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Molecular and Cellular Biology, January 2003, p. 26-37, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.26-37.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Transformation Suppressor Pdcd4 Is a Novel Eukaryotic Translation Initiation Factor 4A Binding Protein That Inhibits Translation

Hsin-Sheng Yang,1* Aaron P. Jansen,1 Anton A. Komar,2 Xiaojing Zheng,2 William C. Merrick,2 Sylvain Costes,3 Stephen J. Lockett,3 Nahum Sonenberg,4 and Nancy H. Colburn1

Gene Regulation Section, Center for Cancer Research,1 Image Analysis Laboratory, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland 21702,3 Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4935,2 Department of Biochemistry and McGill Cancer Research Centre, University of McGill, Montreal, Quebec H3G 1Y6, Canada4

Received 26 August 2002/ Returned for modification 19 September 2002/ Accepted 2 October 2002

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.

* Corresponding author. Mailing address: Gene Regulation Section, Bldg. 567, Rm. 180, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702. Phone: (301) 846-6564. Fax: (301) 846-6907. E-mail: hyang{at}ncifcrf.gov.

Molecular and Cellular Biology, January 2003, p. 26-37, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.26-37.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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