Role of programmed cell death 4 in diseases: a double-edged sword.

Abstract

The molecule of programmed cell death 4 (PDCD4) is named based on its upregulation during apoptosis. It is now known that PDCD4 is highly conserved during evolution and widely expressed in the immune cells and non-immune cells of humans and other animals. PDCD4, as an inhibitor of gene transcription and translation, is very important in maintaining the normal function of cells.1, 2 PDCD4 protein contains an N-terminal domain and two MA-3 domains in the central and C-terminal regions. The MA-3 domains can competitively bind to the translation initiation factor eIF4A with eIF4G to inhibit eIF4A activity and to impact the translation of specific mRNAs containing structured 5′-untranslated regions (5′UTRs).2 In this eIF4A-dependent manner, PDCD4 is able to inhibit the translational initiation of multiple genes, including tumor suppressor gene p53, apoptosis-related gene pro-caspase 3, autophagy-related gene Atg5 and metabolism-related gene LXR-α.3, 4, 5, 6 With its N-terminal domain, PDCD4 interacts with specific RNA secondary structures, such as c-myb and A-myb (proto-oncogene) mRNAs, and thereby suppresses translation elongation.7 The N-terminal domain is also responsible for PDCD4 functional interference by binding to certain proteins, such as poly (A)-binding protein (PABP), Daxx (a scaffold protein with roles in diverse processes, including transcriptional regulation and DNA-damage signaling), transcription factor Twist1 and the p65 subunit of NF-κB.8, 9, 10, 11 In addition, PDCD4 can also inhibit the activation of the ERK/P38 MAPK pathway and thereby suppress the expression of cytokines, such as Interleukin-10 (IL-10) (Figure 1a).12