Download PDF
Semin Thromb Hemost 2004; 30(4): 491-498
DOI: 10.1055/s-2004-833484
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Change in Protein Phenotype without a Nucleus: Translational Control in Platelets

Andrew S. Weyrich1 , 4 , 6 , Stephan Lindemann7 , Neal D. Tolley4 , Larry W. Kraiss3 , 4 , Dan A. Dixon8 , Tracey M. Mahoney4 , Stephen P. Prescott1 , 5 , Tom M. McIntyre1 , 2 , 4 , Guy A. Zimmerman1 , 4
  • 1Departments of Internal Medicine, University of Utah, Salt Lake City, Utah
  • 2Departments of Pathology and Surgery, University of Utah, Salt Lake City, Utah
  • 3Departments of Surgery, University of Utah, Salt Lake City, Utah
  • 4Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah
  • 5Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
  • 6Associate Professor, University of Utah, Salt Lake City, Utah
  • 7Department of Medicine, Johannes Gutenberg University, Mainz, Germany
  • 8Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
Further Information

Publication History

Publication Date:
08 September 2004 (online)

    Permissions and Reprints

For most cells the nucleus takes center stage. Not only is it the largest organelle in eukaryotic cells, it carries most of the genome and transcription of DNA to RNA largely takes place in the nucleus. Because transcription is a major step in gene regulation, the absence of a nucleus is limiting from a biosynthetic standpoint. Consequently, the anucleate status of platelets has stereotyped it as a cell without synthetic potential. It is now clear, however, that this viewpoint is far too simplistic. In response to physiologic stimuli, platelets synthesize biologically relevant proteins that are regulated via gene expression programs at the translational level. This process does not require a nucleus; instead, it uses mRNAs and other translational factors that appear to be retained in specialized fashion as megakaryocytes generate platelets during thrombopoiesis. We highlight the molecular machinery and pathways used by platelets to translate mRNA into protein and offer insight into how these synthesized products may regulate thrombotic and inflammatory events.

KEYWORDS

Megakaryocytes - nucleus - platelets - RNA - translation

REFERENCES

  • 1 Batar P AD. GL. Platelet turnover and aging. In: Michelson AD Platelets. San Diego, CA; Elsevier Science 2002: 53-64
    Google Scholar
  • 2 Woulfe D, Yang J, Prevost N, O'Brien P J, Brass L. Signal transduction during the initiation, extension, and perpetuation of platelet plug formation. In: Michelson AD Platelets. San Diego, CA; Elsevier Science 2002: 197-213
    Google Scholar
  • 3 Weyrich A S, Lindemann S, Zimmerman G A. The evolving role of platelets in inflammation.  J Thromb Haemost. 2003;  2 1-9
    PubMedGoogle Scholar
  • 4 Parise L V. Integrin alpha(IIb)beta(3) signaling in platelet adhesion and aggregation.  Curr Opin Cell Biol. 1999;  11 597-601
    CrossrefPubMedGoogle Scholar
  • 5 Reed G L. Platelet secretion. In: Michelson AD Platelets. San Diego, CA; Elsevier Science 2002: 181-195
    Google Scholar
  • 6 Italiano Jr J E, Shivdasani R A. Megakaryocytes and beyond: the birth of platelets.  J Thromb Haemost. 2003;  1 1174-1182
    CrossrefPubMedGoogle Scholar
  • 7 Italiano Jr J, Hartwig J H. Megakaryocyte development and platelet formation. In: Michelson AD Platelets. San Diego, CA; Elsevier 2002: 21-35
    Google Scholar
  • 8 Weyrich A S, Zimmerman G A. Evaluating the relevance of the platelet transcriptome.  Blood. 2003;  102 1550-1551
    CrossrefPubMedGoogle Scholar
  • 9 Gnatenko D V, Dunn J J, McCorkle S R, Weissmann D, Perrotta P L, Bahou W F. Transcript profiling of human platelets using microarray and serial analysis of gene expression.  Blood. 2003;  101 2285-2293
    CrossrefPubMedGoogle Scholar
  • 10 Mathews M B, Sonenberg N, Hershey J WB. Origins and principles of translational control. In: Mathews MB, Sonenberg N, Hershey JWB Translational Control of Gene Expression. Cold Spring Harbor, NY; Cold Spring Harbor Laboratory Press 2000: 1-31
    Google Scholar
  • 11 Lindemann S, McIntyre T M, Prescott S M, Zimmerman G A, Weyrich A S. Expanding the functional repertoire of platelets in thrombosis and inflammation: signal-dependent protein synthesis. In: Fitzgerald DJ, Quinn MA Platelet Function: Assessment, Diagnosis, and Treatment. Totowa, NJ; The Humana Press 2003
    Google Scholar
  • 12 Lindemann S, Tolley N D, Dixon D A et al.. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis.  J Cell Biol. 2001;  154 485-490
    CrossrefPubMedGoogle Scholar
  • 13 Lindemann S, Tolley N D, Eyre J R, Kraiss L W, Mahoney T M, Weyrich A S. Integrins regulate the intracellular distribution of eukaryotic initiation factor 4E in platelets. A checkpoint for translational control.  J Biol Chem. 2001;  276 33947-33951
    CrossrefPubMedGoogle Scholar
  • 14 Pabla R, Weyrich A S, Dixon D A et al.. Integrin-dependent control of translation: Engagement of integrin αIIbβ3 regulates synthesis of proteins in activated human platelets.  J Cell Biol. 1999;  144 175-184
    CrossrefPubMedGoogle Scholar
  • 15 Weyrich A S, Dixon D A, Pabla R et al.. Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets.  Proc Natl Acad Sci USA. 1998;  95 5556-5561
    CrossrefPubMedGoogle Scholar
  • 16 Kraiss L W, Weyrich A S, Alto N M et al.. Fluid flow activates a regulator of translation, p70/p85 s6 kinase, in human endothelial cells.  Am J Physiol Heart Circ Physiol. 2000;  278 1537-1544
    PubMedGoogle Scholar
  • 17 Mahoney T S, Weyrich A S, Dixon D A, McIntyre T, Prescott S M, Zimmerman G A. Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes.  Proc Natl Acad Sci USA. 2001;  98 10284-10289
    CrossrefPubMedGoogle Scholar
  • 18 Booyse F M, Rafelson M E. Protein synthesis and platelet function. In: Johnson SA, Guest M Dynamics of thrombus formation and dissolution. Philadelphia, PA; JB Lippincott 1969: 149
    Google Scholar
  • 19 Booyse F M, Hoveke T P, Rafelson M E. Studies on human platelets. II. Protein synthetic activity of various platelet populations.  Biochim Biophys Acta. 1968;  157 660-663
    PubMedGoogle Scholar
  • 20 Booyse F M, Rafelson Jr M E. Studies on human platelets. I. Synthesis of platelet protein in a cell-free system.  Biochim Biophys Acta. 1968;  166 689-697
    PubMedGoogle Scholar
  • 21 Booyse F, Rafelson Jr M E. In vitro incorporation of amino-acids into the contractile protein of human blood platelets.  Nature. 1967;  215 283-284
    PubMedGoogle Scholar
  • 22 Roth G J, Hickey M J, Chung D W, Hickstein D D. Circulating human blood platelets retain appreciable amounts of poly (a)+ RNA.  Biochem Biophys Res Commun. 1989;  160 705-710
    CrossrefPubMedGoogle Scholar
  • 23 Hershey J WB, Merrick W. The pathway and mechanism of initiation of protein synthesis. In: Sonenberg N, Hershey JWB, Mathews MB Translational Control of Gene Expression. Cold Spring Harbor, NY; Cold Spring Harbor Laboratory Press 2000: 33-88
    Google Scholar
  • 24 Rosenwald I B, Pechet L, Han A et al.. Expression of translation initiation factors eIF-4E and eIF-2α and a potential physiologic role of continuous protein synthesis in human platelets.  Thromb Haemost. 2001;  85 142-151
    PubMedGoogle Scholar
  • 25 Richter J D. Cytoplasmic polyadenylation in development and beyond.  Microbiol Mol Biol Rev. 1999;  63 446-456
    PubMedGoogle Scholar
  • 26 Jacobson A. Poly(A) metabolism and translation: the closed loop model. In: Hershey JWB, Mathews MB, Sonenberg N Translational Control. Cold Spring Harbor, NY; Cold Spring Harbor Laboratory Press 1996: 451-480
    Google Scholar
  • 27 Sachs A. Physical and functional interactions between the mRNA cap structure and the poly(a) tail. In: Sonenberg N, Hershey JWB, Mathews MB Translational Control of Gene Expression. Cold Spring Harbor, NY; Cold Spring Harbor Laboratory Press 2000: 447-465
    Google Scholar
  • 28 Sottile J, Mosher D F, Fullenweider J, George J N. Human platelets contain mRNA transcripts for platelet factor 4 and actin.  Thromb Haemost. 1989;  62 1100-1102
    PubMedGoogle Scholar
  • 29 Dixon D A, Tolley N D, Zimmerman G A. Convenient and rapid ribonuclease protection assay for use with primary cell cultures.  Biotechniques. 2001;  31 992-993
    PubMedGoogle Scholar
  • 30 Kochetov A V, Ischenko I V, Vorobiev D G et al.. Eukaryotic mRNAs encoding abundant and scarce proteins are statistically dissimilar in many structural features.  FEBS Lett. 1998;  440 351-355
    CrossrefPubMedGoogle Scholar
  • 31 Papkoff J, Chen R H, Blenis J, Forsman J. P42 mitogen-activated protein kinase and p90 ribosomal S6 kinase are selectively phosphorylated and activated during thrombin-induced platelet activation and aggregation.  Mol Cell Biol. 1994;  14 463-472
    PubMedGoogle Scholar
  • 32 Nguyen Y H, Mills A A, Stanbridge E J. Assembly of the QM protein onto the 60S ribosomal subunit occurs in the cytoplasm.  J Cell Biochem. 1998;  68 281-285
    CrossrefPubMedGoogle Scholar
  • 33 Kieffer N, Guichard J, Farcet J P, Vainchenker W, Breton-Gorius J. Biosynthesis of major platelet proteins in human blood platelets.  Eur J Biochem. 1987;  164 189-195
    CrossrefPubMedGoogle Scholar
  • 34 Belloc F, Hourdille P, Boisseau M R, Bernard P. Protein synthesis in human platelets correlation with platelet size.  Nouv Rev Fr Hematol. 1982;  24 369-373
    PubMedGoogle Scholar
  • 35 Hesketh J, Jodar D, Johannessen A, Partridge K, Pryme I, Tauler A. Enrichment of specific mRNAs in cytoskeletal-bound and membrane-bound polysomes in Chinese hamster ovary cells.  Biochem Soc Trans. 1996;  24 187S
    PubMedGoogle Scholar
  • 36 Clark I E, Wyckoff D, Gavis E R. Synthesis of the posterior determinant nanos is spatially restricted by a novel cotranslational regulatory mechanism.  Curr Biol. 2000;  10 1311-1314
    CrossrefPubMedGoogle Scholar
  • 37 Houng A K, Maggini L, Clement C Y, Reed G L. Identification and structure of activated-platelet protein-1, a protein with RNA-binding domain motifs that is expressed by activated platelets.  Eur J Biochem. 1997;  243 209-218
    CrossrefPubMedGoogle Scholar
  • 38 Gingras A-C, Raught B, Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation.  Annu Rev Biochem. 1999;  68 913-963
    CrossrefPubMedGoogle Scholar
  • 39 Hefner Y, Borsch-Haubold A G, Murakami M et al.. Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases.  J Biol Chem. 2000;  275 37542-37551
    CrossrefPubMedGoogle Scholar
  • 40 Gingras A C, Kennedy S G, O’Leary M A, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the AKT(PKB) signaling pathway.  Genes Dev. 1998;  12 502-513
    PubMedGoogle Scholar
  • 41 Singh J, Kaul D. RNA-mediated regulation of receptor-ck gene in human platelets.  Mol Cell Biochem. 1997;  173 189-192
    CrossrefPubMedGoogle Scholar
  • 42 Lemaitre D, Vericel E, Polette A, Lagarde M. Effects of fatty acids on human platelet glutathione peroxidase: Possible role of oxidative stress.  Biochem Pharmacol. 1997;  53 479-486
    CrossrefPubMedGoogle Scholar
  • 43 McBane II R D, Ford M A, Karnicki K, Stewart M, Owen W G. Fibrinogen, fibrin and crosslinking in aging arterial thrombi.  Thromb Haemost. 2000;  84 83-87
    PubMedGoogle Scholar
  • 44 Wysokinski W, McBane R, Chesebro J H, Owen W G. Reversibility of platelet thrombosis in vivo. Quantitative analysis in porcine carotid arteries.  Thromb Haemost. 1996;  76 1108-1113
    PubMedGoogle Scholar
  • 45 Sakata K, Shigemasa K, Uebaba Y, Nagai N, Ohama K. Expression of matrix metalloproteinases-2 and -9 by cells isolated from the peritoneal fluid of women with ovarian carcinoma.  Acta Cytol. 2002;  46 697-703
    PubMedGoogle Scholar
  • 46 Owen W G, Bichler J, Ericson D, Wysokinski W. Gating of thrombin in platelet aggregates by po2-linked lowering of extracellular Ca2+ concentration.  Biochemistry. 1995;  34 9277-9281
    CrossrefPubMedGoogle Scholar
  • 47 Abraham R T, Wiederrecht G J. Immunopharmacology of rapamycin.  Annu Rev Immunol. 1996;  14 483-510
    CrossrefPubMedGoogle Scholar
  • 48 Sousa J E, Costa M A, Abizaid A et al.. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study.  Circulation. 2001;  103 192-195
    PubMedGoogle Scholar
  • 49 Kaplanski G, Porat R, Aiura K, Erban J K, Gelfand J A, Dinarello C A. Activated platelets induce endothelial secretion of interleukin-8 in vitro via an interleukin-1-mediated event.  Blood. 1993;  81 2492-2495
    PubMedGoogle Scholar
  • 50 Hawrylowicz C M, Santoro S A, Platt F M, Unanue E R. Activated platelets express IL-1 activity.  J Immunol. 1989;  143 4015-4018
    PubMedGoogle Scholar
  • 51 Duquette M, Laneuville O. Translational regulation of prostaglandin endoperoxide h synthase-1 mRNA in megakaryocytic MEG-01 cells. Specific protein binding to a conserved 20-nucleotide cis element in the 3′-untranslated region.  J Biol Chem. 2002;  277 44631-44637
    CrossrefPubMedGoogle Scholar
  • 52 Kunicki T J, Newman P J. Synthesis of analogs of human platelet membrane glycoprotein IIb-IIIa complex by chicken peripheral blood thrombocytes.  Proc Natl Acad Sci USA. 1985;  82 7319-7323
    PubMedGoogle Scholar
  • 53 Waggoner S A, Liebhaber S A. Regulation of alpha-globin mRNA stability.  Exp Biol Med (Maywood). 2003;  228 387-395
    PubMedGoogle Scholar
  • 54 Knowles R B, Sabry J H, Martone M E et al.. Translocation of RNA granules in living neurons.  J Neurosci. 1996;  16 7812-7820
    PubMedGoogle Scholar

Andrew S WeyrichPh.D. 

Human Molecular Biology and Genetics, Bldg. 533

Rm. 4220, University of Utah

Salt Lake City, Utah 84112

Email: andy.weyrich@hmbg.utah.edu