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Cell Cycle Regulation by microRNAs in Stem Cells

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Cell Cycle in Development

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS))

Abstract

The ability to self-renew and to differentiate into at least one-cell lineage defines a stem cell. Self-renewal is a process by which stem cells proliferate without differentiation. Proliferation is achieved through a series of highly regulated events of the cell cycle. MicroRNAs (miRNAs) are a class of short noncoding RNAs whose importance in these events is becoming increasingly appreciated. In this chapter, we discuss the role of miRNAs in regulating the cell cycle in various stem cells with a focus on embryonic stem cells. We also present the evidence indicating that cell cycle-regulating miRNAs are incorporated into a large regulatory network to control the self-renewal of stem cells by inducing or inhibiting differentiation. In addition, we discuss the function of cell cycle-regulating miRNAs in cancer.

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References

  • Alvarez-Saavedra E, Horvitz HR (2010) Many families of C. elegans microRNAs are not essential for development or viability. Curr Biol 20:367–373

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Baek D et al (2008) The impact of microRNAs on protein output. Nature 455:64–71

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bartel DP (2009) MicroRNAs target recognition and regulatory functions. Cell 136:215–233

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ben-Porath I et al (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40:499–507

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Berthet C, Kaldis P (2007) Cell-specific responses to loss of cyclin-dependent kinases. Oncogene 26:4469–4477

    Article  CAS  PubMed  Google Scholar 

  • Bickenbach JR (1981) Identification and behavior of label-retaining cells in oral mucosa and skin. J Dent Res 60:1611–1620

    Article  PubMed  Google Scholar 

  • Bohnsack MT, Czaplinski K, Gorlich D (2004) Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. RNA 10:185–191

    Article  CAS  PubMed  Google Scholar 

  • Brons IG et al (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448:191–195

    Article  CAS  PubMed  Google Scholar 

  • Card DA et al (2008) Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Mol Cell Biol 28:6426–6438

    Article  PubMed  Google Scholar 

  • Cherington PV, Smith BL, Pardee AB (1979) Loss of epidermal growth factor requirement and malignant transformation. Proc Natl Acad Sci USA 76:3937–3941

    Article  CAS  PubMed  Google Scholar 

  • Creighton CJ et al (2010) Discovery of novel microRNAs in female reproductive tract using next generation sequencing. PLoS One 5:e9637

    Article  PubMed Central  PubMed  Google Scholar 

  • Dalton S (2009) Exposing hidden dimensions of embryonic stem cell cycle control. Cell Stem Cell 4:9–10

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Forman JJ, Coller HA (2010) The code within the code: microRNAs target coding regions. Cell Cycle 9:1533–1541

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fornari F et al (2008) MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 27:5651–5661

    Article  CAS  PubMed  Google Scholar 

  • Friedman RC et al (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105

    Article  CAS  PubMed  Google Scholar 

  • Fujii-Yamamoto H et al (2005) Cell cycle and developmental regulations of replication factors in mouse embryonic stem cells. J Biol Chem 280:12976–12987

    Article  CAS  PubMed  Google Scholar 

  • Galardi S et al (2007) miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem 282:23716–23724

    Article  CAS  PubMed  Google Scholar 

  • Gregory RI et al (2004) The microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240

    Article  CAS  PubMed  Google Scholar 

  • Han J et al (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027

    Article  CAS  PubMed  Google Scholar 

  • Han J et al (2006) Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell 125:887–901

    Article  CAS  PubMed  Google Scholar 

  • Harmes DC, DiRenzo J (2009) Cellular quiescence in mammary stem cells and breast tumor stem cells: got testable hypotheses? J Mammary Gland Biol Neoplasia 14:19–27

    Article  PubMed Central  PubMed  Google Scholar 

  • He S, Nakada D, Morrison SJ (2009) Mechanisms of stem cell self-renewal. Annu Rev Cell Dev Biol 25:377–406

    Article  CAS  PubMed  Google Scholar 

  • Houbaviy HB, Murray MF, Sharp PA (2003) Embryonic stem cell-specific MicroRNAs. Dev Cell 5:351–358

    Article  CAS  PubMed  Google Scholar 

  • Hutvágner G et al (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293:834–838

    Article  PubMed  Google Scholar 

  • Ivanovska I et al (2008) MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol Cell Biol 28:2167–2174

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jirmanova L et al (2002) Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells. Oncogene 21:5515–5528

    Article  CAS  PubMed  Google Scholar 

  • Kim VN, Han J, Siomi MC (2009a) Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10:126–139

    Article  CAS  PubMed  Google Scholar 

  • Kim YK et al (2009b) Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res 37:1672–1681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • le Sage C et al (2007) Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J 26:3699–3708

    Article  PubMed  Google Scholar 

  • Lee RC, Feinbaum RL, Ambros VT (1993) C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854

    Article  CAS  PubMed  Google Scholar 

  • Li L, Clevers H (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327:542–545

    Article  CAS  PubMed  Google Scholar 

  • Liu C et al (2010) Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell 6:433–444

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lu J et al (2005) MicroRNA expression profiles classify human cancers. Nature 435:834–838

    Article  CAS  PubMed  Google Scholar 

  • Lund E et al (2004) Nuclear export of microRNA precursors. Science 303:95–98

    Article  CAS  PubMed  Google Scholar 

  • Marson A et al (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134:521–533

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Massagué J (2004) G1 cell-cycle control and cancer. Nature 432:298–306

    Article  PubMed  Google Scholar 

  • Melton C, Judson RL, Blelloch R (2010) Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature 463:621–626

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mikkola HK, Orkin SH (2006) The journey of developing hematopoietic stem cells. Development 133:3733–3744

    Article  CAS  PubMed  Google Scholar 

  • Miska EA et al (2007) Most Caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genet 3:e215

    Article  PubMed Central  PubMed  Google Scholar 

  • Murchison EP et al (2005) Characterization of Dicer-deficient murine embryonic stem cells. Proc Natl Acad Sci USA 102:12135–12140

    Article  CAS  PubMed  Google Scholar 

  • Ohnuma S et al (1999) p27Xic1, a Cdk inhibitor, promotes the determination of glial cells in Xenopus retina. Cell 99:499–510

    Article  CAS  PubMed  Google Scholar 

  • Osawa M et al (1996) Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273:242–245

    Article  CAS  PubMed  Google Scholar 

  • Pardee AB (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71:1286–1290

    Article  CAS  PubMed  Google Scholar 

  • Parker SB et al (1995) p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science 267:1024–1027

    Article  CAS  PubMed  Google Scholar 

  • Pasquinelli AE et al (2000) Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 408:86–89

    Article  CAS  PubMed  Google Scholar 

  • Petrocca F et al (2008) E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13:272–286

    Article  CAS  PubMed  Google Scholar 

  • Qi J et al (2009) microRNAs regulate human embryonic stem cell division. Cell Cycle 8:3729–3741

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Qu Q et al (2010) Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nat Cell Biol 12:31–40

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reinhart BJ et al (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906

    Article  CAS  PubMed  Google Scholar 

  • Reya T et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  CAS  PubMed  Google Scholar 

  • Rossant J (2008) Stem cells and early lineage development. Cell 132:527–531

    Article  CAS  PubMed  Google Scholar 

  • Sabapathy K et al (1997) Regulation of ES cell differentiation by functional and conformational modulation of p53. EMBO J 16:6217–6229

    Article  CAS  PubMed  Google Scholar 

  • Savatier P et al (1996) Withdrawal of differentiation inhibitory activity/leukemia inhibitory factor up-regulates D-type cyclins and cyclin-dependent kinase inhibitors in mouse embryonic stem cells. Oncogene 12:309–322

    CAS  PubMed  Google Scholar 

  • Selbach M et al (2008) Widespread changes in protein synthesis induced by microRNAs. Nature 455:58–63

    Article  CAS  PubMed  Google Scholar 

  • Stead E et al (2002) Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities. Oncogene 21:8320–8333

    Article  CAS  PubMed  Google Scholar 

  • Stein GS et al (2006) An architectural perspective of cell-cycle control at the G1/S phase cell-cycle transition. J Cell Physiol 209:706–710

    Article  CAS  PubMed  Google Scholar 

  • Tesar PJ et al (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448:196–199

    Article  CAS  PubMed  Google Scholar 

  • Thomson JA et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

    Article  CAS  PubMed  Google Scholar 

  • Ullah Z et al (2008) Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. Genes Dev 22:3024–3036

    Article  CAS  PubMed  Google Scholar 

  • Ventura A et al (2008) Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 132:875–886

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Voorhoeve PM et al (2006) A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 124:1169–1181

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Blelloch R (2009) Cell cycle regulation by MicroRNAs in embryonic stem cells. Cancer Res 69:4093–4096

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Y et al (2007) DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet 39:380–385

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Y et al (2008) Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet 40:1478–1483

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yi R et al (2003) Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17:3011–3016

    Article  CAS  PubMed  Google Scholar 

  • Yi R et al (2008) A skin microRNA promotes differentiation by repressing “stemness”. Nature 452:225–229

    Article  CAS  PubMed  Google Scholar 

  • Zhao C et al (2009) A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nat Struct Mol Biol 16:365–371

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhao C et al (2010) MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling. Proc Natl Acad Sci USA 107:1876–1881

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Ruohola-Baker for the permission to use the graph in the Fig. 19.3. Grant support to Blelloch laboratory includes National Institutes of Health K08 NS48118 and RO1 NS057221, California Institute of Regenerative Medicine Seed Grant RS1-0161-1, and the Pew Foundation. YMW was supported by a training grant from the California Institute of Regenerative Medicine.

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Authors and Affiliations

  1. The Institute of Molecular Medicine, Peking University, Beijing, China

    Yangming Wang

  2. The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA

    Robert Blelloch

  3. Center for Reproductive Sciences, University of California San Francisco, San Francisco, CA, USA

    Robert Blelloch

  4. Department of Urology, University of California San Francisco, San Francisco, CA, USA

    Robert Blelloch

Authors
  1. Yangming Wang
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  2. Robert Blelloch
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Corresponding author

Correspondence to Yangming Wang .

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Editors and Affiliations

  1. CNRS UMR 6061, Fac. Médecine, Université de Rennes 1, Rennes CX, 35043, France

    Jacek Z. Kubiak

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Wang, Y., Blelloch, R. (2011). Cell Cycle Regulation by microRNAs in Stem Cells. In: Kubiak, J. (eds) Cell Cycle in Development. Results and Problems in Cell Differentiation. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-19065-0_19

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