Reversal of Creatine Kinase Translational Repression by 3′ Untranslated Sequences

Ch’ng, J. L. C.; Shoemaker, D. L.; Schimmel, Paul; Holmes, Edward W.

doi:10.1126/science.2343304

Cited by 72 publications

(34 citation statements)

References 23 publications

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“…These similarities and the results ofour previous studies exploring the mechanisms of posttranscriptional regulation of histone gene expression in serum-deprived T2 cells lead us to suggest that the translational block of histone and TK genes under hyperoxia may involve mRNA-binding factors that modulate translation and degradation oftheir mRNA (2 1 ). Precedent for this type ofgene regulation comes from recent studies showing that proteins which bind to the 5UTR or 3'UTR of mRNA play an important role in regulation of translation efficiency of genes such as ferritin and transferrin receptor genes (22,23), protamine gene (24), interferon-beta gene (25), and the creatine kinase gene (26). Furthermore, numerous studies focused on the toxic effects of reactive 02 species strongly support the involvement of such trans-acting factors in hyperoxia-induced growth arrest, these factors being either the products of newly induced genes or modifications of preexisting proteins as discussed below.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of lung epithelial cell proliferation by hyperoxia. Posttranscriptional regulation of proliferation-related genes.

Clément

Edeas²,

Chadelat³

et al. 1992

J. Clin. Invest.

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The alveolar surface of the lung is a major target for oxidant injury. After injury, repair of the alveolar epithelium is dependent on the ability of epithelial type 2 (T2) cells to proliferate. The regulation of T2 cell proliferation and the effect of reactive oxygen (02) species on this lung cell proliferation have not been well defined. To investigate this process we focused on the regulation of two late cell cycle genes, histone and thymidine kinase, in T2 cells and fibroblasts exposed in vitro to varying periods of hyperoxia (95% 02). Hyperoxia for 24 to 48 h arrested cell proliferation in a SV40T-immortalized T2 cell line we have developed and in primary and SV40T-immortalized lung fibroblasts. Despite the cessation of proliferation, histone and TK mRNA continued to be expressed at high levels; mRNA half-lives were markedly prolonged but neither protein was translated. Thus proliferation arrest induced by hyperoxia was associated with posttranscriptional control of at least two late cell cycle-related genes. This form of proliferation arrest is also seen when primary and SV40T-T2 cells but not fibroblasts are serum deprived, suggesting that T2 cells in vitro may be uniquely sensitive to alterations in their redox state and that these alterations in turn affect translational control of a subset of proliferation-related genes. (J. Clin. Invest. 1992. 90:1812-1818

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Section: Resultsmentioning

confidence: 99%

Inhibition of lung epithelial cell proliferation by hyperoxia. Posttranscriptional regulation of proliferation-related genes.

Clément

Edeas²,

Chadelat³

et al. 1992

J. Clin. Invest.

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“…Studies in the U937 cell line showed that an inhibition of translation elongation or termination was due to a soluble cytoplasmic factor(s), probably a protein, that bound to a region of the 3' UTR near the termination codon (15,43). The 3' UTR may function to increase protein translation.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, other studies have implicated changes in the 3' UTR of mRNA in the regulation of translation (13). The 3' UTR is involved in the inhibition of translation of y-interferon in Xenopus oocytes (14), and creatine kinase in the U937 cell line (15). Studies with ornithine decarboxylase, which is under translational control by polyamines, have demonstrated coordinated regulation of translation by both the 5' and 3' UTR's (16,17).…”

Section: Introductionmentioning

confidence: 99%

Regulation of lipoprotein lipase translation by epinephrine in 3T3-L1 cells. Importance of the 3' untranslated region.

Yukht¹,

Davis²,

Ong³

et al. 1995

J. Clin. Invest.

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Lipoprotein lipase (LPL) is a central enzyme in lipoprotein metabolism and is in part responsible for adipocyte lipid accumulation. Catecholamines are known to decrease the activity of LPL in adipocytes, and we have previously demonstrated that this inhibition occurs posttranscriptionally, with a prominent inhibition of LPL translation. To better characterize the inhibition of LPL translation, 3T3-L1 cells were differentiated into adipocytes, and exposed to epinephrine. Epinephrine induced a dose-dependent decrease in LPL synthesis using [35S]methionine incorporation, with no change in LPL mRNA levels, demonstrating translational regulation of LPL in this cell line. The poly A-enriched RNA from epinephrine-treated cells was translated well in vitro, and there was no difference in the polysome profiles from control and epinephrine-treated cells, suggesting that epinephrine did not affect mRNA editing, and did not induce an inhibition of translation initiation. To obtain evidence for the presence of an inhibitory factor, a cytoplasmic extract from control, and epinephrine-treated adipocytes was human. When compared to the control cell extract, the epinephrine-treated cell extract sharply inhibited LPL translation in vitro, yet had no effect on the translation of other mRNAs. Epinephrine-treated cells had fourfold more of this inhibitor activity than control cells, and this translation inhibition was partially reversed by heat treatment. To determine what region of the LPL mRNA was involved in the translation inhibition, different LPL constructs were synthesized. The inhibitory effect of the epinephrine-treated cell extract was dependent on the presence of the first 40 nucleotides of the 3' (untranslated region UTR) (nucleotides 1599-1638), whereas deletion of the 5' UTR and other areas of the 3' UTR had no effect on translation inhibition. When a sense RNA strand corresponding to this region was added to the in vitro translation reaction, it restored translation towards normal, suggesting that the sense strand was competing for a transacting binding protein.Thus, epinephrine-treated adipocytes produced a transacting factor, probably a protein, that interacted with a region on the LPL mRNA between nucleotides 1599 and 1638, resulting in an inhibition of translation. These studies add new insight into the hormonal regulation of LPL. (J.

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“…Modulation of translation by protein binding to the 5' or 3' UTR of mRNAs has been implicated as a general cellular regulatory mechanism for many genes including ferritin (22)(23)(24), transferrin receptor (9,25), and creatine kinase (26). Although the proteins and RNA elements of the ferritin and Prm-2 mRNAs differ, comparison of the RNA-protein complexes of ferritin and Prm-2 mRNAs reveals the strikingly similar interactions with cytoplasmic proteins (7,22,23).…”

Section: Methodsmentioning

confidence: 99%

Cytoplasmic protein binding to highly conserved sequences in the 3' untranslated region of mouse protamine 2 mRNA, a translationally regulated transcript of male germ cells.

Kwon

Hecht

1991

Proc. Natl. Acad. Sci. U.S.A.

137

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The expression of the protamines, the predominant nuclear proteins of mammalian spermatozoa, is regulated translationally during male germ-cell development. The 3' untranslated region (UTR) of protamine 1 mRNA has been reported to control its time of translation. To understand the mechanisms controlling translation of the protamine mRNAs, we have sought to identify cis elements of the 3' UTR of protamine 2 mRNA that are recognized by cytoplasmic factors. From gel retardation assays, two sequence elements are shown to form specific RNA-protein complexes. Protein binding sites of the two complexes were determined by RNase T1 mapping, by blocking the putative binding sites with antisense oligonucleotides, and by competition assays. The sequences of these elements, located between nucleotides +537 and +572 in protamine 2 mRNA, are highly conserved among postmeiotic translationally regulated nuclear proteins of the mammalian testis. Two closely linked protein binding sites were detected. UV-crosslinking studies revealed that a protein of about 18 kDa binds to one of the conserved sequences. These data demonstrate specific protein binding to a highly conserved 3' UTR of translationally regulated testicular mRNA.

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Reversal of Creatine Kinase Translational Repression by 3′ Untranslated Sequences

Cited by 72 publications

References 23 publications

Inhibition of lung epithelial cell proliferation by hyperoxia. Posttranscriptional regulation of proliferation-related genes.

Inhibition of lung epithelial cell proliferation by hyperoxia. Posttranscriptional regulation of proliferation-related genes.

Regulation of lipoprotein lipase translation by epinephrine in 3T3-L1 cells. Importance of the 3' untranslated region.

Cytoplasmic protein binding to highly conserved sequences in the 3' untranslated region of mouse protamine 2 mRNA, a translationally regulated transcript of male germ cells.

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