The Expression of Poly(A)-binding Protein Gene Is Translationally Regulated in a Growth-dependent Fashion through a 5′-Terminal Oligopyrimidine Tract Motif

Hornstein, Eran; Git, Anna; Braunstein, Ilana; Avni, Dror; Meyuhas, Oded

doi:10.1074/jbc.274.3.1708

Cited by 71 publications

(93 citation statements)

References 51 publications

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“…46). For example, during liver regrowth after partial hepatectomy, TOP mRNA translation correlates with increased activity of S6K1 and phosphorylation of rpS6 (1,14,18,32). In contrast, cell cycle arrest is associated with selective translational arrest of TOP mRNA translation (12,19,28).…”

Section: Discussionmentioning

confidence: 99%

Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs

Kimball¹,

Orellana²,

O'Connor³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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. Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs. Am J Physiol Endocrinol Metab 285: E637-E644, 2003. First published May 28, 2003 10.1152/ ajpendo.00340.2002In the present study, differential responses of regulatory proteins involved in translation initiation in skeletal muscle and liver during sepsis were studied in neonatal pigs treated with lipopolysaccharide (LPS). LPS did not alter eukaryotic initiation factor (eIF)2B activity in either tissue. In contrast, binding of eIF4G to eIF4E to form the active mRNA-binding complex was repressed in muscle and enhanced in liver. Phosphorylation of eIF4E-binding protein, 4E-BP1, and ribosomal protein S6 kinase, S6K1, was reduced in muscle during sepsis but increased in liver. Finally, changes in 4E-BP1 and S6K1 phosphorylation were associated with altered phosphorylation of the protein kinase mammalian target of rapamycin (mTOR). Overall, the results suggest that translation initiation in both skeletal muscle and liver is altered during neonatal sepsis by modulation of the mRNA-binding step through changes in mTOR activation. Moreover, the LPS-induced changes in factors that regulate translation initiation are more profound than previously reported changes in global rates of protein synthesis in the neonate. This finding suggests that the initiator methionyl-tRNA-rather than the mRNA-binding step in translation initiation may play a more critical role in maintaining protein synthesis rates in the neonate during sepsis. eukaryotic initiation factor 2B; eukaryotic initiation factor 4G; eukaryotic initiation factor 4E; lipopolysaccharide PREVIOUS STUDIES (48, 49) have shown that, in adult rodents, the function of three proteins that play important regulatory roles in translation initiation, i.e., eukaryotic initiation factors eIF2B and eIF4F and the ribosomal protein S6 kinase (S6K1), is downregulated in skeletal muscle of septic rats. eIF2B is a guanine nucleotide exchange factor whose substrate, eIF2, mediates the binding of initiator methionyl-tRNA (mettRNA i ) to the 40S ribosomal subunit (reviewed in Ref. 16). Thus eIF2B modulates the first step in translation initiation, and changes in its activity result in corresponding alterations in global rates of protein synthesis. Binding of mRNA to the 40S ribosomal subunit is mediated by a heterotrimeric complex referred to as eIF4F. The heterotrimeric complex referred to as eIF4F mediates the binding of mRNA to the 40S ribosomal subunit. The three proteins that comprise the eIF4F complex are eIF4A, an RNA helicase, eIF4E, the protein that binds to the m 7 GTP cap structure at the 5Ј-end of the mRNA, and eIF4G, a scaffolding protein that, in addition to eIF4A and eIF4E, also binds to the eIF3 ⅐ 40S ribosomal subunit complex. Thus mRNA binds to the 40S ribosomal subunit through the association of eIF4E with eIF4G.

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Section: Discussionmentioning

confidence: 99%

Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs

Kimball¹,

Orellana²,

O'Connor³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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“…mammalian cells, PABP expression is regulated at the mRNA translational level through two cis-regulatory elements: the terminal oligopyrimidine tract and the autoregulatory sequence (ARS) (23)(24)(25)(26). Although how PABP mRNA translation is controlled has been well studied, the consequence of unregulated PABP expression on cellular physiology is not clear.…”

Section: Effect Of Pabp Overexpression On the Gene Expression Profile-inmentioning

confidence: 99%

“…Therefore, control of PABP expression may be critical for cellular physiology. Accumulated evidences show that PABP expression is regulated primarily at the post-transcriptional level (21)(22)(23)(24)(25)(26)(27). However, in some instances, transcription of the PABP gene can also be regulated (28).…”

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confidence: 99%

Reduced Stability of Mitogen-activated Protein Kinase Kinase-2 mRNA and Phosphorylation of Poly(A)-binding Protein (PABP) in Cells Overexpressing PABP

Musa

Bag

2006

Journal of Biological Chemistry

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The poly(A)-binding protein (PABP) is an important regulator of mRNA translation and stability. The cellular level of PABP is controlled by regulating its mRNA translation by a feedback mechanism. The important aspect of this mechanism is that PABP binds to an adenosine-rich cis-element at the 5-untranslated region of its own mRNA and inhibits its translation. To assess the importance of controlling the PABP level, we studied the effect of PABP overexpression on the transcription profile using the microarray technique. In PABP-overexpressing cells, 19 mRNAs showed a reduction in cellular levels due to reduced mRNA stability, and one showed an increase due to increased mRNA stability. Among these mRNAs, the MKK-2 mRNA encodes the protein kinase activator of ERK1/2 kinase, which is involved in the phosphorylation of eukaryotic initiation factor (eIF) 4E. As a result, mRNA translation may be regulated by the cellular level of MKK-2. In this study, we show that the abundance of the MKK-2 polypeptide is reduced in PABP-overexpressing cells. In these cells, the levels of phosphorylated PABP, eIF4E, and ERK2 are also reduced. Treatment of HeLa cells with the MKK-2 inhibitor U0126 reduced PABP phosphorylation, suggesting that the phosphorylation of PABP is mediated by the MKK-2/ ERK signaling pathway. Thus, a novel signaling pathway involving MKK-2 and ERK1/2 may down-regulate the activity of PABP and eIF4E by controlling their phosphorylation and compensates for the effect of excess cellular PABP.Regulation of the rate of protein synthesis is important for the control of cellular growth and differentiation. Cells respond to changes in growth conditions by fine-tuning the rate of mRNA translation. Initiation of mRNA translation is the rate-limiting step and is often regulated by controlling the interaction between the 5Ј-cap of the mRNA and several initiation factors, including eukaryotic initiation factor (eIF) 2 4E, eIF4G, and eIF4A (1). A recent study has shown that the poly(A)-binding protein (PABP) also behaves like a genuine initiation factor because depletion of PABP from a cell-free extract prevents initiation of mRNA translation (2). The 3Ј-poly(A) tail-bound PABP interacts with eIF4G and circularizes the translating mRNA. This process is believed to enhance mRNA translation by promoting recirculation of terminating ribosomal subunits from the 3Ј-end of the mRNA for another round of initiation (3-6). Although this model is widely accepted, it has not been proven to occur in vivo. In addition, if PABP is essential for mRNA translation, it is possible that PABP participates in mRNA translation by a yet unknown mechanism, as the presence of 3Ј-poly(A) (and thus circularization of mRNA) is not essential for translation initiation of capped mRNAs (7,8).PABP binds to the 3Ј-poly(A) track of eukaryotic mRNA. It also interacts with polypeptides involved in regulating the translation and stability of mRNA (9 -12). Among the four highly conserved RNA-binding domains of PABP, the first two show specificity toward poly(A),...

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“…Cell Culture and DNA Transfection-HEK 293 cells were grown and transfected as well as starved for serum or amino acids as described previously (4,5,21). P1798.C7 mouse lymphosarcoma cells were grown as suspension cultures and mitotically arrested by treatment with 0.1 M dexamethasone (Sigma) for 24 h and hormonally withdrawn as described previously (7).…”

Section: Methodsmentioning

confidence: 99%

Lithium Can Relieve Translational Repression of TOP mRNAs Elicited by Various Blocks along the Cell Cycle in a Glycogen Synthase Kinase-3- and S6-Kinase-independent Manner

Stolovich

Lerer

Bolkier

et al. 2005

Journal of Biological Chemistry

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TOP mRNAs are translationally controlled by mitogenic, growth, and nutritional stimuli through a 5-terminal oligopyrimidine tract. Here we show that LiCl can alleviate the translational repression of these mRNAs when progression through the cell cycle is blocked at G 0 , G 1 /S, or G 2 /M phases in different cell lines and by various physiological and chemical means. This derepressive effect of LiCl does not involve resumption of cell division. Unlike its efficient derepressive effect in mitotically arrested cells, LiCl alleviates inefficiently the repression of TOP mRNAs in amino acid-deprived cells and has no effect in lymphoblastoids whose TOP mRNAs are constitutively repressed even when they are proliferating. LiCl is widely used as a relatively selective inhibitor of glycogen synthase kinase-3. However, inhibition per se of this enzyme by more specific drugs failed to derepress the translation of TOP mRNAs, implying that relief of the translational repression of TOP mRNAs by LiCl is carried out in a glycogen synthase kinase-3-independent manner. Moreover, this effect is apparent, at least in some cell lines, in the absence of S6-kinase 1 activation and ribosomal protein S6 phosphorylation, thus further supporting the notion that translational control of TOP mRNAs does not rely on either of these variables.

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The Expression of Poly(A)-binding Protein Gene Is Translationally Regulated in a Growth-dependent Fashion through a 5′-Terminal Oligopyrimidine Tract Motif

Cited by 71 publications

References 51 publications

Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs

Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs

Reduced Stability of Mitogen-activated Protein Kinase Kinase-2 mRNA and Phosphorylation of Poly(A)-binding Protein (PABP) in Cells Overexpressing PABP

Lithium Can Relieve Translational Repression of TOP mRNAs Elicited by Various Blocks along the Cell Cycle in a Glycogen Synthase Kinase-3- and S6-Kinase-independent Manner

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