title: An evolutionarily conserved interaction of tumor suppressor protein Pdcd4 with the poly(A)-binding protein contributes to translation suppression by Pdcd4.
abstract: The tumor suppressor protein programmed cell death 4 (Pdcd4) has been implicated in the translational regulation of specific mRNAs, however, the identities of the natural Pdcd4 target mRNAs and the mechanisms by which Pdcd4 affects their translation are not well understood. Pdcd4 binds to the eukaryotic translation initiation factor eIF4A and inhibits its helicase activity, which has suggested that Pdcd4 suppresses translation initiation of mRNAs containing structured 5'-untranslated regions. Recent work has revealed a second inhibitory mechanism, which is eIF4A-independent and involves direct RNA-binding of Pdcd4 to the target mRNAs. We have now identified the poly(A)-binding protein (PABP) as a novel direct interaction partner of Pdcd4. The ability to interact with PABP is shared between human and Drosophila Pdcd4, indicating that it has been highly conserved during evolution. Mutants of Pdcd4 that have lost the ability to interact with PABP fail to stably associate with ribosomal complexes in sucrose density gradients and to suppress translation, as exemplified by c-myb mRNA. Overall, our work identifies PABP as a novel functionally relevant Pdcd4 interaction partner that contributes to the regulation of translation by Pdcd4.
authors.affiliation: Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Olesja
authors.initials: O
authors.lastname: Fehler
authors.affiliation: Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Singh
authors.affiliation: Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Haas
authors.affiliation: Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Ulrich
authors.affiliation: Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Müller
authors.affiliation: Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ohnheiser
authors.affiliation: Institute for Biochemistry, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149 Münster, Germany klempna@uni-muenster.de.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Klempnauer
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D009154:Mutation; D039102:Poly(A)-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D020598:Proto-Oncogene Proteins c-myb / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D029721:Drosophila Proteins; C114487:PDCD4 protein, human; C572267:Pdcd4 protein, Drosophila; D039102:Poly(A)-Binding Proteins; D020598:Proto-Oncogene Proteins c-myb; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D012313:RNA