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Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif

Tee, Andrew R. and Proud, Christopher G. (2002) Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif Molecular and Cellular Biology, 22, (6), pp. 1674-1683. (doi:10.1128/MCB.22.6.1674-1683.2002).

Record type: Article

Abstract

Eukaryotic initiation factor 4E (eIF4E) binding proteins (4E-BPs) regulate the assembly of initiation complexes required for cap-dependent mRNA translation. 4E-BP1 undergoes insulin-stimulated phosphorylation, resulting in its release from eIF4E, allowing initiation complex assembly. 4E-BP1 undergoes caspase-dependent cleavage in cells undergoing apoptosis. Here we show that cleavage occurs after Asp24, giving rise to the N-terminally truncated polypeptide {Delta}4E-BP1, which possesses the eIF4E-binding site and all the known phosphorylation sites. {Delta}4E-BP1 binds to eIF4E and fails to become sufficiently phosphorylated upon insulin stimulation to bring about its release from eIF4E. Therefore, {Delta}4E-BP1 acts as a potent inhibitor of cap-dependent translation. Using a mutagenesis approach, we identify a novel regulatory motif of four amino acids (RAIP) which lies within the first 24 residues of 4E-BP1 and which is necessary for efficient phosphorylation of 4E-BP1. This motif is conserved among sequences of 4E-BP1 and 4E-BP2 but is absent from 4E-BP3. Insulin increased the phosphorylation of 4E-BP3 but not sufficiently to cause its release from eIF4E. However, a chimeric protein that was generated by replacing the N terminus of 4E-BP3 with the N-terminal sequence of 4E-BP1 (containing this RAIP motif) underwent a higher degree of phosphorylation and was released from eIF4E. This suggests that the N-terminal sequence of 4E-BP1 is required for optimal regulation of 4E-BPs by insulin.

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Published date: March 2002

Identifiers

Local EPrints ID: 56346
URI: http://eprints.soton.ac.uk/id/eprint/56346
ISSN: 0270-7306
PURE UUID: 0818f15f-6ca5-4add-a439-3c66c385837e

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Date deposited: 07 Aug 2008
Last modified: 17 Jul 2017 14:31

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Contributors

Author: Andrew R. Tee
Author: Christopher G. Proud

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