Thrombopoietin Production Is Inhibited by a Translational Mechanism

Ghilardi, Nico; Wiestner, Adrian; Skoda, Radek C.

doi:10.1182/blood.v92.11.4023.423k54_4023_4030

Cited by 27 publications

(47 citation statements)

References 46 publications

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“…4). Targeted mutagenesis (Ghilardi et al, 1998) confirmed that upstream AUG#7 is primarily responsible for blocking translation of TPO. This is because its near-optimal context (GCCGCCUCCaugG) prevents leaky scanning and the overlapping arrangement precludes reinitiation.…”

Section: Human Thrombopoietin -An Example Of Severely Restricted Tranmentioning

confidence: 90%

“…that view (Kozak, 2001b). Indeed many studies have shown that the strongest inhibition is caused by an upORF that overlaps the start of the downstream cistron (Babik et al, 1999;Bates et al, 1991;Byrne et al, 1995;Cao and Geballe, 1995;Ghilardi et al, 1998;Hansen et al, 2002;Kos et al, 2002;Lee et al, 1999;Liu et al, 1999), which would not be the case if ribosomes could move backwards to reinitiate.…”

Section: Definition and General Rulesmentioning

confidence: 99%

“…A more fundamental complication vis-à-vis which genes to count is the propensity for a single gene to produce transcripts with different 5 0 leader sequences, only some of which have upstream AUG codons (Anant et al, 2002;Aplan et al, 1991;Eerola et al, 2001;Huo and Scarpulla, 1999;Kawakubo and Samuel, 2000;Laurin et al, 2000;Perälä et al, 1994;Perrais et al, 2001;Sanchez-Góngora et al, 2000;Suva et al, 1989;Tanaka et al, 2001;Tsuda et al, 2000;Zimmermann et al, 2000). The significance of a particular form of RNA cannot always be deduced from its abundance, inasmuch as a minor transcript is sometimes the major functional mRNA (Andrea and Walsh, 1995;Babik et al, 1999;Ghilardi et al, 1998;Mitsuhashi and Nikodem, 1989;Nielsen et al, 1990) and incompletely processed transcripts are sometimes more abundant than the fullyspliced, translatable mRNA (Boularand et al, 1995;Frost et al, 2000;Xie et al, 1991;Zachar et al, 1987). Translational regulation mediated by small upORFs is important, as discussed below, but equally important are non-translational mechanisms -use of alternative promoters or splice sites -that simplify the 5 0 UTR by eliminating upORFs in certain tissues or at certain times when elevated synthesis of the protein is required (Aizencang et al, 2000;Anusaksathien et al, 2001;Arrick et al, 1994;Babik et al, 1999;Brown et al, 1999;Horiuchi et al, 1990;Landers et al, 1997;Lee et al, 2000;Nonaka et al, 1989;Phelps et al, 199...…”

Section: Identifying Candidate Genes That Might Be Regulated By Reinimentioning

confidence: 99%

“…Thus, it is not surprising that eliminating upstream AUG codons does not improve translation in every case (Rao et al, 1988;Wood et al, 1996). In many cases, however, mutations targeted to the upstream AUG codons confirmed their role in restricting translation from downstream (Anant et al, 2002;Babik et al, 1999;Bates et al, 1991;Brown et al, 1999;Child et al, 1999a;Gereben et al, 2002;Ghilardi et al, 1998;Griffin et al, 2001;Harigai et al, 1996;Kos et al, 2002;Lee et al, 1999;Marth et al, 1988;Meijer et al, 2000;Pecqueur et al, 2001;Ren and Stiles, 1994;Steel et al, 1996;Tanaka et al, 2001;Tsai et al, 2002;Wang and Wessler, 1998;Wang and Rothnagel, 2001;Wera et al, 1995;Wu et al, 2002). This occurs by a variety of mechanisms, as summarized in Fig.…”

Section: Identifying Candidate Genes That Might Be Regulated By Reinimentioning

confidence: 99%

“…Because of the strong context at AUGs #1 and #2, upORFs 1 and 2 would be more effective than upORFs 5 and 6 in setting up this reinitiation shunt. The depicted scheme is based on experiments described by Ghilardi et al (1998) and Wiestner et al (1998). Additional mutations diagrammed near the bottom of the figure were described by , , and Kondo et al (1998). downstream.…”

Section: Other Uses Of Upstream Orfsmentioning

confidence: 99%

See 4 more Smart Citations

Pushing the limits of the scanning mechanism for initiation of translation

Kozak¹

2002

Gene

801

876

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Selection of the translational initiation site in most eukaryotic mRNAs appears to occur via a scanning mechanism which predicts that proximity to the 5' end plays a dominant role in identifying the start codon. This "position effect" is seen in cases where a mutation creates an AUG codon upstream from the normal start site and translation shifts to the upstream site. The position effect is evident also in cases where a silent internal AUG codon is activated upon being relocated closer to the 5' end. Two mechanisms for escaping the first-AUG rule--reinitiation and context-dependent leaky scanning--enable downstream AUG codons to be accessed in some mRNAs. Although these mechanisms are not new, many new examples of their use have emerged. Via these escape pathways, the scanning mechanism operates even in extreme cases, such as a plant virus mRNA in which translation initiates from three start sites over a distance of 900 nt. This depends on careful structural arrangements, however, which are rarely present in cellular mRNAs. Understanding the rules for initiation of translation enables understanding of human diseases in which the expression of a critical gene is reduced by mutations that add upstream AUG codons or change the context around the AUG(START) codon. The opposite problem occurs in the case of hereditary thrombocythemia: translational efficiency is increased by mutations that remove or restructure a small upstream open reading frame in thrombopoietin mRNA, and the resulting overproduction of the cytokine causes the disease. This and other examples support the idea that 5' leader sequences are sometimes structured deliberately in a way that constrains scanning in order to prevent harmful overproduction of potent regulatory proteins. The accumulated evidence reveals how the scanning mechanism dictates the pattern of transcription--forcing production of monocistronic mRNAs--and the pattern of translation of eukaryotic cellular and viral genes.

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Section: Human Thrombopoietin -An Example Of Severely Restricted Tranmentioning

confidence: 90%

Section: Definition and General Rulesmentioning

confidence: 99%

Section: Identifying Candidate Genes That Might Be Regulated By Reinimentioning

confidence: 99%

Section: Identifying Candidate Genes That Might Be Regulated By Reinimentioning

confidence: 99%

Section: Other Uses Of Upstream Orfsmentioning

confidence: 99%

See 3 more Smart Citations

Pushing the limits of the scanning mechanism for initiation of translation

Kozak¹

2002

Gene

801

876

View full text Add to dashboard Cite

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Some thoughts about translational regulation: Forward and backward glances

Kozak

2007

J of Cellular Biochemistry

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This review discusses the need to re-examine some popular but unproven ideas about regulation of translation in eukaryotes. Translational control is invoked often on superficial grounds, such as a discrepancy between mRNA and protein levels which could be explained instead by rapid turnover of the protein. It is essential to verify that there is translational control (i.e., essential to rule out alternative mechanisms) before asking how translation is regulated. Many of the postulated control mechanisms are dubious. It is easy to create artifactual regulation (a slight increase or decrease in translation) by over-expressing recombinant RNA-binding proteins. The internal-initiation hypothesis is the source of other misunderstandings. Recent claims about the involvement of internal ribosome entry sequences (IRESs) in cancer and other diseases are discussed. The scanning model for initiation provides a more credible framework for understanding many aspects of translation, including ways to restrict the production of potent regulatory proteins which would be harmful if over-expressed. The rare production in eukaryotes of dicistronic mRNAs (e.g., from retrotransposons) raises questions about how the 3' cistron gets translated. Some proposed mechanisms are discussed, but the available evidence does not allow resolution of the issue.

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Thrombopoietin Measurement as a Key Component in the Evaluation of Pediatric Thrombocytosis

Nelson

Marcogliese

Bergstrom

et al. 2016

Pediatr Blood Cancer

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JAK2, MPL, and CALR mutations, which underlie essential thrombocythemia (ET) in most adults, are infrequent in children. Consequently, additional tests are needed to confirm pediatric ET diagnoses. We report a child with suspected ET and p JAK2, MPL, and CALR analyses. Serum thrombopoietin was markedly elevated, leading to analysis of the thrombopoietin gene, TPHO, which contains an upstream open reading frame (uORF) known to repress THPO translation. Sequencing revealed a de novo, germline stopgain mutation in the uORF, explaining the elevated thrombopoietin and thrombocytosis. This suggests that screening thrombopoietin levels and, if elevated, THPO 5’ UTR sequencing could be diagnostic.

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Thrombopoietin Production Is Inhibited by a Translational Mechanism

Cited by 27 publications

References 46 publications

Pushing the limits of the scanning mechanism for initiation of translation

Pushing the limits of the scanning mechanism for initiation of translation

Some thoughts about translational regulation: Forward and backward glances

Thrombopoietin Measurement as a Key Component in the Evaluation of Pediatric Thrombocytosis

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