A Novel Function of the MA-3 Domains in Transformation and Translation Suppressor Pdcd4 Is Essential for Its Binding to Eukaryotic Translation Initiation Factor 4A

Abstract

〈n ␣-helical MA-3 domain appears in several translation initiation factors, including human eukaryotic translation initiation factor 4G (eIF4G) and DAP-5/NAT1/p97, as well as in the tumor suppressor Pdcd4. The function of the MA-3 domain is, however, unknown. C-terminal eIF4G (eIG4Gc) contains an MA-3 domain that is located within the eIF4A-binding region, suggesting a role for eIF4A binding. Interestingly, C-terminal DAP-5/NAT1/p97 contains an MA-3 domain, but it does not bind to eIF4A. Mutation of amino acid residues conserved between Pdcd4 and eIF4Gc but not in DAP-5/NAT1/p97 to the amino acid residues found in the DAP-5/NAT1/p97 indicates that some of these amino acid residues within the MA-3 domain are critical for eIF4A-binding activity. Translation initiation of capped mRNA is proposed to occur by a ribosomal scanning mechanism (20). A 43S ribosomal complex comprised of a 40S ribosomal subunit, the initiator Met-tRNAi, and translation initiation factors binds to the cap structure of mRNA at the 5Ј end and scans downstream along the 5Ј-untranslated region (5ЈUTR) searching for the initiation codon. The rate-limiting step for this process is the binding of the 40S ribosomal subunit to mRNA. Several eukaryotic translation initiation factors (eIFs), including the critical factor eIF4A, participate in this process.Translation initiation factor eIF4A is a member of the DEAD-box RNA helicase protein family. The DEAD-box family proteins catalyze RNA unwinding and/or rearrangement. eIF4A is an ATP-dependent RNA helicase that functions in translation initiation to catalyze the unwinding of mRNA secondary structure at the 5ЈUTR (36

Pdcd4 directly binds the coding region of c-myb mRNA and suppresses its translation

“…Pdcd4 has been shown to suppress cap-dependent initiation of translation by interacting with eIF4A and inhibiting its helicase activity (Yang et al, 2003a(Yang et al, , 2004; Translation suppression by Pdcd4 P Singh et al however, because the Pdcd4-responsive region is located within the coding region of c-myb mRNA, we also considered the possibility that Pdcd4 might function by slowing down elongating ribosomes or causing ribosomal drop-off. Ribosomal drop-off has been implicated in the translational inhibition caused by microRNAs that target the coding region of certain mRNAs (Nottrott et al, 2006;Petersen et al, 2006).…”

“…Pdcd4 affects transcription of certain genes by modulating the activities of specific transcription factors, such as c-Jun (Yang et al, 2003b;Bitomsky et al, 2004), Sp1 and p53 (Bitomsky et al, 2008). As a translation regulator, Pdcd4 interacts with the eukaryotic translation initiation factor eIF4A, a RNA helicase that catalyzes the unwinding of mRNA secondary structures in 5 0 -untranslated regions (UTRs) (Yang et al, 2003a(Yang et al, , 2004. Binding of Pdcd4 to eIF4A is mediated by the MA-3 domains, whose structure and complex formation with eIF4A have been analyzed in detail (LaRondeLeBlanc et al, 2007;Waters et al, 2007Waters et al, , 2011Suzuki et al, 2008;Chang et al, 2009;Loh et al, 2009).…”

“…Binding of Pdcd4 to eIF4A is mediated by the MA-3 domains, whose structure and complex formation with eIF4A have been analyzed in detail (LaRondeLeBlanc et al, 2007;Waters et al, 2007Waters et al, , 2011Suzuki et al, 2008;Chang et al, 2009;Loh et al, 2009). Because binding of Pdcd4 to eIF4A inhibits the helicase activity of eIF4A (Yang et al, 2003a;Yang et al, 2004), it is believed that Pdcd4 functions as a suppressor of cap-dependent translation of mRNAs with structured 5 0 -UTRs. This assumption was supported by studies, which assessed the effects of Pdcd4 on the translation of artificial RNAs containing 5 0 -hairpin structures (Yang et al, 2003a(Yang et al, , 2004; however, because physiological translational target mRNAs for Pdcd4 have not yet been unambiguously identified, it is presently unclear whether translation of all RNAs containing structured 5 0 -UTRs are suppressed by Pdcd4 or whether there are mechanisms that allow Pdcd4 to target specific mRNAs.…”

Expression patterns of the tumor suppressor PDCD4 and correlation with β-catenin expression in gastric cancers

“…PDCD4/ Pdcd4 protein associates with eIF4A, which binds to eIF4G in the initiation complex eIF4F and inhibits the RNA helicase activity of eIF4A, thereby inhibiting cap-dependent translation (24)(25)(26)(27).…”

Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

“…Molecules regulated by Pdcd4 include p21 (Go¨ke et al, 2004), Cdk4, ornithine decarboxylase (Jansen et al, 2005), carbonic anhydrase II (LankatButtgereit et al, 2004) and JNK/c-Jun/AP-1 (Bitomsky et al, 2004;Yang et al, 2006). Pdcd4 interacts with the translation initiation factors eIF4A and eIF4G and inhibits translation (Yang et al, 2004;Zakowicz et al, 2005). However, little is known of specific gene promoters and cognate transcription factors that mediate Pdcd4-regulated gene expression.…”