Translational pathophysiology: a novel molecular mechanism of human disease

Blood - Tập 95 - Trang 3280-3288 - 2000
Mario Cazzola, Radek C. Skoda

Tóm tắt

AbstractIn higher eukaryotes, the expression of about 1 gene in 10 is strongly regulated at the level of messenger RNA (mRNA) translation into protein. Negative regulatory effects are often mediated by the 5′-untranslated region (5′-UTR) and rely on the fact that the 40S ribosomal subunit first binds to the cap structure at the 5′-end of mRNA and then scans for the first AUG codon. Self-complementary sequences can form stable stem-loop structures that interfere with the assembly of the preinitiation complex and/or ribosomal scanning. These stem loops can be further stabilized by the interaction with RNA-binding proteins, as in the case of ferritin. The presence of AUG codons located upstream of the physiological start site can inhibit translation by causing premature initiation and thereby preventing the ribosome from reaching the physiological start codon, as in the case of thrombopoietin (TPO). Recently, mutations that cause disease through increased or decreased efficiency of mRNA translation have been discovered, defining translational pathophysiology as a novel mechanism of human disease. Hereditary hyperferritinemia/cataract syndrome arises from various point mutations or deletions within a protein-binding sequence in the 5′-UTR of the L-ferritin mRNA. Each unique mutation confers a characteristic degree of hyperferritinemia and severity of cataract in affected individuals. Hereditary thrombocythemia (sometimes called familial essential thrombocythemia or familial thrombocytosis) can be caused by mutations in upstream AUG codons in the 5′-UTR of the TPO mRNA that normally function as translational repressors. Their inactivation leads to excessive production of TPO and elevated platelet counts. Finally, predisposition to melanoma may originate from mutations that create translational repressors in the 5′-UTR of the cyclin-dependent kinase inhibitor–2A gene.

Tài liệu tham khảo

Lewin, 1997, Genes VI. Semenza, 1994, Transcriptional regulation of gene expression: mechanisms and pathophysiology., Hum Mutat., 3, 180, 10.1002/humu.1380030304 Alberts, 1989, Molecular Biology of the Cell. Gray, 1998, Control of translation initiation in animals., Annu Rev Cell Dev Biol., 14, 399, 10.1146/annurev.cellbio.14.1.399 Kozak, 1999, Initiation of translation in prokaryotes and eukaryotes., Gene., 234, 187, 10.1016/S0378-1119(99)00210-3 Barabino, 1999, Last but not least: regulated poly(A) tail formation., Cell., 99, 9, 10.1016/S0092-8674(00)80057-4 Rao, 1988, The 5′ untranslated sequence of the c-sis/platelet-derived growth factor 2 transcript is a potent translational inhibitor., Mol Cell Biol., 8, 284, 10.1128/MCB.8.1.284 Bernstein, 1997, PDGF2/c-sis mRNA leader contains a differentiation-linked internal ribosomal entry site (D-IRES)., J Biol Chem., 272, 9356, 10.1074/jbc.272.14.9356 Kim, 1992, Post-transcriptional regulation of the human transforming growth factor-beta 1 gene., J Biol Chem., 267, 13702, 10.1016/S0021-9258(18)42270-3 Grens, 1990, The 5′- and 3′-untranslated regions of ornithine decarboxylase mRNA affect the translational efficiency., J Biol Chem., 265, 11810, 10.1016/S0021-9258(19)38470-4 Manzella, 1990, Regulation of rat ornithine decarboxylase mRNA translation by its 5′-untranslated region., J Biol Chem., 265, 11817, 10.1016/S0021-9258(19)38471-6 Theil, 1994, Iron regulatory elements (IREs): a family of mRNA non-coding sequences., Biochem J., 304, 1, 10.1042/bj3040001 Klausner, 1993, Regulating the fate of mRNA: the control of cellular iron metabolism., Cell., 72, 19, 10.1016/0092-8674(93)90046-S Gunshin, 1997, Cloning and characterization of a mammalian proton-coupled metal-ion transporter., Nature., 388, 482, 10.1038/41343 Nielsen, 1995, Growth-dependent translation of IGF-II mRNA by a rapamycin-sensitive pathway., Nature., 377, 358, 10.1038/377358a0 Nielsen, 1999, A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development., Mol Cell Biol., 19, 1262, 10.1128/MCB.19.2.1262 Rogers, 1999, Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5′-untranslated region sequences., J Biol Chem., 274, 6421, 10.1074/jbc.274.10.6421 Ghilardi, 1998, Thrombopoietin production is inhibited by a translational mechanism., Blood., 92, 4023, 10.1182/blood.V92.11.4023 Namen, 1988, Stimulation of B-cell progenitors by cloned murine interleukin-7., Nature., 333, 571, 10.1038/333571a0 Bamford, 1996, Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type I region /IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation., Proc Natl Acad Sci U S A., 93, 2897, 10.1073/pnas.93.7.2897 Nishimura, 1998, Translational efficiency is up-regulated by alternative exon in murine IL-15 mRNA., J Immunol., 160, 936, 10.4049/jimmunol.160.2.936 Arrick, 1991, Inhibition of translation of transforming growth factor-beta 3 mRNA by its 5′ untranslated region., Mol Cell Biol., 11, 4306, 10.1128/MCB.11.9.4306 Arrick, 1994, Enhanced translational efficiency of a novel transforming growth factor beta 3 mRNA in human breast cancer cells., Mol Cell Biol., 14, 619, 10.1128/MCB.14.1.619 Huez, 1998, Two independent internal ribosome entry sites are involved in translation initiation of vascular endothelial growth factor mRNA., Mol Cell Biol., 18, 6178, 10.1128/MCB.18.11.6178 Harigai, 1996, A cis-acting element in the BCL-2 gene controls expression through translational mechanisms., Oncogene., 12, 1369 Phelps, 1998, Coupled transcriptional and translational control of cyclin-dependent kinase inhibitor p18INK4c expression during myogenesis., Mol Cell Biol., 18, 2334, 10.1128/MCB.18.4.2334 Mize, 1998, The inhibitory upstream open reading frame from mammalian S-adenosylmethionine decarboxylase mRNA has a strict sequence specificity in critical positions., J Biol Chem., 273, 32500, 10.1074/jbc.273.49.32500 Parola, 1994, The peptide product of a 5′ leader cistron in the beta 2 adrenergic receptor mRNA inhibits receptor synthesis., J Biol Chem., 269, 4497, 10.1016/S0021-9258(17)41806-0 McGraw, 1998, Polymorphisms of the 5′ leader cistron of the human beta2-adrenergic receptor regulate receptor expression., J Clin Invest., 102, 1927, 10.1172/JCI4862 Ossipow, 1993, CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials., Proc Natl Acad Sci U S A., 90, 8219, 10.1073/pnas.90.17.8219 Descombes, 1991, A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA., Cell., 67, 569, 10.1016/0092-8674(91)90531-3 Acland, 1990, Subcellular fate of the int-2 oncoprotein is determined by choice of initiation codon., Nature., 343, 662, 10.1038/343662a0 Florkiewicz, 1989, Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons., Proc Natl Acad Sci U S A., 86, 3978, 10.1073/pnas.86.11.3978 Prats, 1989, High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons., Proc Natl Acad Sci U S A., 86, 1836, 10.1073/pnas.86.6.1836 Arnaud, 1999, A new 34-kilodalton isoform of human fibroblast growth factor 2 is cap dependently synthesized by using a non-AUG start codon and behaves as a survival factor., Mol Cell Biol., 19, 505, 10.1128/MCB.19.1.505 Hann, 1988, A non-AUG translational initiation in c-myc exon 1 generates an N-terminally distinct protein whose synthesis is disrupted in Burkitt's lymphomas., Cell., 52, 185, 10.1016/0092-8674(88)90507-7 Hann, 1992, Translational activation of the non-AUG-initiated c-myc 1 protein at high cell densities due to methionine deprivation., Genes Dev., 6, 1229, 10.1101/gad.6.7.1229 Carter, 1999, Differential expression of Myc1 and Myc2 isoforms in cells transformed by eIF4E: evidence for internal ribosome repositioning in the human c-myc 5′UTR., Oncogene., 18, 4326, 10.1038/sj.onc.1202890 Saris, 1991, The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG., EMBO J., 10, 655, 10.1002/j.1460-2075.1991.tb07994.x Packham, 1997, Mammalian cells express two differently localized Bag-1 isoforms generated by alternative translation initiation., Biochem J., 328, 807, 10.1042/bj3280807 Yang, 1999, Cloning and characterization of the human BAG-1 gene promoter: upregulation by tumor-derived p53 mutants., Oncogene., 18, 4546, 10.1038/sj.onc.1202843 Kozak, 1996, Interpreting cDNA sequences: some insights from studies on translation., Mamm Genome., 7, 563, 10.1007/s003359900171 Miller, 1990, cis-Acting sequences involved in the translational control of GCN4 expression., Biochim Biophys Acta., 1050, 151, 10.1016/0167-4781(90)90157-W Ruan, 1996, The upstream open reading frame of the mRNA encoding S-adenosylmethionine decarboxylase is a polyamine-responsive translational control element., J Biol Chem., 271, 29576, 10.1074/jbc.271.47.29576 Cao, 1996, Inhibition of nascent-peptide release at translation termination., Mol Cell Biol., 16, 7109, 10.1128/MCB.16.12.7109 Su, 1998, The G185R mutation disrupts function of the iron transporter Nramp2., Blood., 92, 2157, 10.1182/blood.V92.6.2157 Zhou, 1998, HFE gene knockout produces mouse model of hereditary hemochromatosis., Proc Natl Acad Sci U S A., 95, 2492, 10.1073/pnas.95.5.2492 Fleming, 1999, Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1., Proc Natl Acad Sci U S A., 96, 3143, 10.1073/pnas.96.6.3143 Rouault, 1989, The iron-responsive element binding protein: a method for the affinity purification of a regulatory RNA-binding protein., Proc Natl Acad Sci U S A., 86, 5768, 10.1073/pnas.86.15.5768 Haile, 1989, Regulation of interaction of the iron-responsive element binding protein with iron-responsive RNA elements., Mol Cell Biol., 9, 5055, 10.1128/MCB.9.11.5055 Samaniego, 1994, Molecular characterization of a second iron-responsive element binding protein, iron regulatory protein 2: structure, function, and post-translational regulation., J Biol Chem., 269, 30904, 10.1016/S0021-9258(18)47367-X Gray, 1994, Iron regulatory protein prevents binding of the 43S translation pre-initiation complex to ferritin and eALAS mRNAs., EMBO J., 13, 3882, 10.1002/j.1460-2075.1994.tb06699.x Muckenthaler, 1998, IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F., Mol Cell., 2, 383, 10.1016/S1097-2765(00)80282-8 Haile, 1992, Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster., Proc Natl Acad Sci U S A., 89, 7536, 10.1073/pnas.89.16.7536 Iwai, 1998, Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins., Proc Natl Acad Sci U S A., 95, 4924, 10.1073/pnas.95.9.4924 Rogers, 1996, Ferritin translation by interleukin-6: the role of sequences upstream of the start codons of the heavy and light subunit genes., Blood., 87, 2525, 10.1182/blood.V87.6.2525.bloodjournal8762525 Girelli, 1995, A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract., Br J Haematol., 90, 931, 10.1111/j.1365-2141.1995.tb05218.x Bonneau, 1995, Bilateral cataract and high serum ferritin: a new dominant genetic disorder?, J Med Genet., 32, 778, 10.1136/jmg.32.10.778 Beaumont, 1995, Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract., Nature Genet., 11, 444, 10.1038/ng1295-444 Girelli, 1995, Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the “Verona mutation”)., Blood., 86, 4050, 10.1182/blood.V86.11.4050.bloodjournal86114050 Aguilar-Martinez, 1996, A novel mutation in the iron responsive element of ferritin l-subunit gene as a cause for hereditary hyperferritinemia-cataract syndrome [letter]., Blood., 88, 1895, 10.1182/blood.V88.5.1895.bloodjournal8851895 Merkt, 1997, Hereditary hyperferritinemia-cataract syndrome., Dtsch Med Wochenschr., 122, 504, 10.1055/s-2008-1047644 Cazzola, 1997, Hereditary hyperferritinemia-cataract syndrome: relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA., Blood., 90, 814, 10.1182/blood.V90.2.814 Girelli, 1997, Hereditary hyperferritinemia-cataract syndrome caused by a 29-base pair deletion in the iron responsive element of ferritin L-subunit gene., Blood., 90, 2084, 10.1182/blood.V90.5.2084 Arnold, 1997, Hyperferritinaemia in the absence of iron overload., Gut., 41, 408, 10.1136/gut.41.3.408 Martin, 1998, A point mutation in the bulge of the iron-responsive element of the L ferritin gene in two families with the hereditary hyperferritinemia-cataract syndrome., Blood., 91, 319, 10.1182/blood.V91.1.319 Mumford, 1998, Hereditary hyperferritinemia-cataract syndrome: two novel mutations in the L-ferritin iron-responsive element [letter]., Blood., 91, 367, 10.1182/blood.V91.1.367 Cicilano, 1999, Recurrent mutations in the IRE of L-ferritin in hereditary hyperferritinemia-cataract syndrome., Haematologica., 84, 489 Balas, 1999, Description of a new mutation in the L-ferrin iron-responsive element associated with hereditary hyperferritinemia-cataract syndrome in a Spanish family [letter]., Blood., 93, 4020, 10.1182/blood.V93.11.4020 Cremonesi, 1999, Development of a DG-DGGE method for rapid mutational scanning in ferritin L-chain IRE: an approach for screening of hereditary hyperferritinemia cataract syndrome (HHCS) [abstract]. Proceedings of the World Congress on Iron Metabolism., 164 Beaumont, 1999, Genetic studies on patients with elevated serum ferritin levels and no iron overload: evaluation at a two year recruitment [abstract]. Proceedings of the World Congress on Iron Metabolism., 161 Brools, 1999, A novel mutation of the “bulge cytosine” in the human L ferritin iron responsive element causes hyperferritinemia/cataract syndrome [abstract]. Proceedings of the World Congress on Iron Metabolism., 163 Kato, 1999, L-ferritin-Baltimore-1: a novel mutation in the iron response element (C32G) as a cause of the hyperferritinemia-cataract syndrome [abstract]., Blood., 94, 407a Girelli, 1999, Molecular, biochemical and clinical findings in a series of families with the hereditary hyperferritinemia-cataract syndrome. [abstract]., Blood., 94, 644a Allerson, 1999, Clinical severity and thermodynamic effects of iron-responsive element mutations in hereditary hyperferritinemia-cataract syndrome., J Biol Chem., 274, 26439, 10.1074/jbc.274.37.26439 Levi, 1998, Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome., Blood., 91, 4180, 10.1182/blood.V91.11.4180 Arosio, 1999, Hereditary hyperferritinemia cataract syndrome: a de novo mutation in the iron responsive element of the L-ferritin gene., Haematologica., 84, 560 Luukkonen, 1995, Efficiency of reinitiation of translation on human immunodeficiency virus type 1 mRNAs is determined by the length of the upstream open reading frame and by intercistronic distance., J Virol., 69, 4086, 10.1128/JVI.69.7.4086-4094.1995 Kaushansky, 1998, Thrombopoietin., N Engl J Med., 339, 746, 10.1056/NEJM199809103391107 Stoffel, 1996, Thrombopoietin in thrombocytopenic mice: evidence against regulation at the mRNA level and for a direct regulatory role of platelets., Blood., 87, 567, 10.1182/blood.V87.2.567.bloodjournal872567 Cohen-Solal, 1996, Constitutive expression of Mpl ligand transcripts during thrombocytopenia or thrombocytosis., Blood., 88, 2578, 10.1182/blood.V88.7.2578.bloodjournal8872578 Schlemper, 1994, Familial essential thrombocythemia: clinical characteristics of 11 cases in one family., Ann Hematol., 68, 153, 10.1007/BF01727421 Wiestner, 1998, An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia., Nature Genet., 18, 49, 10.1038/ng0198-49 Kondo, 1998, Familial essential thrombocythemia associated with one-base deletion in the 5′-untranslated region of the thrombopoietin gene., Blood., 92, 1091, 10.1182/blood.V92.4.1091 Ghilardi, 1999, A single-base deletion in the thrombopoietin (TPO) gene causes familial essential thrombocytosis through a mechanism of more efficient translation of TPO mRNA [letter]., Blood., 94, 1480, 10.1182/blood.V94.4.1480 Kikuchi, 1995, Familial thrombocytosis., Br J Haematol., 89, 900, 10.1111/j.1365-2141.1995.tb08432.x Ghilardi, 1999, Hereditary thrombocythemia in a Japanese family is caused by a novel point mutation in the thrombopoietin gene., Br J Haematol., 107, 310, 10.1046/j.1365-2141.1999.01710.x Jorgensen, 1998, Familial thrombocytosis associated with overproduction of thrombopoietin due to a novel splice donor site mutation [abstract]., Blood., 92, 205a Fickers, 1974, Thrombocythaemia: familial occurrence and transition into blastic crisis., Acta Haematol., 51, 257, 10.1159/000208303 Slee, 1981, Familial myeloproliferative disease., Acta Med Scand., 210, 321, 10.1111/j.0954-6820.1981.tb09824.x Eyster, 1986, Familial essential thrombocythemia., Am J Med., 80, 497, 10.1016/0002-9343(86)90727-8 Fernandez-Robles, 1990, Familial essential thrombocythemia., Pediatr Hematol Oncol., 7, 373, 10.3109/08880019009033414 Janssen, 1990, Essential thrombocythemia in two sisters originating from different stem cell levels., Blood., 75, 1633, 10.1182/blood.V75.8.1633.1633 Yagisawa, 1990, Familial essential thrombocythemia in a daughter and mother [in Japanese]., Nippon Naika Gakkai Zasshi., 79, 531, 10.2169/naika.79.531 Williams, 1991, Benign familial thrombocytosis., Am J Hematol., 37, 124, 10.1002/ajh.2830370211 Perez-Encinas, 1994, Familial myeloproliferative syndrome., Am J Hematol., 46, 225, 10.1002/ajh.2830460312 Ulibarrena, 1997, Familial essential thrombocythemia associated with von Willebrand disease [letter]., Med Clin (Barc)., 109, 237 Cohen, 1997, Benign familial microcytic thrombocytosis with autosomal dominant transmission., Clin Genet., 52, 47, 10.1111/j.1399-0004.1997.tb02513.x Kunishima, 1998, Genes for thrombopoietin and c-mpl are not responsible for familial thrombocythaemia: a case study., Br J Haematol., 100, 383, 10.1046/j.1365-2141.1998.00571.x Holland, 1999, CDKN2A (P16(INK4a)) and CDK4 mutation analysis in 131 Australian melanoma probands: effect of family history and multiple primary melanomas., Genes Chromosomes Cancer., 25, 339, 10.1002/(SICI)1098-2264(199908)25:4<339::AID-GCC5>3.0.CO;2-H Kamb, 1994, Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus., Nature Genet., 8, 23, 10.1038/ng0994-22 Liu, 1999, Mutation of the CDKN2A 5′ UTR creates an aberrant initiation codon and predisposes to melanoma., Nature Genet., 21, 128, 10.1038/5082 Picard, 1996, Overexpression of the ferritin H subunit in cultured erythroid cells changes the intracellular iron distribution., Blood., 87, 2057, 10.1182/blood.V87.5.2057.2057 Galanello, 1998, Studies of Nramp2, transferrin receptor and transferrin genes as candidate genes for human hereditary microcytic anemia due to defective iron absorption and utilization [abstract]., Blood., 92, 669a Poort, 1996, A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis., Blood., 88, 3698, 10.1182/blood.V88.10.3698.bloodjournal88103698 Burton, 1994, A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells., Proc Natl Acad Sci U S A., 91, 4935, 10.1073/pnas.91.11.4935 Rogers, 1999, Translation of the Alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5′-untranslated region sequences., J Biol Chem., 274, 6421, 10.1074/jbc.274.10.6421