The Transformation Suppressor PDCD4 is a Novel Eukaryotic Translation Initiation Factor 4A Binding Protein that Inhibits Translation

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, United States
Molecular and Cellular Biology (Impact Factor: 4.78). 02/2003; 23(1):26-37. DOI: 10.1128/MCB.23.1.26-37.2003
Source: PubMed


Pdcd4 is a novel transformation suppressor that inhibits tumor promoter-induced neoplastic transformation and the activation
of AP-1-dependent transcription required for transformation. A yeast two-hybrid analysis revealed that Pdcd4 associates with
the eukaryotic translation initiation factors eIF4AI and eIF4AII. Immunofluorescent confocal microscopy showed that Pdcd4
colocalizes with eIF4A in the cytoplasm. eIF4A is an ATP-dependent RNA helicase needed to unwind 5′ mRNA secondary structure.
Recombinant Pdcd4 specifically inhibited the helicase activity of eIF4A and eIF4F. In vivo translation assays showed that
Pdcd4 inhibited cap-dependent but not internal ribosome entry site (IRES)-dependent translation. In contrast, Pdcd4D418A, a mutant inactivated for binding to eIF4A, failed to inhibit cap-dependent or IRES-dependent translation or AP-1 transactivation.
Recombinant Pdcd4 prevented eIF4A from binding to the C-terminal region of eIF4G (amino acids 1040 to 1560) but not to the
middle region of eIF4G(amino acids 635 to 1039). In addition, both Pdcd4 and Pdcd4D418A bound to the middle region of eIF4G. The mechanism by which Pdcd4 inhibits translation thus appears to involve inhibition
of eIF4A helicase, interference with eIF4A association-dissociation from eIF4G, and inhibition of eIF4A binding to the C-terminal
domain of eIF4G. Pdcd4 binding to eIF4A is linked to its transformation-suppressing activity, as Pdcd4-eIF4A binding and consequent
inhibition of translation are required for Pdcd4 transrepression of AP-1.

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