Feedback Inhibition of Poly(A)-binding Protein mRNA Translation

Bag, Jnanankur

doi:10.1074/jbc.m107676200

Cited by 38 publications

(19 citation statements)

References 58 publications

(55 reference statements)

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“…We confirm the lack of positional requirement for effective inhibition by wild type PABP (38). Moreover, we observe that PABP variants lacking the C terminus are much less efficient in repressing the translation of mRNAs carrying cap-distal A-tracts.…”

supporting

confidence: 67%

“…In contrast, in plant or yeast extracts, which lack endogenous IRP, a cap-distal IRE-IRP complex can arrest ribosomal scanning and efficiently inhibit translation (36,37). As to PABP-mediated translational repression, recent evidence indicates that, in HeLa cells, PABP bound to the A-rich tract in the reporter mRNA 5Ј-UTR, up to 200 nt from the 5Ј cap, stalls the migration of the 40 S ribosomal subunit along the mRNA, preventing it from reaching the AUG and forming the elongating 80 S complex (38).…”

mentioning

confidence: 99%

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Identification of a C-terminal Poly(A)-binding Protein (PABP)-PABP Interaction Domain

Melo

Dhália

et al. 2003

Journal of Biological Chemistry

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The poly(A)-binding protein (PABP), bound to the 3 poly(A) tail of eukaryotic mRNAs, plays critical roles in mRNA translation and stability. PABP autoregulates its synthesis by binding to a conserved A-rich sequence present in the 5-untranslated region of PABP mRNA and repressing its translation. PABP is composed of two parts: the highly conserved N terminus, containing 4 RNA recognition motifs (RRMs) responsible for poly(A) and eIF4G binding; and the more variable C terminus, which includes the recently described PABC domain, and promotes intermolecular interaction between PABP molecules as well as cooperative binding to poly(A). Here we show that, in vitro, GST-PABP represses the translation of reporter mRNAs containing 20 or more A residues in their 5-untranslated regions and remains effective as a repressor when an A 61 tract is placed at different distances from the cap, up to 126 nucleotides. Deletion of the PABP C terminus, but not the PABC domain alone, significantly reduces its ability to inhibit translation when bound to sequences distal to the cap, but not to proximal ones. Moreover, cooperative binding by multiple PABP molecules to poly(A) requires the C terminus, but not the PABC domain. Further analysis using pull-down assays shows that the interaction between PABP molecules, mediated by the C terminus, does not require the PABC domain and is enhanced by the presence of RRM 4. In vivo, fusion proteins containing parts of the PABP C terminus fused to the viral coat protein MS2 have an enhanced ability to prevent the expression of chloramphenicol acetyltransferase reporter mRNAs containing the MS2 binding site at distal distances from the cap. Altogether, our results identify a proline-and glutamine-rich linker located between the RRMs and the PABC domain as being strictly required for PABP/PABP interaction, cooperative binding to poly(A) and enhanced translational repression of reporter mRNAs in vitro and in vivo.

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confidence: 67%

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confidence: 99%

Identification of a C-terminal Poly(A)-binding Protein (PABP)-PABP Interaction Domain

Melo

Dhália

et al. 2003

Journal of Biological Chemistry

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“…[47][48][49][50] The total regulatory system (autoregulation mechanisms of YB-1 and PABP synthesis together with the mechanism of positive regulation of YB-1 mRNA translation by PABP) can maintain YB-1-and PABP concentrations and their ratio in the cell at a level optimal for translation of the majority of cellular mRNAs 10 and provide a prompt response to changing amounts of newly synthesized mRNAs. This is of particular importance for rapidly dividing cells showing high activities in transcription and translation.…”

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confidence: 99%

Specific PABP effect on translation ofYB-1mRNA is neutralized by polyadenylation through a “mini-loop” at 3′ UTR

2012

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“…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).…”

mentioning

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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Feedback Inhibition of Poly(A)-binding Protein mRNA Translation

Cited by 38 publications

References 58 publications

Identification of a C-terminal Poly(A)-binding Protein (PABP)-PABP Interaction Domain

Identification of a C-terminal Poly(A)-binding Protein (PABP)-PABP Interaction Domain

Specific PABP effect on translation ofYB-1mRNA is neutralized by polyadenylation through a “mini-loop” at 3′ UTR

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

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