Organization and Structure of the 5′ Flanking Region of the Rat Serine Dehydratase Gene1

Noda, Chiseko; Ohguri, Miho; Matsuda, Koichi; Nakamura, Toshikazu; Hasegawa, Akira; Yagi, Shusuke; Ichihara, Akira

doi:10.1093/oxfordjournals.jbchem.a123253

Cited by 11 publications

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“…From a practical perspective, the frequent presence of 5' introns (sometimes directly abutting or even interrupting the AUG codon) necessitates caution in picking a probable start site for translation, and caution in scoring upstream AUG triplets . Many claims ofmRNAs with AUG-burdened 5' noncoding sequences (46,114,125,213,236,238,292,348,387) have been resolved by finding that the 5' portion of the cDNA corresponds not to the mature mRNA but to an intron-containing form (36,135,225,235,284,316,388,407,408). (see reference 193 for additional examples.)…”

Section: ' Noncoding Exons Introns and Upstream Aug Codonsmentioning

confidence: 99%

An analysis of vertebrate mRNA sequences: intimations of translational control.

Kozak¹

1991

The Journal of Cell Biology

1,578

1,042

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Abstract. Five structural features in mRNAs have been found to contribute to the fidelity and efficiency of initiation by eukaryotic ribosomes. Scrutiny of vertebrate cDNA sequences in light of these criteria reveals a set of transcripts-encoding oncoproteins, growth factors, transcription factors, and other regulatory proteins-that seem designed to be translated poorly. Thus, throttling at the level of translation may be a critical component of gene regulation in vertebrates. An alternative interpretation is that some (perhaps many) cDNAs with encumbered 5' noncoding sequences represent mRNA precursors, which would imply extensive regulation at a posttranscriptional step that precedes translation .NITIATIO N oftranslation in multicellular eukaryotes is influenced by five aspects ofmRNA structure : (a) the m7G cap (355); (b) theprimary sequence or context surround ing the AUG codon (187,190,194); (c) the position of the AUG codon, i.e., whether it is the first AUG in the message (186); (d) leader length (198,199) ; and (e) secondary structure both upstream (188, 195) and downstream (196) from the AUG codon . Elsewhere (200) I have reviewed the evidence for these five features and explained how they work together to determine the fidelity and efficiency ofinitiation. A scanning mechanism for initiation can explain many of the effects of cap, context, position, etc . The scanning model (193) in its simplest form postulates that a 40S ribosomal subunit, carrying Met-tRNA;^" and an imperfectly defined set of initiation factors (302), enters at the 5' end of the mRNA and migrates linearly until it reaches the first AUG codon, whereupon a 60S subunit joins and the first peptide bond is formed . Evidence in support of the model has been adduced previously (62,193,197). More recent evidence for scanning includes the apparent queuing of 40S ribosomal subunits on long leader sequences (199) and the stalling of 40S subunits on the 5' side of a stable hairpin structure introduced between the cap and the AUG codon (195). The possibility of initiation by a mechanism other than scanning has been proposed (158) and is evaluated elsewhere (197) .The trick to identifying elements in 5' noncoding sequences that can modulate translation was to isolate each feature (200), an approach made possible by the techniques ofgenetic engineering . For example, by devising a transcript in which the first AUG codon was in an unfavorable context and hence "leaky," we were able to show that downstream

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Section: ' Noncoding Exons Introns and Upstream Aug Codonsmentioning

confidence: 99%

An analysis of vertebrate mRNA sequences: intimations of translational control.

Kozak¹

1991

The Journal of Cell Biology

1,578

1,042

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“…This gene was cloned and its molecular sequence was determined. 19) Furthermore, the genetic mechanisms of the active responses of glucocorticoids and glucagon were determined. 20) These genetic techniques quickly became popular at that time.…”

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Reminiscence of 40-year research on nitrogen metabolism

Ichihara

2010

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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This article summarizes my research over 40 years. The main theme of my work is nitrogen metabolism of amino acids, though later I focused on protein turnover in the cell. In the first years of my research work, I was busy dissecting the pathways involved in the metabolism of certain amino acids and their related enzymes. Then I became interested in the physiology and regulation of matabolism of these amino acids. For that, I used primary cultured hepatocytes, which contain many liver-specific enzymes. However, this play field was very rough around 1970 and hence I had to smooth them (differentiated) first. We discovered a specific growth factor (hepatocyte growth factor, HGF) in rat platelets. Exceptionally, I also worked on branched chain amino acids (valine, leucine and isoleucine). These amino acids are not efficiently metabolized in the liver, so I had to consider the physiology of extrahepatic tissues as well. Finally, I came across a huge protease complex, the proteasome. Whether these players, small amino acid metabolizing enzymes and the huge protease complex, danced well in harmony on my playground or not, I still do not know.

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Interpreting cDNA sequences: Some insights from studies on translation

1996

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This review discusses some rules for assessing the completeness of a cDNA sequence and identifying the start site for translation. Features commonly invoked-such as an ATG codon in a favorable context for initiation, or the presence of an upstream in-frame terminator codon, or the prediction of a signal peptide-like sequence at the amino terminus-have some validity; but examples drawn from the literature illustrate limitations to each of these criteria. The best advice is to inspect a cDNA sequence not only for these positive features but also for the absence of certain negative indicators. Three specific warning signs are discussed and documented: (i) The presence of numerous ATG codons upstream from the presumptive start site for translation often indicates an aberration (sometimes a retained intron) at the 5' end of the cDNA. (ii) Even one strong, upstream, out-of-frame ATG codon poses a problem if the reading frame set by the upstream ATG overlaps the presumptive start of the major open reading frame. Many cDNAs that display this arrangement turn out to be incomplete; that is, the out-of-frame ATG codon is within, rather than upstream from, the protein coding domain. (iii) A very weak context at the putative start site for translation often means that the cDNA lacks the authentic initiator codon. In addition to presenting some criteria that may aid in recognizing incomplete cDNA sequences, the review includes some advice for using in vitro translation systems for the expression of cDNAs. Some unresolved questions about translational regulation are discussed by way of illustrating the importance of verifying mRNA structures before making deductions about translation.

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Organization and Structure of the 5′ Flanking Region of the Rat Serine Dehydratase Gene1

Cited by 11 publications

References 0 publications

An analysis of vertebrate mRNA sequences: intimations of translational control.

An analysis of vertebrate mRNA sequences: intimations of translational control.

Reminiscence of 40-year research on nitrogen metabolism

Interpreting cDNA sequences: Some insights from studies on translation

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