title: Tumor suppressor PDCD4 represses internal ribosome entry site-mediated translation of antiapoptotic proteins and is regulated by S6 kinase 2.
abstract: Apoptosis can be regulated by extracellular signals that are communicated by peptides such as fibroblast growth factor 2 (FGF-2) that have important roles in tumor cell proliferation. The prosurvival effects of FGF-2 are transduced by the activation of the ribosomal protein S6 kinase 2 (S6K2), which increases the expression of the antiapoptotic proteins X chromosome-linked Inhibitor of Apoptosis (XIAP) and Bcl-x(L). We now show that the FGF-2-S6K2 prosurvival signaling is mediated by the tumor suppressor programmed cell death 4 (PDCD4). We demonstrate that PDCD4 specifically binds to the internal ribosome entry site (IRES) elements of both the XIAP and Bcl-x(L) messenger RNAs and represses their translation by inhibiting the formation of the 48S translation initiation complex. Phosphorylation of PDCD4 by activated S6K2 leads to the degradation of PDCD4 and thus the subsequent derepression of XIAP and Bcl-x(L) translation. Our results identify PDCD4 as a specific repressor of the IRES-dependent translation of cellular mRNAs (such as XIAP and Bcl-x(L)) that mediate FGF-2-S6K2 prosurvival signaling and provide further insight into the role of PDCD4 in tumor suppression.
authors.affiliation: Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
authors.forename: Urszula
authors.initials: U
authors.lastname: Liwak
authors.forename: Nehal
authors.initials: N
authors.lastname: Thakor
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Jordan
authors.forename: Rajat
authors.initials: R
authors.lastname: Roy
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lewis
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Pardo
authors.forename: Michael
authors.initials: M
authors.lastname: Seckl
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012270:Ribosomes; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D016222:Fibroblast Growth Factor 2; D019893:Ribosomal Protein S6 Kinases