Translational Control of β and α Globin Chain Synthesis

Fuhr, Joseph E.; Natta, Clayton

doi:10.1038/newbio240274a0

Cited by 31 publications

(11 citation statements)

References 10 publications

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“…The importance of translational regulation in iron homeostasis is well known. Hemoglobin was one of the first mammalian proteins shown to be under translational control (22,25), and the hemin-inactivated protein kinase inhibits global translation by phosphorylating and inhibiting eIF-2␣ (17). The specific repression of ferritin mRNA translation is perhaps the best-understood example of eukaryotic translational control (5,45).…”

Section: Discussionmentioning

confidence: 99%

Delayed Translational Silencing of Ceruloplasmin Transcript in Gamma Interferon-Activated U937 Monocytic Cells: Role of the 3′ Untranslated Region

Mazumder

Fox

1999

Molecular and Cellular Biology

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Ceruloplasmin (Cp) is an acute-phase protein with ferroxidase, amine oxidase, and pro-and antioxidant activities. The primary site of Cp synthesis in human adults is the liver, but it is also synthesized by cells of monocytic origin. We have shown that gamma interferon (IFN-␥) induces the synthesis of Cp mRNA and protein in monocytic cells. We now report that the induced synthesis of Cp is terminated by a mechanism involving transcript-specific translational repression. Cp protein synthesis in U937 cells ceased after 16 h even in the presence of abundant Cp mRNA. RNA isolated from cells treated with IFN-␥ for 24 h exhibited a high in vitro translation rate, suggesting that the transcript was not defective. Ribosomal association of Cp mRNA was examined by sucrose centrifugation. When Cp synthesis was high, i.e., after 8 h of IFN-␥ treatment, Cp mRNA was primarily associated with polyribosomes. However, after 24 h, when Cp synthesis was low, Cp mRNA was primarily in the nonpolyribosomal fraction. Cytosolic extracts from cells treated with IFN-␥ for 24 h, but not for 8 h, contained a factor which blocked in vitro Cp translation. Inhibitor expression was cell type specific and present in extracts of human cells of myeloid origin, but not in several nonmyeloid cells. The inhibitory factor bound to the 3 untranslated region (3-UTR) of Cp mRNA, as shown by restoration of in vitro translation by synthetic 3-UTR added as a "decoy" and detection of a binding complex by RNA gel shift analysis. Deletion mapping of the Cp 3-UTR indicated an internal 100-nucleotide region of the Cp 3-UTR that was required for complex formation as well as for silencing of translation. Although transcript-specific translational control is common during development and differentiation and global translational control occurs during responses to cytokines and stress, to our knowledge, this is the first report of translational silencing of a specific transcript following cytokine activation.Translational control of protein synthesis has specific advantages compared to transcriptional regulation; notably, it offers both rapid induction and rapid reversibility. Translational control is also efficient, since it offers a range of response levels even in the presence of a constant amount of mRNA, thus avoiding energetically inefficient cycling of mRNA by synthesis and degradation. Translational regulation is particularly important during organismal development and cell differentiation and in cells responding to changes in nutrient status or stress (50).Translational control can be loosely divided into two classes: global and transcript-specific control. In global control, the synthesis of many proteins is simultaneously regulated, often in response to stress. In mammalian cells, two protein kinases, double-stranded RNA-dependent protein kinase (PKR) and hemin-regulated inhibitor, globally inhibit protein synthesis by phosphorylation of the eukaryotic translation initiation factor 2 ␣-subunit (eIF2␣) (10). In transcript-specific translational control, th...

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Section: Discussionmentioning

confidence: 99%

Delayed Translational Silencing of Ceruloplasmin Transcript in Gamma Interferon-Activated U937 Monocytic Cells: Role of the 3′ Untranslated Region

Mazumder

Fox

1999

Molecular and Cellular Biology

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“…The difference in alpha/beta ratio between bone marrow cells and reticulocytes of our homozygous patients was less than the average found by Braverman and Bank (6), but there was a considerable range in this parameter among the patients they studied. Several factors influencing the relative amount of alpha and beta globin chain synthesis have been identified in cell-free systems (18,(25)(26)(27)(28), but whether any of these is operative in intact erythroid cells is unknown. Such knowledge might be of value, however, because deliberate reduction of alpha chain synthesis, producing more nearly balanced synthesis of globin chains, might reduce the severity of the disease in the beta thalassemia homozygote (29).…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin Messenger RNA from Human Bone Marrow ISOLATION AND TRANSLATION IN HOMOZYGOUS AND HETEROZYGOUS β-THALASSEMIA

Nienhuis¹,

Canfield²,

Anderson³

1973

J. Clin. Invest.

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“…Recently, several reports utilizing globin and viral mRNAs have also suggested that messenger specific initiation factors are found in eukaryotic cells (3,4). In addition to specific protein factors involved in the translational control of protein synthesis, a number of investigators have raised the possibility that an RNA molecule may also be involved in translational control by directly effecting the initiation of protein synthesis (5)(6)(7)(8).…”

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confidence: 99%

Separation of Specific Initiation Factors Involved in the Translation of Myosin and Myoglobin Messenger RNAs and the Isolation of a New RNA Involved in Translation

Heywood

Kennedy

Bester

1974

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

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Two messenger specific factors, phosphocellulose fractions 3 and 4, have been isolated from the initiation factor 3 fraction of red muscle initiation factors by chromatography on phosphocellulose. When added to a reticulocyte cell-free system containing both myoglobin and myosin mRNAs, phosphocellulose fraction 3 is found to specifically stimulate the synthesis of myoglobin while phosphocellulose fraction 4 is found to specifically stimulate the synthesis of myosin. In addition, a new RNA, isolated from the initiation factor 3 fraction, is shown to specifically inhibit the translation of heterologous mRNAs.Myosin and myoglobin mRNA have been translated in heterologous cell-free systems (1, 2). In these systems the mRNAs to be tested have competed with endogenous mRNAs for the various constituents of the cellular apparatus involved in protein synthesis. Under these conditions, the addition of specific initiation factor 3 (IF-3) fractions has been required to make this competition more favorable and allow for more efficient synthesis of these proteins. Red muscle cells contain specific factors for the translation of both myosin and myoglobin, whereas white muscle cells lack the specific initiation factor for myoglobin synthesis (2). These results have led us to suggest that muscle cells contain a multiplicity of specific initiation factors. Recently, several reports utilizing globin and viral mRNAs have also suggested that messenger specific initiation factors are found in eukaryotic cells (3,4). In addition to specific protein factors involved in the translational control of protein synthesis, a number of investigators have raised the possibility that an RNA molecule may also be involved in translational control by directly effecting the initiation of protein synthesis (5-8).We report here the separation of myosin and myoglobin specific factor activity by chromatography of red-muscle IF-3 on phosphocellulose. Multiple protein fractions are obtained, and two of these fractions are found to have different specificities in translating myosin and myoglobin mRNA in a reticulocyte cell-free system. In addition, a new RNA species, isolated from IF-3 fraction, is shown to specifically inhibit the translation of heterologous mRNAs. This RNA has been termed translation control RNA (tcRNA).

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Translational Control of β and α Globin Chain Synthesis

Cited by 31 publications

References 10 publications

Delayed Translational Silencing of Ceruloplasmin Transcript in Gamma Interferon-Activated U937 Monocytic Cells: Role of the 3′ Untranslated Region

Delayed Translational Silencing of Ceruloplasmin Transcript in Gamma Interferon-Activated U937 Monocytic Cells: Role of the 3′ Untranslated Region

Hemoglobin Messenger RNA from Human Bone Marrow ISOLATION AND TRANSLATION IN HOMOZYGOUS AND HETEROZYGOUS β-THALASSEMIA

Separation of Specific Initiation Factors Involved in the Translation of Myosin and Myoglobin Messenger RNAs and the Isolation of a New RNA Involved in Translation

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