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.

Role of Eukaryotic Initiation Factors during Cellular Stress and Cancer Progression

“…This favors translation, as the MA-3 protein binding domain of PDCD4 is known to interact with eIF4A Nterminal domain and inhibit its helicase activity. Activation of the helicase activity stimulates the autoinductive pathway and increases levels of oncogenic proteins [56,148,150]. Further, PDCD4 inhibits eIF4A-eIF4G interaction by interacting with eIF4A as well as eIF4G.…”

eIF4A RNA Helicase Associates with Cyclin-Dependent Protein Kinase A in Proliferating Cells and Is Modulated by Phosphorylation

“…eIF4A is the canonical DEAD box RNA-stimulated ATPase and helicase that facilitates translation initiation by unwinding long and complex 59 untranslated region secondary structures common to many eukaryotic mRNAs (Rogers et al, 2002;Tuteja et al, 2008;Parsyan et al, 2011;Andreou and Klostermeier, 2013;Linder and Fuller-Pace, 2013;Marintchev, 2013;Lu et al, 2014;Fehler et al, 2014). eIF4A and the poorly conserved, enigmatic protein eIF4B bind to eIF4G or eIFiso4G in plant cap-binding complexes (Browning and Bailey-Serres, 2015).…”

MRF Family Genes Are Involved in Translation Control, Especially under Energy-Deficient Conditions, and Their Expression and Functions Are Modulated by the TOR Signaling Pathway

“…Indeed, p53 mRNA with a highly structured 59-UTR has been identified as an endogenous target mRNA of hPDCD4 (Wedeken et al, 2011). hPDCD4 also appears to have an additional mechanism of translational suppression; it binds to a secondary structure located in the coding region of c-myb mRNA and blocks translation elongation through interaction with the poly(A) binding protein (Fehler et al, 2014). Thus, the mechanisms of hPDCD4 action in translation control appear to be complex.…”