Post-transcriptional gene regulatory mechanisms in eukaryotes: an overview.

Expression of a gene can be controlled at many levels, including transcription, mRNA splicing, mRNA stability, translation and post-translational events such as protein stability and modification. The majority of studies to date have focused on transcriptional control mechanisms, but the importance of post-transcriptional mechanisms in regulating gene expression in eukaryotes is becoming increasingly clear. In this short review, selected examples of post-transcriptional gene regulatory mechanisms operating in both lower and higher eukaryotes will be used to highlight the plethora of such mechanisms already identified. The underlying theme is that post-transcriptional gene regulation relies on specific RNA-protein interactions that either result in the targeted degradation of the mRNA or prevent access of the ribosome to the translation start codon. Such interactions can occur in the 5' or 3' untranslated regions of an mRNA or within the decoded portion of the molecule. The importance of these regulatory mechanisms in a range of biological systems is also illustrated.

[1]  S. Peltz,et al.  mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor. , 1993, Genes & development.

[2]  F Sherman,et al.  mRNA sequences influencing translation and the selection of AUG initiator codons in the yeast Saccharomyces cerevisiae , 1996, Molecular microbiology.

[3]  M. Kozak,et al.  Effects of intercistronic length on the efficiency of reinitiation by eucaryotic ribosomes. , 1987, Molecular and cellular biology.

[4]  N. Sonenberg,et al.  PHAS-I as a link between mitogen-activated protein kinase and translation initiation. , 1994, Science.

[5]  S. Peltz,et al.  Interrelationships of the pathways of mRNA decay and translation in eukaryotic cells. , 1996, Annual review of biochemistry.

[6]  N. Sonenberg,et al.  Repression of cap‐dependent translation by 4E‐binding protein 1: competition with p220 for binding to eukaryotic initiation factor‐4E. , 1995, The EMBO journal.

[7]  S. Moyer,et al.  Characterization of the infections of permissive and nonpermissive cells by host range mutants of vesicular stomatitis virus defective in RNA methylation. , 1984, Virology.

[8]  M. Kozak,et al.  Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs , 1989, Molecular and cellular biology.

[9]  H. Rubin,et al.  A direct evidence for the involvement of poly(A) in protein synthesis. , 1987, Biochemical and biophysical research communications.

[10]  J. Hershey,et al.  2 The Pathway and Mechanism of Eukaryotic Protein Synthesis , 1996 .

[11]  Tsuey-Ming Chen,et al.  Interplay of two functionally and structurally distinct domains of the c-fos AU-rich element specifies its mRNA-destabilizing function , 1994, Molecular and cellular biology.

[12]  M. Hentze,et al.  Position is the critical determinant for function of iron-responsive elements as translational regulators , 1992, Molecular and cellular biology.

[13]  R. Parker,et al.  Premature translational termination triggers mRNA decapping , 1994, Nature.

[14]  J P Reboud,et al.  [Initiation of protein synthesis in eukaryotic cells]. , 1969, Comptes rendus hebdomadaires des seances de l'Academie des sciences. Serie D: Sciences naturelles.

[15]  R. Losson,et al.  The 5' untranslated region of the PPR1 regulatory gene dictates rapid mRNA decay in yeast. , 1993, Gene.

[16]  A. Sachs,et al.  Common themes in translational and transcriptional regulation. , 1997, Trends in biochemical sciences.

[17]  Mick F. Tuite,et al.  Post-Transcriptional Control of Gene Expression , 1990, NATO ASI Series.

[18]  S. Morley,et al.  Differential stimulation of phosphorylation of initiation factors eIF-4F, eIF-4B, eIF-3, and ribosomal protein S6 by insulin and phorbol esters. , 1990, The Journal of biological chemistry.

[19]  R D Klausner,et al.  Evidence that the pathway of transferrin receptor mRNA degradation involves an endonucleolytic cleavage within the 3′ UTR and does not involve poly(A) tail shortening. , 1994, The EMBO journal.

[20]  A. Gingras,et al.  Activation of the translational suppressor 4E-BP1 following infection with encephalomyocarditis virus and poliovirus. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[21]  W. J. Lucas,et al.  Visualizing mRNA expression in plant protoplasts: factors influencing efficient mRNA uptake and translation. , 1989, The Plant cell.

[22]  A. Cigan,et al.  Mutational analysis of the HIS4 translational initiator region in Saccharomyces cerevisiae , 1988, Molecular and cellular biology.

[23]  M. Wickens,et al.  The 3'-untranslated regions of c-mos and cyclin mRNAs stimulate translation by regulating cytoplasmic polyadenylation. , 1994, Genes & development.

[24]  A. De Benedetti,et al.  Preferential translation of heat shock mRNAs in HeLa cells deficient in protein synthesis initiation factors eIF-4E and eIF-4 gamma. , 1992, Journal of Biological Chemistry.

[25]  I. London,et al.  Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2 alpha kinase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Kozak.  The scanning model for translation: an update , 1989, The Journal of cell biology.

[27]  X. Bu,et al.  Platelet‐derived growth factor stimulates phosphorylation of the 25 kDa mRNA cap binding protein (eIF‐4E) in human lung fibroblasts , 1991, FEBS letters.

[28]  A fluorescence study of the binding of eucaryotic initiation factors to messenger RNA and messenger RNA analogues. , 1987, Biochemistry.

[29]  P. Bernstein,et al.  Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant. , 1992, Genes & development.

[30]  M. Hentze,et al.  Translational repression by a complex between the iron‐responsive element of ferritin mRNA and its specific cytoplasmic binding protein is position‐dependent in vivo. , 1990, The EMBO journal.

[31]  G. Shaw,et al.  Translational blockade imposed by cytokine-derived UA-rich sequences. , 1989, Science.

[32]  R. Rhoads,et al.  Immunological detection of the messenger RNA cap-binding protein. , 1985, The Journal of biological chemistry.

[33]  R. Rhoads,et al.  Chromatographic resolution of in vivo phosphorylated and nonphosphorylated eukaryotic translation initiation factor eIF-4E: increased cap affinity of the phosphorylated form. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[34]  V. M. Pain.  Initiation of protein synthesis in eukaryotic cells. , 1996, European journal of biochemistry.

[35]  A. Jacobson,et al.  Tales of poly(A): a review. , 1990, Gene.

[36]  A. Cigan,et al.  Sequence and structural features associated with translational initiator regions in yeast--a review. , 1987, Gene.

[37]  V. Walbot,et al.  RNA pseudoknot domain of tobacco mosaic virus can functionally substitute for a poly(A) tail in plant and animal cells. , 1990, Genes & development.

[38]  A. Jacobson,et al.  A coding region segment is necessary, but not sufficient for rapid decay of the HIS3 mRNA in yeast. , 1992, Gene.

[39]  F Sherman,et al.  mRNA structures influencing translation in the yeast Saccharomyces cerevisiae , 1988, Molecular and cellular biology.

[40]  M. Culbertson,et al.  Gene products that promote mRNA turnover in Saccharomyces cerevisiae , 1992, Molecular and cellular biology.

[41]  R. Aebersold,et al.  Phosphorylation of eIF-4E on Serine 209 by Protein Kinase C Is Inhibited by the Translational Repressors, 4E-binding Proteins (*) , 1996, The Journal of Biological Chemistry.

[42]  A. Hinnebusch,et al.  Effect of sequence context at stop codons on efficiency of reinitiation in GCN4 translational control , 1994, Molecular and cellular biology.

[43]  D. Gallie.  The cap and poly(A) tail function synergistically to regulate mRNA translational efficiency. , 1991, Genes & development.

[44]  S. Peltz,et al.  Nonsense-mediated mRNA decay in yeast. , 1994, Progress in nucleic acid research and molecular biology.

[45]  H BRICAIRE,et al.  Journal of Endocrinology , 1939, Nature.

[46]  R. Rhoads,et al.  Phosphorylation of Eukaryotic Protein Synthesis Initiation Factor 4E at Ser-209 (*) , 1995, The Journal of Biological Chemistry.

[47]  W. Marzluff,et al.  The histone 3'-terminal stem-loop is necessary for translation in Chinese hamster ovary cells. , 1996, Nucleic acids research.

[48]  Ronald W. Davis,et al.  The poly(A) binding protein is required for poly(A) shortening and 60S ribosomal subunit-dependent translation initiation , 1989, Cell.

[49]  A. Sachs,et al.  A common function for mRNA 5' and 3' ends in translation initiation in yeast. , 1995, Genes & development.

[50]  M. Kozak,et al.  Downstream secondary structure facilitates recognition of initiator codons by eukaryotic ribosomes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[51]  R. Jackson,et al.  The immediate downstream codon strongly influences the efficiency of utilization of eukaryotic translation initiation codons. , 1994, The EMBO journal.

[52]  N. Sonenberg,et al.  The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4 gamma and the translational repressors 4E-binding proteins , 1995, Molecular and cellular biology.

[53]  M. Kozak,et al.  A short leader sequence impairs the fidelity of initiation by eukaryotic ribosomes. , 1991, Gene expression.

[54]  J. Hershey,et al.  Regulated phosphorylation and low abundance of HeLa cell initiation factor eIF-4F suggest a role in translational control. Heat shock effects on eIF-4F. , 1987, The Journal of biological chemistry.

[55]  I. Kerr,et al.  Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon , 1990, Cell.

[56]  R. Planta,et al.  Effect of deletions in the 5'-noncoding region on the translational efficiency of phosphoglycerate kinase mRNA in yeast. , 1989, Gene.

[57]  C. Woodley,et al.  Studies on the role of eukaryotic nucleotide exchange factor in polypeptide chain initiation. , 1984, The Journal of biological chemistry.

[58]  R. Panniers,et al.  Cap binding protein complex that restores protein synthesis in heat-shocked Ehrlich cell lysates contains highly phosphorylated eIF-4E. , 1990, The Journal of biological chemistry.

[59]  R. Schneider,et al.  Adenovirus inhibition of cellular protein synthesis involves inactivation of cap-binding protein , 1991, Cell.

[60]  K. Abromeit.  Music Received , 2023, Notes.

[61]  C. Proud,et al.  Insulin and phorbol ester stimulate initiation factor eIF-4E phosphorylation by distinct pathways in Chinese hamster ovary cells overexpressing the insulin receptor. , 1996, European journal of biochemistry.

[62]  N. Standart,et al.  Translation of 15‐lipoxygenase mRNA is inhibited by a protein that binds to a repeated sequence in the 3′ untranslated region. , 1994, The EMBO journal.

[63]  M. Berry,et al.  Knowing when not to stop: selenocysteine incorporation in eukaryotes. , 1996, Trends in biochemical sciences.

[64]  V. M. Pain,et al.  A Reevaluation of the Cap-binding Protein, eIF4E, as a Rate-limiting Factor for Initiation of Translation in Reticulocyte Lysate (*) , 1996, The Journal of Biological Chemistry.

[65]  R. W. Donaldson,et al.  Epidermal growth factor or okadaic acid stimulates phosphorylation of eukaryotic initiation factor 4F. , 1991, The Journal of biological chemistry.

[66]  A. Hinnebusch.  Translational control of GCN4: an in vivo barometer of initiation-factor activity. , 1994, Trends in biochemical sciences.

[67]  H. O. Voorma,et al.  Phosphorylation state of the cap-binding protein eIF4E during viral infection. , 1996, Virology.

[68]  D. Cavener,et al.  Eukaryotic start and stop translation sites. , 1991, Nucleic acids research.

[69]  M. Kozak.  Effects of long 5' leader sequences on initiation by eukaryotic ribosomes in vitro. , 1991, Gene expression.

[70]  M. Shago,et al.  Translation of the Saccharomyces cerevisiae tcm1 gene in the absence of a 5'-untranslated leader. , 1990, Nucleic acids research.

[71]  A. Christensen,et al.  Circular polysomes predominate on the rough endoplasmic reticulum of somatotropes and mammotropes in the rat anterior pituitary. , 1987, The American journal of anatomy.

[72]  Robert L. Tanguay,et al.  Poly(A) binds to initiation factors and increases cap-dependent translation in vitro. , 1994, The Journal of biological chemistry.

[73]  M. Kozak.  Adherence to the first-AUG rule when a second AUG codon follows closely upon the first. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[74]  C. Berset,et al.  A novel inhibitor of cap‐dependent translation initiation in yeast: p20 competes with eIF4G for binding to eIF4E , 1997, The EMBO journal.

[75]  A. Shatkin,et al.  Characterization of ribosome-protected fragments from reovirus messenger RNA. , 1976, The Journal of biological chemistry.

[76]  M. Kozak.  Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes , 1986, Cell.

[77]  A. Gingras,et al.  Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function , 1994, Nature.

[78]  A. Jacobson,et al.  mRNA poly(A) tail, a 3' enhancer of translational initiation , 1990, Molecular and cellular biology.

[79]  G. Shaw,et al.  A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation , 1986, Cell.

[80]  R. Parker,et al.  Mutations affecting stability and deadenylation of the yeast MFA2 transcript. , 1992, Genes & development.

[81]  Aaron J. Shatkin,et al.  5′-Terminal structure and mRNA stability , 1977, Nature.

[82]  M. Tuite,et al.  The effects of 5′‐capping, 3′‐polyadenylation and leader composition upon the translation and stability of mRNA in a cell‐free extract derived from the yeast Saccharomyces cerevisiae , 1992, Molecular microbiology.

[83]  J. Warner,et al.  Methylated, blocked 5' termini of yeast mRNA. , 1976, The Journal of biological chemistry.

[84]  A. Hinnebusch.  Evidence for translational regulation of the activator of general amino acid control in yeast. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[85]  N. Zanchin,et al.  Characterization of the in Vivo Phosphorylation Sites of the mRNA·Cap-binding Complex Proteins Eukaryotic Initiation Factor-4E and p20 in Saccharomyces cerevisiae(*) , 1995, The Journal of Biological Chemistry.

[86]  C. Proud,et al.  Regulation of protein synthesis in Swiss 3T3 fibroblasts. Rapid activation of the guanine-nucleotide-exchange factor by insulin and growth factors. , 1992, The Biochemical journal.

[87]  J. Ross,et al.  Control of messenger RNA stability in higher eukaryotes. , 1996, Trends in genetics : TIG.

[88]  C. Proud,et al.  Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. , 1993, The Biochemical journal.

[89]  M. Kozak.  Context effects and inefficient initiation at non-AUG codons in eucaryotic cell-free translation systems , 1989, Molecular and cellular biology.

[90]  D. Kolakofsky,et al.  Positions +5 and +6 can be major determinants of the efficiency of non‐AUG initiation codons for protein synthesis. , 1994, The EMBO journal.

[91]  I. Stansfield,et al.  The end in sight: terminating translation in eukaryotes. , 1995, Trends in biochemical sciences.

[92]  Daniel R Schoenberg,et al.  Purification and Characterization of an Estrogen-regulated Xenopus Liver Polysomal Nuclease Involved in the Selective Destabilization of Albumin mRNA (*) , 1995, The Journal of Biological Chemistry.

[93]  A. Brown,et al.  Inhibition of translational initiation in the yeast Saccharomyces cerevisiae as a function of the stability and position of hairpin structures in the mRNA leader. , 1993, The Journal of biological chemistry.