Selection of initiation sites by eucaryotic ribosomes: effect of inserting AUG triplets upstream from the coding sequence for preproinsulin

Kozak, Marilyn

doi:10.1093/nar/12.9.3873

Cited by 382 publications

(282 citation statements)

References 37 publications

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“…Two in vitro-translated DAP-2 products were detected (47 kDa and 55 kDa; Figure 4a), consistent with the positions of ATG codons at nucleotides 411 and 609 as translational start sites ( Figure 1a). The ATG at position 609 is probably used because its surrounding sequence matches the vertebrate transcriptional start site (Kozak, 1984). However, it is not known whether this start site is used in Drosophila.…”

Section: Dna-binding Propertiesmentioning

confidence: 99%

Cloning and characterization of the Drosophila homologue of the AP-2 transcription factor

et al. 1998

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The AP-2 family of transcription factors (AP-2a, AP-2b and AP-2g) is temporally and spatially regulated in mammals and has also been implicated in oncogenesis. Here we report the isolation of genomic and cDNA clones encoding the Drosophila homologue of AP-2, designated DAP-2. The predicted amino acid sequence exhibits 42 ± 45% overall identity with the vertebrate AP-2 proteins. A sequence of 107 amino acids within the DNA binding and dimerization domain of the vertebrate AP-2 proteins is highly conserved (90 ± 92%) with the DAP-2 homologue. An in vitro translation product of DAP-2 cDNA binds speci®cally to AP-2 consensus binding sites. DAP-2 was also shown to be functionally conserved in vivo because transient transfection of a DAP-2 expression plasmid activated transcription through AP-2 binding sites in both mammalian and Drosophila cell lines. DAP-2 is expressed during early embryogenesis and DAP-2 transcripts are also detected in the adult. Whole-mount in situ hybridizations demonstrated that DAP-2 is expressed initially at stage 9 of Drosophila embryonic development and that DAP-2 transcripts are detected in regions of the brain, eyeantennal disc, optical lobe, antenno-maxillary complex, and in a subset of cells of the ventral nerve cord. The cloning of DAP-2 and the identi®cation of the DAP-2 expression pattern during embryogenesis provides a starting point to address the function of AP-2 during di erentiation and development in a well understood model system.

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Section: Dna-binding Propertiesmentioning

confidence: 99%

Cloning and characterization of the Drosophila homologue of the AP-2 transcription factor

et al. 1998

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“…A further modification of the scanning model of translation initiation states that 40s ribosomal subunits may bypass AUG codons if they do not exist in an optimal sequence context (Kozak, 1984;Losson et al, 1983). The results reported here would tend to support this model since for the A,, serotype which possesses a favourable initiation site for P20a a significant amount of this protein is synthesized.…”

Section: B E C L a R K E A N D Othersmentioning

confidence: 61%

“…Consistent with this model is the observation that 95% of eukaryotic mRNAs do not contain AUG codons upstream of the translational initiation site (Kozak, 19836). A recent modification of this model has been that initiation of translation at internal AUGs can occur provided that the upstream AUGs are closely followed by in-phase terminator codons (Liu et al, 1984;Kozak, 1984).…”

Section: B E C L a R K E A N D Othersmentioning

confidence: 99%

Two Initiation Sites for Foot-and-Mouth Disease Virus Polyprotein in vivo

Clarke¹,

Sangar²,

Burroughs

et al. 1985

Journal of General Virology

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SUMMARYTypically, the translation of eukaryotic mRNAs into protein is initiated at a single site. However, we have recently shown that not one but two primary products, P20a and P I6, are translated from the 5' end of the coding region of the genome of foot-andmouth disease virus (FMDV). In this paper we show by partial protease digestion of these proteins that they differ only at their N termini, thus confirming the presence of two initiation sites for translation of FMDV RNA. Sequence analysis of two subtypes of the virus (Al0 and A12) confirms the presence of two initiator AUG codons in the expected position on the genome. By correlation with protein synthesis data from these subtypes it appears that the relative use of each initiation site is dependent on its surrounding nucleotide sequence. In addition, the ratio of the two proteins when synthesized in vitro differs markedly from that when they are synthesized in vivo, suggesting the presence of a control mechanism for synthesis of P20a in vivo which may be absent in vitro. We also show that the cleavage site between these two proteins and the structural protein precursor, P88, is located closer to the N terminus of the polyprotein than has previously been reported.

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“…Reinitiation of translation refers to the mechanism that allows the ribosome to bind and initiate at a downstream start codon after a stop codon has been met upstream [32][33][34][35] and reviewed in Jackson et al 36 A substantial number (445%) of mammalian genes contain at least one short upstream ORF (upORF) preceding the coding domain of the gene. 34,36 The process of reinitiation is often inefficient.…”

Section: Discussionmentioning

confidence: 99%

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX

et al. 2015

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Mutations in the Aristaless-related homeobox gene (ARX) lead to a range of X-linked intellectual disability phenotypes, with truncating variants generally resulting in severe X-linked lissencephaly with ambiguous genitalia (XLAG), and polyalanine expansions and missense variants resulting in infantile spasms. We report two male patients with early-onset infantile spasms in whom a novel c.34G4T (p.(E12*)) variant was identified in the ARX gene. A similar variant c.81C4G (p.(Y27*)), has previously been described in two affected cousins with early-onset infantile spasms, leading to reinitiation of ARX mRNA translation resulting in an N-terminal truncated protein. We show that the novel c.34G4T (p.(E12*)) variant also reinitiated mRNA translation at the next AUG codon (c.121-123 (p.M41)), producing the same N-terminally truncated protein. The production of both of these truncated proteins was demonstrated to be at markedly reduced levels using in vitro cell assays. Using luciferase reporter assays, we demonstrate that transcriptional repression capacity of ARX was diminished by both the loss of the N-terminal corepressor octapeptide domain, as a consequence of truncation, and the marked reduction in mutant protein expression. Our study indicates that premature termination mutations very early in ARX lead to reinitiation of translation to produce N-terminally truncated protein at markedly reduced levels of expression. We conclude that even low levels of N-terminally truncated ARX is sufficient to improve the patient's phenotype compared with the severe phenotype of XLAG that includes malformations of the brain and genitalia normally seen in complete loss-of-function mutations in ARX.

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Selection of initiation sites by eucaryotic ribosomes: effect of inserting AUG triplets upstream from the coding sequence for preproinsulin

Cited by 382 publications

References 37 publications

Cloning and characterization of the Drosophila homologue of the AP-2 transcription factor

Cloning and characterization of the Drosophila homologue of the AP-2 transcription factor

Two Initiation Sites for Foot-and-Mouth Disease Virus Polyprotein in vivo

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX

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