Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Mollie K. Meffert
 + 5482 word(s) 5482 2020-12-31 10:16:36 |
2 update layout and reference
Rita Xu
 -2640 word(s) 2842 2021-01-05 07:48:28 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Meffert, M.K. Pluripotency Factor Lin28. Encyclopedia. Available online: https://encyclopedia.pub/entry/5957 (accessed on 05 July 2024).
Meffert MK. Pluripotency Factor Lin28. Encyclopedia. Available at: https://encyclopedia.pub/entry/5957. Accessed July 05, 2024.
Meffert, Mollie K.. "Pluripotency Factor Lin28" Encyclopedia, https://encyclopedia.pub/entry/5957 (accessed July 05, 2024).
Meffert, M.K. (2020, December 31). Pluripotency Factor Lin28. In Encyclopedia. https://encyclopedia.pub/entry/5957
Meffert, Mollie K.. "Pluripotency Factor Lin28." Encyclopedia. Web. 31 December, 2020.
Pluripotency Factor Lin28
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cells9122710

Lin28 is an RNA-binding protein that can function as a pluripotency factor and is enriched in stem and progenitor cells and embryonic tissues.  Lin28 can regulate protein synthesis by binding mRNAs to regulate their translation, and by governing microRNA production through binding let-7 family precursor microRNAs to block their processing to mature functional microRNAs.   Lin28 was first discovered in C.elegans and is highly evolutionarily-conserved across the animal kingdom.  In most vertebrates, including mammals, there are two Lin28 paralogs, termed Lin28A and Lin28B.   An appreciation for the complex interactions between the NF-κB transcription factor and the Lin28 RNA binding protein/let-7 microRNA pathways has grown substantially over the past decade.  In many biological settings, accumulated evidence has revealed that Lin28 can be upregulated from low basal levels in adult tissues following injury or in plastic responses. Both the NF-κB and Lin28/let-7 pathways are master regulators impacting cell survival, growth and proliferation, and an understanding of how interfaces between these pathways participate in governing pluripotency, progenitor differentiation, and neuroplastic responses remains an emerging area of research.

transcription factor,NF-κB Lin28

1. Introduction

While using mobility shift assays to study the gene rearrangement events that lead to antibody diversity, Ranjan Sen and David Baltimore discovered a nuclear factor that bound to the κ light-chain enhancer in extracts from B cell tumors and so called it nuclear factor kappa B (NF-κB) [1]. A series of subsequent investigations showed that NF-κB activity could be induced without new protein synthesis [2], that it exists in an inhibited latent form in the cytoplasm [3], and that this retention is mediated by inhibitor of NF-κB (IκB) proteins [4]. NF-κB is now known to be expressed in essentially all cell types with a vast array of activators and functional outputs. While NF-κB has been most widely studied in the immune system, a growing body of literature has examined its role in embryonic stem cells and the premature and mature nervous system [5][6][7].

The details of NF-κB activation and function, reviewed extensively elsewhere [8][9][10], are briefly summarized here. NF-κB exists as a homo- or heterodimer composed of five potential subunits: RelA (p65), RelB, c-Rel, p50, and p52. RelA, RelB, and c-Rel are synthesized as mature proteins and contain transcription activation domains (TADs) and the p50 and p52 subunits are the N-terminal cleavage products of the precursor proteins p105 and p100, respectively. While p50 is generated constitutively, the generation of p52 is signal-induced. Under basal conditions, the latent NF-κB dimer remains in the cytoplasm bound by inhibitory IκB proteins. Members of the IκB group include IκBα, IκBβ, IκBε, the nuclear IκBs (BCL-3, IκBζ, IκBNS), and the C-terminal portions of p105 (IκBγ) and p100 (IκBδ). Each IκB contains tandem ankyrin repeats that bind NF-κB and occlude the nuclear localization sequence (NLS) in NF-κB dimers. The initial step in NF-κB activation involves stimulus-induced modification and removal of the IκB inhibitor. IκB is phosphorylated at two critical serine residues by the IκB kinase complex (IKK), which leads to subsequent polyubiquitination and degradation of IκB by the proteasome. Degradation of IκB exposes the NLS on NF-κB and allows for the dimer to stably translocate to the nucleus where it can bind cognate κB sites in the promoters and enhancers of target genes and regulate their transcription. IKK-mediated activation of NF-κB occurs through either the canonical or alternative pathway. In the canonical pathway, the IKKα/IKKβ complex phosphorylates IκBα at Ser32 and Ser36 and IκBβ at Ser19 and Ser23. The alternative ‘noncanonical’ pathway proceeds through IKKα-mediated phosphorylation of the NF-κB precursor protein, p100, at Ser176 and Ser180 leading to proteasomal removal of an IκB-resembling ankyrin repeat in p100 and the generation of p52 and its translocation to the nucleus with its main heterodimer partner, RelB.

Critical features of the NF-κB pathway include the poised dimers latent in the cytoplasm which permit rapid response to stimuli, the canonical feedback mechanism in which NF-κB-mediated IκB induction allows regulated resolution of activation, and the numerous and diverse array of NF-κB activators and NF-κB-regulated genes (online resource: http://www.bu.edu/nf-kb/gene-resources/target-genes/). Collectively, these features contribute to the prominent function of NF-κB in a plethora of biological systems, including the mature and developing nervous system.

2. Lin28 Paralogs

Lin28 is an RNA-binding protein that was originally discovered in Caenorhabditis elegans as a regulator of developmental timing and has since been shown to exhibit functional and sequence conservation in Xenopus, zebrafish, Drosophila, mouse, and humans [11][12][13][14][15]. Unlike C. elegans with a single LIN28 gene, mammals have two Lin28 paralogs, possibly having arisen from a gene duplication event, which encode the Lin28a (discovered first and originally referred to as Lin-28) and Lin28b proteins [16]. Lin28a and Lin28b share extensive amino acid sequence homology and each contain multiple RNA-binding domains: a cold shock domain (CSD) and two CCHC zinc knuckle domains. Lin28a and Lin28b can each regulate translation via direct binding to mRNAs and by regulating the biogenesis of precursor microRNAs (miRNAs) containing a Lin28 recognition motif, principally the Lethal-7 (let-7) miRNA family [17]. Let-7, one of the first discovered miRNAs, was also initially discovered in C. elegans as a regulator of developmental timing [18], but was subsequently found to be widely distributed in bilateral animals [19].

Let-7, like most miRNAs, begins as an RNA polymerase II-dependent transcript called the primary miRNA transcript (pri-miRNA). The pri-miRNA is processed in the nucleus by the RNase III enzyme Drosha and the double-stranded RNA binding protein DGCR8 (together called the microprocessor complex) to form the 60-70-nt-long pre-miRNA. The pre-miRNA is exported from the nucleus to the cytoplasm by exportin 5 and the Ran-GTP cycle where it is processed by another RNase III enzyme, Dicer, which removes the loop of the step-loop structure to produce a 22-bp RNA duplex. One of the strands of the RNA duplex is then loaded onto an Argonaute protein (Ago) and directs Ago to the 3′ untranslated region (UTR) of target mRNAs where it prevents protein synthesis by translation inhibition and/or transcript destabilization [20]. Regulation along each step of this biogenesis pathway is used to manipulate mature levels of the potent let-7 family in governing growth and pluripotency.

Sequence conservation suggested that let-7 miRNAs might act broadly to regulate gene expression in diverse animals, and this expectation has been borne out in conserved let-7 miRNA binding sites and gene regulatory networks across animal phylogeny [19]. Following observations that mature let-7 miRNAs are differentially expressed at different developmental stages [19][21][22], and that primary let-7 transcripts and pre-let-7 miRNAs are present in both undifferentiated and differentiated human embryonic stem cells (suggesting inhibition of biogenesis at a post-Drosha step) [21][23], several labs showed that Lin28 binds directly to let-7 and inhibits its maturation [24][25][26][27][28].

Unlike C. elegans, mammals and most vertebrates contain multiple members of the let-7 miRNA family. In humans, the 12 let-7 family members (let-7a-1, -2, -3; let-7b; let-7c; let-7d; let-7e; let-7f-1, -2; let-7g; let-7i; miR-98) (miRBase.org) are clustered at eight different chromosomal loci [17]. Collectively, these miRNAs are classified as a family because of a shared consensus ‘seed’ sequence that functions as a critical component of base-pairing with target mRNAs. Let-7 miRNAs gradually increase during development and, collectively, are amongst the most highly expressed miRNAs in the adult brain [29]. Let-7 miRNAs have been classified as tumor suppressors due to their conserved regulation of many oncogenes, pluripotency factors, and growth-related mRNAs, and because of their concerted downregulation in cancer [30][30]. Elevated let-7 family miRNA levels are required for differentiation, developmental transitions, and to avoid oncogenesis, but the let-7 family of miRNAs must be suppressed to allow for translation of mRNAs necessary for pluripotency, self-renewal, regeneration, and other plastic states. To achieve this regulation of mature let-7 levels, the biogenesis pathway of the let-7 family of miRNAs is tightly controlled [20].

Both Lin28 paralogs have been shown to participate in regulating mature let-7 family miRNA abundance by inhibiting let-7 miRNA processing through recognition of a bulged GGAG-like motif present in the terminal loop of most [25][31][32], but not all [32], let-7 precursor RNAs. Recognition of this motif by the Lin28 zinc knuckle domain is accompanied by binding of the Lin28 CSD to a ‘NGAU’ motif also present in the let-7 precursor RNAs [32]. Though both Lin28a and Lin28b have been seen in the nucleus as well as the cytoplasm, Lin28b is believed to localize predominately in the nucleolus while Lin28a mainly localizes to the cytoplasm [17]. Lin28b has been best characterized to inhibit the biogenesis of let-7 miRNAs by preventing nuclear Drosha-mediated processing of the pri-let-7 transcript. Lin28a functions mainly in the cytoplasm to inhibit processing of the pre-let-7 miRNA by recruiting TUT4 (Zcchc11) which catalyzes the addition of a polyuridine tail to pre-let-7 to prevent Dicer processing and promote precursor degradation by recruiting an exonuclease [17][31][33]. Lin28 exists in a negative feedback loop with let-7 as there are conserved let-7 binding sites within the 3′ UTR of both the Lin28A and Lin28B transcripts [26]. In these reinforcing loops, a reduction in let-7 levels, for example, would be expected to further elevate translation of Lin28 transcripts. The tissue and cellular expression profiles for Lin28a and Lin28b in mammals remain somewhat enigmatic, with low or undetectable levels reported in adults for most regions, with the exception of the testes, in atlas sources for mouse and human (e.g., www.proteinatlas.org).  This stands in possible discrepancy to accumulating reports of Lin28a and Lin28b presence and function in adult organisms or differentiated cells and tissues [34][35][36][37][38][39][40][41][42][43][44][45][46][47], despite clear downregulation in levels from early development. Ineffective detection is not unfamiliar amongst low abundance proteins and transcripts which may not be readily quantified or documented in databases and could be contributed to by a failure to capture signal-dependent upregulation.

As previously indicated, Lin28 can also regulate translation through direct binding to mRNAs. The reported effects of Lin28 on the translation of bound mRNAs are mixed and may depend upon the mRNA or cellular setting, as illustrated in the following examples. In mouse embryonic stem cells, Lin28a localized to the periendoplasmic reticulum area and was reported to inhibit the translation of mRNAs destined for the ER by interaction with AAGNNG, AAGNG, and less frequently UGUG motifs, leading to reduced synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins [48]. Alternatively, Lin28 binding has also been shown to enhance the translation of targeted mRNAs. In human embryonic stem cells, Lin28 was shown to preferentially associate with a subset of cellular mRNAs containing Lin28-responsive elements and Lin28 downregulation shifted these mRNAs from polysomal to nonpolysomal fractions and decreased levels of proteins encoded by the targeted mRNAs [49]. Interestingly, the authors also observed that deletion of a 35-amino-acid section in the carboxyl-terminus of Lin28 prevented its interaction with RNA helicase A and was proposed to function as a dominant-negative inhibitor to decreases target mRNA translation based on polysome shift assays [49]. Also in human embryonic stem cells, a crosslinking and immunoprecipitation approach with high-throughput sequencing (CLIP-seq) revealed that Lin28 binds roughly a quarter of all human transcripts. This study defined a GGAGA sequence Lin28-binding motif within loop structures in mRNAs, similar to the interaction site of Lin28 within let-7 precursors [50]. Gene Ontology analysis revealed that genes involved in “RNA splicing” were significantly enriched among Lin28 targets and that while Lin28 appeared to have no effect on steady state mRNA levels, its overexpression increased levels of several proteins involved in splicing regulation (e.g., FUS/TLS, hnRNP F, TDP-43 and TIA-1) and resulted in broad changes to alternative splicing [50].

3. Lin28 and NF-κB in Pluripotency and Progenitors

Lin28a and Lin28b are known for being highly expressed in early development and in undifferentiated cells, as well as during oncogenic transformation [51]. A profound role for Lin28a in pluripotency was recognized with the demonstration that Lin28a expression could be used to reprogram human somatic cells to pluripotent stem cells when combined with three other factors: Oct4, Sox2, and Nanog [52]. More recently, it was shown that Lin28b, like Lin28a, can cooperate with Oct4, Sox2, and Nanog in reprogramming fibroblasts to pluripotency and that reactivation of both the endogenous gene loci of LIN28A and LIN28B is required to reprogram with maximal efficiency [53]. Lin28a and Lin28b expression levels also correlate well with successful conversion to pluripotency in other reprogramming settings and can function to overcome the hurdle of maturation in the successful production of both mouse and human induced pluripotent stem cells (iPSCs) [53][54][55][56]. The precise functions of discrete reprogramming factors remains an active area of investigation, but one critical role for the Lin28 RNA binding proteins in mouse and human fibroblasts appears to be in regulating metabolism through mitochondrial oxidative phosphorylation to promote pluripotency [53]. Lin28a protein has also been shown to be stabilized through direct and indirect phosphorylation downstream of activation of the mitogen-activated protein kinase (MAPK) pathway, and this can serve to couple cellular signaling to the post-transcriptional control of pluripotency through heightened Lin28a levels [41][57].  The MAPK pathway is, additionally, both regulated by and an upstream activator of IKK-mediated NF-κB signaling [58][59].

In the nervous system, both Lin28 paralogs are enriched in neuronal precursor cells (NPC) and have been shown to play overlapping functions in enhancing NPC proliferation in mice and humans, and regulating neurogenic potential during early brain development [60][61]. Lin28 also controls progenitor and neuronal cell fate during postnatal neurogenesis [62]. Additionally, it has been shown that altering expression levels of Lin28b in cultured sympathetic neuroblasts can alter proliferation and forced expression of Lin28b in embryonic mouse sympathoadrenal neuroblasts can lead to postnatal neuroblastoma formation; however, some of these effects may be let-7 independent [63]. Several reports also show that Lin28 can mediate axon regeneration in both the murine PNS and CNS [36][64].

Like Lin28, NF-κB has been shown to play crucial roles in neurogenesis and neural stem cells [65]; specifically, NF-κB appears to be more involved in promoting proliferation of progenitors rather than their survival [66][67]. In this context, NF-κB activation was found to elevate expression of genes involved in cell cycle progression and in the increased proliferation of rodent neural stem cells [68]. While NF-κB expression does not necessarily equate to activation, NF-κB was found early on to be highly expressed in murine radial glia and neuronal precursors in regions of neurogenesis, including the subventricular zone, during development and in adulthood [69]. A defect in neurogenesis, resulting from deficiency of the p50 subunit of NF-κB, was linked to a short-term memory defect in mice [67]. NF-κB activation has been reported to promote the retention of cells in the progenitor pool and to inhibit further differentiation to neurons during development in the mouse nervous system [70]. More recently, studies utilizing human embryonic stem cells investigated a discrete role for NF-κB in promoting neuronal differentiation specifically in committed NPCs [71]. In this in vitro context, the effects of NF-κB in promoting neuronal differentiation of NPCs were linked to an NF-κB-dependent metabolic gene program that enhanced oxidative phosphorylation [71]. Reprogramming of metabolism from an emphasis on glycolysis in NPCs towards mitochondrial oxidative phosphorylation in mature neurons has been shown to accompany neuronal differentiation [72]. Interestingly, Lin28a was also shown to increase glycolysis and oxidative phosphorylation by enhancing translation of several metabolic enzymes in the context of tissue repair in both mouse and human settings [73]. Further, both Lin28a and Lin28b have well-established regulatory roles in glucose metabolism and can enhance glucose uptake and insulin sensitivity through gene regulation downstream of lowered let-7 miRNAs [34][40].

There remain some apparent discrepancies, particularly concerning the role of NF-κB in pluripotency associated with cellular reprogramming. Inflammatory or aging-associated chronic NF-κB activation is reported in mouse studies to impair reprogramming towards iPSCs [74][75]. In contrast, NF-κB activation has been shown to promote maintenance of the undifferentiated state in healthy human iPSCs and in several of the above-mentioned studies in mouse neural stem cells [76]. One potential explanation could lie in different cell-intrinsic versus systemic outcomes of NF-κB activation; a systemic impact of NF-κB activation on inhibiting gonadotrophin-releasing hormone (GnRH) release is postulated to mediate the subsequent impairment in neurogenesis [74]. The regulation by NF-κB of gene programs associated with proliferation and pluripotency has also been linked in mouse and human studies to a variety of cancers, including those of the brain [77][78][79]. Constitutively activated NF-κB leads to increased proliferation of neural stem cells in the absence of growth factors and is a common feature of glioblastoma [79][80]. Other components of the NF-κB signaling pathway have been implicated in glioblastoma such as deletions of the IκBα gene in 24.2% of glioblastoma patients [81], which would release a check on NF-κB activation. Blockade of NF-κB activity, in contrast, is reported to inhibit readouts of pluripotency in cancer stem cells, such as self-renewal, migration, apoptosis, and expression of pluripotency-related genes [82].

References

  1. Sen, R.; Baltimore, D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 1986, 46, 705–716, doi:10.1016/0092-8674(86)90346-6.
  2. Sen, R.; Baltimore, D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 1986, 47, 921–928, doi:10.1016/0092-8674(86)90807-x.
  3. Baeuerle, P.A.; Baltimore, D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell 1988, 53, 211–217, doi:10.1016/0092-8674(88)90382-0.
  4. Baeuerle, P.A.; Baltimore, D. I kappa B: A specific inhibitor of the NF-kappa B transcription factor. Science 1988, 242, 540–546, doi:10.1126/science.3140380.
  5. Deng, P.; Zhou, C.; Alvarez, R.; Hong, C.; Wang, C.-Y. Inhibition of IKK/NF-κB Signaling Enhances Differentiation of Mesenchymal Stromal Cells from Human Embryonic Stem Cells. Stem Cell Rep. 2016, 6, 456–465, doi:10.1016/j.stemcr.2016.02.006.
  6. Zhang, Y.; Hu, W. NFκB signaling regulates embryonic and adult neurogenesis. Biol. 2012, 7, doi:10.1007/s11515-012-1233-z.
  7. Kaltschmidt, B.; Kaltschmidt, C. NF-kappaB in the nervous system. Cold Spring Harb. Perspect. Biol. 2009, 1, a001271, doi:10.1101/cshperspect.a001271.
  8. Hayden, M.S.; Ghosh, S. Shared principles in NF-kappaB signaling. Cell 2008, 132, 344–362, doi:10.1016/j.cell.2008.01.020.
  9. Napetschnig, J.; Wu, H. Molecular basis of NF-κB signaling. Rev. Biophys. 2013, 42, 443–468, doi:10.1146/annurev-biophys-083012-130338.
  10. Zhang, Q.; Lenardo, M.J.; Baltimore, D. 30 Years of NF-κB: A Blossoming of Relevance to Human Pathobiology. Cell 2017, 168, 37–57, doi:10.1016/j.cell.2016.12.012.
  11. Ambros, V.; Horvitz, H.R. Heterochronic mutants of the nematode Caenorhabditis elegans. Science 1984, 226, 409–416, doi:10.1126/science.6494891.
  12. Moss, E.G.; Lee, R.C.; Ambros, V. The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA. Cell 1997, 88, 637–646, doi:10.1016/s0092-8674(00)81906-6.
  13. Faas, L.; Warrander, F.C.; Maguire, R.; Ramsbottom, S.A.; Quinn, D.; Genever, P.; Isaacs, H.V. Lin28 proteins are required for germ layer specification in Xenopus. Development 2013, 140, 976–986, doi:10.1242/dev.089797.
  14. Ouchi, Y.; Yamamoto, J.; Iwamoto, T. The heterochronic genes lin-28a and lin-28b play an essential and evolutionarily conserved role in early zebrafish development. PLoS ONE 2014, 9, e88086, doi:10.1371/journal.pone.0088086.
  15. Moss, E.G.; Tang, L. Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites. Biol. 2003, 258, 432–442, doi:10.1016/s0012-1606(03)00126-x.
  16. Guo, Y.; Chen, Y.; Ito, H.; Watanabe, A.; Ge, X.; Kodama, T.; Aburatani, H. Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma. Gene 2006, 384, 51–61, doi:10.1016/j.gene.2006.07.011.
  17. Piskounova, E.; Polytarchou, C.; Thornton, J.E.; LaPierre, R.J.; Pothoulakis, C.; Hagan, J.P.; Iliopoulos, D.; Gregory, R.I. Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 2011, 147, 1066–1079, doi:10.1016/j.cell.2011.10.039.
  18. Reinhart, B.J.; Slack, F.J.; Basson, M.; Pasquinelli, A.E.; Bettinger, J.C.; Rougvie, A.E.; Horvitz, H.R.; Ruvkun, G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000, 403, 901–906, doi:10.1038/35002607.
  19. Pasquinelli, A.E.; Reinhart, B.J.; Slack, F.; Martindale, M.Q.; Kuroda, M.I.; Maller, B.; Hayward, D.C.; Ball, E.E.; Degnan, B.; Müller, P.; et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000, 408, 86–89, doi:10.1038/35040556.
  20. Lee, H.; Han, S.; Kwon, C.S.; Lee, D. Biogenesis and regulation of the let-7 miRNAs and their functional implications. Protein Cell 2016, 7, 100–113, doi:10.1007/s13238-015-0212-y.
  21. Suh, M.-R.; Lee, Y.; Kim, J.Y.; Kim, S.-K.; Moon, S.-H.; Lee, J.Y.; Cha, K.-Y.; Chung, H.M.; Yoon, H.S.; Moon, S.Y.; et al. Human embryonic stem cells express a unique set of microRNAs. Biol. 2004, 270, 488–498, doi:10.1016/j.ydbio.2004.02.019.
  22. Thomson, J.M.; Newman, M.; Parker, J.S.; Morin-Kensicki, E.M.; Wright, T.; Hammond, S.M. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006, 20, 2202–2207, doi:10.1101/gad.1444406.
  23. Wulczyn, F.G.; Smirnova, L.; Rybak, A.; Brandt, C.; Kwidzinski, E.; Ninnemann, O.; Strehle, M.; Seiler, A.; Schumacher, S.; Nitsch, R. Post-transcriptional regulation of the let-7 microRNA during neural cell specification. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2007, 21, 415–426, doi:10.1096/fj.06-6130com.
  24. Viswanathan, S.R.; Daley, G.Q.; Gregory, R.I. Selective blockade of microRNA processing by Lin28. Science 2008, 320, 97–100, doi:10.1126/science.1154040.
  25. Newman, M.A.; Thomson, J.M.; Hammond, S.M. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA N. Y. N 2008, 14, 1539–1549, doi:10.1261/rna.1155108.
  26. Rybak, A.; Fuchs, H.; Smirnova, L.; Brandt, C.; Pohl, E.E.; Nitsch, R.; Wulczyn, F.G. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Cell Biol. 2008, 10, 987–993, doi:10.1038/ncb1759.
  27. Piskounova, E.; Viswanathan, S.R.; Janas, M.; LaPierre, R.J.; Daley, G.Q.; Sliz, P.; Gregory, R.I. Determinants of microRNA processing inhibition by the developmentally regulated RNA-binding protein Lin28. Biol. Chem. 2008, 283, 21310–21314, doi:10.1074/jbc.C800108200.
  28. Heo, I.; Joo, C.; Cho, J.; Ha, M.; Han, J.; Kim, V.N. Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Cell 2008, 32, 276–284, doi:10.1016/j.molcel.2008.09.014.
  29. Ludwig, N.; Leidinger, P.; Becker, K.; Backes, C.; Fehlmann, T.; Pallasch, C.; Rheinheimer, S.; Meder, B.; Stähler, C.; Meese, E.; et al. Distribution of miRNA expression across human tissues. Nucleic Acids Res. 2016, 44, 3865–3877, doi:10.1093/nar/gkw116.
  30. Shell, S.; Park, S.-M.; Radjabi, A.R.; Schickel, R.; Kistner, E.O.; Jewell, D.A.; Feig, C.; Lengyel, E.; Peter, M.E. Let-7 expression defines two differentiation stages of cancer. Natl. Acad. Sci. USA 2007, 104, 11400–11405, doi:10.1073/pnas.0704372104.
  31. Heo, I.; Joo, C.; Kim, Y.-K.; Ha, M.; Yoon, M.-J.; Cho, J.; Yeom, K.-H.; Han, J.; Kim, V.N. TUT4 in concert with Lin28 suppresses microRNA biogenesis through pre-microRNA uridylation. Cell 2009, 138, 696–708, doi:10.1016/j.cell.2009.08.002.
  32. Ustianenko, D.; Chiu, H.-S.; Treiber, T.; Weyn-Vanhentenryck, S.M.; Treiber, N.; Meister, G.; Sumazin, P.; Zhang, C. LIN28 Selectively Modulates a Subclass of Let-7 MicroRNAs. Cell 2018, 71, 271-283.e5, doi:10.1016/j.molcel.2018.06.029.
  33. Hagan, J.P.; Piskounova, E.; Gregory, R.I. Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Struct. Mol. Biol. 2009, 16, 1021–1025, doi:10.1038/nsmb.1676.
  34. Zhu, H.; Shyh-Chang, N.; Segrè, A.V.; Shinoda, G.; Shah, S.P.; Einhorn, W.S.; Takeuchi, A.; Engreitz, J.M.; Hagan, J.P.; Kharas, M.G.; et al. The Lin28/let-7 axis regulates glucose metabolism. Cell 2011, 147, 81–94, doi:10.1016/j.cell.2011.08.033.
  35. Li, M.; Wang, M.; Liu, Y.; Huang, S.; Yi, X.; Yin, C.; Wang, S.; Zhang, M.; Yu, Q.; Li, P.; et al. TNF-α Upregulates IKKε Expression via the Lin28B/let-7a Pathway to Induce Catecholamine Resistance in Adipocytes. Obesity 2019, 27, 767–776, doi:10.1002/oby.22434.
  36. Wang, X.-W.; Li, Q.; Liu, C.-M.; Hall, P.A.; Jiang, J.-J.; Katchis, C.D.; Kang, S.; Dong, B.C.; Li, S.; Zhou, F.-Q. Lin28 Signaling Supports Mammalian PNS and CNS Axon Regeneration. Cell Rep. 2018, 24, 2540–2552.e6, doi:10.1016/j.celrep.2018.07.105.
  37. Yao, K.; Qiu, S.; Tian, L.; Snider, W.D.; Flannery, J.G.; Schaffer, D.V.; Chen, B. Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas. Cell Rep. 2016, 17, 165–178, doi:10.1016/j.celrep.2016.08.078.
  38. Joshi, S.; Wei, J.; Bishopric, N.H. A cardiac myocyte-restricted Lin28/let-7 regulatory axis promotes hypoxia-mediated apoptosis by inducing the AKT signaling suppressor PIK3IP1. Biophys. Acta 2016, 1862, 240–251, doi:10.1016/j.bbadis.2015.12.004.
  39. Yue, Y.; Zhang, D.; Jiang, S.; Li, A.; Guo, A.; Wu, X.; Xia, X.; Cheng, H.; Tao, T.; Gu, X. LIN28 expression in rat spinal cord after injury. Res. 2014, 39, 862–874, doi:10.1007/s11064-014-1278-2.
  40. Kim, J.D.; Toda, C.; Ramírez, C.M.; Fernández-Hernando, C.; Diano, S. Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity. Diabetes 2017, 66, 2102–2111, doi:10.2337/db16-1558.
  41. Amen, A.M.; Ruiz-Garzon, C.R.; Shi, J.; Subramanian, M.; Pham, D.L.; Meffert, M.K. A Rapid Induction Mechanism for Lin28a in Trophic Responses. Cell 2017, 65, 490–503.e7, doi:10.1016/j.molcel.2016.12.025.
  42. Yu, L.; Jiang, Y.; Tang, B. Lin28a functionally modulates bupivacaine-induced dorsal root ganglion neuron apoptosis through TrkA activation. Pharmacother. 2018, 98, 63–68, doi:10.1016/j.biopha.2017.11.142.
  43. Lei, D.; Shao, Z.; Zhou, X.; Yuan, H. Synergistic neuroprotective effect of rasagiline and idebenone against retinal ischemia-reperfusion injury via the Lin28-let-7-Dicer pathway. Oncotarget 2018, 9, 12137–12153, doi:10.18632/oncotarget.24343.
  44. Ouwenga, R.; Lake, A.M.; O’Brien, D.; Mogha, A.; Dani, A.; Dougherty, J.D. Transcriptomic Analysis of Ribosome-Bound mRNA in Cortical Neurites In Vivo. Neurosci. Off. J. Soc. Neurosci. 2017, 37, 8688–8705, doi:10.1523/JNEUROSCI.3044-16.2017.
  45. Noya, S.B.; Colameo, D.; Brüning, F.; Spinnler, A.; Mircsof, D.; Opitz, L.; Mann, M.; Tyagarajan, S.K.; Robles, M.S.; Brown, S.A. The forebrain synaptic transcriptome is organized by clocks but its proteome is driven by sleep. Science 2019, 366, doi:10.1126/science.aav2642.
  46. Hu, Z.; Ma, J.; Gu, Y. Lin28a is Essential for Synaptic Plasticity in Dentate Granule Cells and Spatial Memory. Bull. 2020, doi:10.1007/s12264-020-00591-7.
  47. Ding, W.; Wang, Y.; Cheng, Y.; Chen, X.; Chen, W.; Zuo, P.; Chen, W.; Qiao, Z.; Fan, X. Lin28 is associated with astrocytic proliferation during intracerebral hemorrhage. J. Clin. Exp. Pathol. 2020, 13, 1136–1145.
  48. Cho, J.; Chang, H.; Kwon, S.C.; Kim, B.; Kim, Y.; Choe, J.; Ha, M.; Kim, Y.K.; Kim, V.N. LIN28A is a suppressor of ER-associated translation in embryonic stem cells. Cell 2012, 151, 765–777, doi:10.1016/j.cell.2012.10.019.
  49. Peng, S.; Chen, L.-L.; Lei, X.-X.; Yang, L.; Lin, H.; Carmichael, G.G.; Huang, Y. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells 2011, 29, 496–504, doi:10.1002/stem.591.
  50. Wilbert, M.L.; Huelga, S.C.; Kapeli, K.; Stark, T.J.; Liang, T.Y.; Chen, S.X.; Yan, B.Y.; Nathanson, J.L.; Hutt, K.R.; Lovci, M.T.; et al. LIN28 binds messenger RNAs at GGAGA motifs and regulates splicing factor abundance. Cell 2012, 48, 195–206, doi:10.1016/j.molcel.2012.08.004.
  51. Tsialikas, J.; Romer-Seibert, J. LIN28: Roles and regulation in development and beyond. Development 2015, 142, 2397–2404, doi:10.1242/dev.117580.
  52. 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. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007, 318, 1917–1920, doi:10.1126/science.1151526.
  53. Zhang, J.; Ratanasirintrawoot, S.; Chandrasekaran, S.; Wu, Z.; Ficarro, S.B.; Yu, C.; Ross, C.A.; Cacchiarelli, D.; Xia, Q.; Seligson, M.; et al. LIN28 Regulates Stem Cell Metabolism and Conversion to Primed Pluripotency. Cell Stem Cell 2016, 19, 66–80, doi:10.1016/j.stem.2016.05.009.
  54. Buganim, Y.; Faddah, D.A.; Cheng, A.W.; Itskovich, E.; Markoulaki, S.; Ganz, K.; Klemm, S.L.; van Oudenaarden, A.; Jaenisch, R. Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 2012, 150, 1209–1222, doi:10.1016/j.cell.2012.08.023.
  55. Wang, L.; Su, Y.; Huang, C.; Yin, Y.; Chu, A.; Knupp, A.; Tang, Y. NANOG and LIN28 dramatically improve human cell reprogramming by modulating LIN41 and canonical WNT activities. Open 2019, 8, doi:10.1242/bio.047225.
  56. Tanabe, K.; Nakamura, M.; Narita, M.; Takahashi, K.; Yamanaka, S. Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts. Natl. Acad. Sci. USA 2013, 110, 12172–12179, doi:10.1073/pnas.1310291110.
  57. Tsanov, K.M.; Pearson, D.S.; Wu, Z.; Han, A.; Triboulet, R.; Seligson, M.T.; Powers, J.T.; Osborne, J.K.; Kane, S.; Gygi, S.P.; et al. LIN28 phosphorylation by MAPK/ERK couples signalling to the post-transcriptional control of pluripotency. Cell Biol. 2017, 19, 60–67, doi:10.1038/ncb3453.
  58. Shi, J.-H.; Sun, S.-C. Tumor Necrosis Factor Receptor-Associated Factor Regulation of Nuclear Factor κB and Mitogen-Activated Protein Kinase Pathways. Immunol. 2018, 9, 1849, doi:10.3389/fimmu.2018.01849.
  59. Ruland, J.; Hartjes, L. CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Rev. Immunol. 2019, 19, 118–134, doi:10.1038/s41577-018-0087-2.
  60. Cimadamore, F.; Amador-Arjona, A.; Chen, C.; Huang, C.-T.; Terskikh, A.V. SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors. Natl. Acad. Sci. USA 2013, 110, E3017–E3026, doi:10.1073/pnas.1220176110.
  61. Yang, M.; Yang, S.-L.; Herrlinger, S.; Liang, C.; Dzieciatkowska, M.; Hansen, K.C.; Desai, R.; Nagy, A.; Niswander, L.; Moss, E.G.; et al. Lin28 promotes the proliferative capacity of neural progenitor cells in brain development. Development 2015, 142, 1616–1627, doi:10.1242/dev.120543.
  62. Romer-Seibert, J.S.; Hartman, N.W.; Moss, E.G. The RNA-binding protein LIN28 controls progenitor and neuronal cell fate during postnatal neurogenesis. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2019, 33, 3291–3303, doi:10.1096/fj.201801118R.
  63. Hennchen, M.; Stubbusch, J.; Abarchan-El Makhfi, I.; Kramer, M.; Deller, T.; Pierre-Eugene, C.; Janoueix-Lerosey, I.; Delattre, O.; Ernsberger, U.; Schulte, J.B.; et al. Lin28B and Let-7 in the Control of Sympathetic Neurogenesis and Neuroblastoma Development. Neurosci. Off. J. Soc. Neurosci. 2015, 35, 16531–16544, doi:10.1523/JNEUROSCI.2560-15.2015.
  64. Nathan, F.M.; Ohtake, Y.; Wang, S.; Jiang, X.; Sami, A.; Guo, H.; Zhou, F.-Q.; Li, S. Upregulating Lin28a Promotes Axon Regeneration in Adult Mice with Optic Nerve and Spinal Cord Injury. Ther. J. Am. Soc. Gene Ther. 2020, 28, 1902–1917, doi:10.1016/j.ymthe.2020.04.010.
  65. Widera, D.; Mikenberg, I.; Kaltschmidt, B.; Kaltschmidt, C. Potential role of NF-kappaB in adult neural stem cells: The underrated steersman? J. Dev. Neurosci. Off. J. Int. Soc. Dev. Neurosci. 2006, 24, 91–102, doi:10.1016/j.ijdevneu.2005.11.017.
  66. Young, K.M.; Bartlett, P.F.; Coulson, E.J. Neural progenitor number is regulated by nuclear factor-kappaB p65 and p50 subunit-dependent proliferation rather than cell survival. Neurosci. Res. 2006, 83, 39–49, doi:10.1002/jnr.20702.
  67. Denis-Donini, S.; Dellarole, A.; Crociara, P.; Francese, M.T.; Bortolotto, V.; Quadrato, G.; Canonico, P.L.; Orsetti, M.; Ghi, P.; Memo, M.; et al. Impaired adult neurogenesis associated with short-term memory defects in NF-kappaB p50-deficient mice. Neurosci. Off. J. Soc. Neurosci. 2008, 28, 3911–3919, doi:10.1523/JNEUROSCI.0148-08.2008.
  68. Widera, D.; Mikenberg, I.; Elvers, M.; Kaltschmidt, C.; Kaltschmidt, B. Tumor necrosis factor alpha triggers proliferation of adult neural stem cells via IKK/NF-kappaB signaling. BMC Neurosci. 2006, 7, 64, doi:10.1186/1471-2202-7-64.
  69. Denis-Donini, S.; Caprini, A.; Frassoni, C.; Grilli, M. Members of the NF-kappaB family expressed in zones of active neurogenesis in the postnatal and adult mouse brain. Brain Res. Dev. Brain Res. 2005, 154, 81–89, doi:10.1016/j.devbrainres.2004.10.010.
  70. Yamanishi, E.; Yoon, K.; Alberi, L.; Gaiano, N.; Mizutani, K. NF-κB signaling regulates the generation of intermediate progenitors in the developing neocortex. Genes Cells Devoted Mol. Cell. Mech. 2015, 20, 706–719, doi:10.1111/gtc.12267.
  71. FitzPatrick, L.M.; Hawkins, K.E.; Delhove, J.M.K.M.; Fernandez, E.; Soldati, C.; Bullen, L.F.; Nohturfft, A.; Waddington, S.N.; Medina, D.L.; Bolaños, J.P.; et al. NF-κB Activity Initiates Human ESC-Derived Neural Progenitor Cell Differentiation by Inducing a Metabolic Maturation Program. Stem Cell Rep. 2018, 10, 1766–1781, doi:10.1016/j.stemcr.2018.03.015.
  72. Zheng, X.; Boyer, L.; Jin, M.; Mertens, J.; Kim, Y.; Ma, L.; Ma, L.; Hamm, M.; Gage, F.H.; Hunter, T. Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. eLife 2016, 5, doi:10.7554/eLife.13374.
  73. Shyh-Chang, N.; Daley, G.Q. Lin28: Primal regulator of growth and metabolism in stem cells. Cell Stem Cell 2013, 12, 395–406, doi:10.1016/j.stem.2013.03.005.
  74. Zhang, G.; Li, J.; Purkayastha, S.; Tang, Y.; Zhang, H.; Yin, Y.; Li, B.; Liu, G.; Cai, D. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 2013, 497, 211–216, doi:10.1038/nature12143.
  75. Li, J.; Tang, Y.; Cai, D. IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Cell Biol. 2012, 14, 999–1012, doi:10.1038/ncb2562.
  76. Takase, O.; Yoshikawa, M.; Idei, M.; Hirahashi, J.; Fujita, T.; Takato, T.; Isagawa, T.; Nagae, G.; Suemori, H.; Aburatani, H.; et al. The role of NF-κB signaling in the maintenance of pluripotency of human induced pluripotent stem cells. PLoS ONE 2013, 8, e56399, doi:10.1371/journal.pone.0056399.
  77. Widera, D.; Kaus, A.; Kaltschmidt, C.; Kaltschmidt, B. Neural stem cells, inflammation and NF-kappaB: Basic principle of maintenance and repair or origin of brain tumours? Cell. Mol. Med. 2008, 12, 459–470, doi:10.1111/j.1582-4934.2007.00208.x.
  78. Kaltschmidt, C.; Banz-Jansen, C.; Benhidjeb, T.; Beshay, M.; Förster, C.; Greiner, J.; Hamelmann, E.; Jorch, N.; Mertzlufft, F.; Pfitzenmaier, J.; et al. A Role for NF-κB in Organ Specific Cancer and Cancer Stem Cells. Cancers 2019, 11, doi:10.3390/cancers11050655.
  79. Soubannier, V.; Stifani, S. NF-κB Signalling in Glioblastoma. Biomedicines 2017, 5, doi:10.3390/biomedicines5020029.
  80. Kaus, A.; Widera, D.; Kassmer, S.; Peter, J.; Zaenker, K.; Kaltschmidt, C.; Kaltschmidt, B. Neural stem cells adopt tumorigenic properties by constitutively activated NF-kappaB and subsequent VEGF up-regulation. Stem Cells Dev. 2010, 19, 999–1015, doi:10.1089/scd.2009.0416.
  81. Bredel, M.; Scholtens, D.M.; Yadav, A.K.; Alvarez, A.A.; Renfrow, J.J.; Chandler, J.P.; Yu, I.L.Y.; Carro, M.S.; Dai, F.; Tagge, M.J.; et al. NFKBIA deletion in glioblastomas. N Engl J Med 2011, 364, 627–637, doi:10.1056/NEJMoa1006312.
  82. Zakaria, N.; Mohd Yusoff, N.; Zakaria, Z.; Widera, D.; Yahaya, B.H. Inhibition of NF-κB Signaling Reduces the Stemness Characteristics of Lung Cancer Stem Cells. Oncol. 2018, 8, 166, doi:10.3389/fonc.2018.00166.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Cell Biology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Mollie K. Meffert
View Times: 615
Revisions: 2 times (View History)
Update Date: 05 Jan 2021
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback