 2009.</ref> Lin28A is found mostly in the cytoplasmic compartment and acts in concert with TUTase 4.<ref>Piskounova, E., Polytarchou, C., Thornton, J.E., LaPierre, R.J., Pothoulakis, C., Hagan, J.P., Iliopoulos, D., and Gregory, R.I. In: ''Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms.'' Cell 147, S.1066–1079, 2011.</ref> | ||
Let-7 is a key target of Lin28 but there are four additional functions: | Let-7 is a key target of Lin28 but there are four additional functions: | ||