title: MiR-133b targets antiapoptotic genes and enhances death receptor-induced apoptosis.
abstract: Despite the importance of microRNAs (miRs) for regulation of the delicate balance between cell proliferation and death, evidence for their specific involvement during death receptor (DR)-mediated apoptosis is scarce. Transfection with miR-133b rendered resistant HeLa cells sensitive to tumor necrosis factor-alpha (TNFα)-induced cell death. Similarly, miR-133b caused exacerbated proapoptotic responses to TNF-related apoptosis-inducing ligand (TRAIL) or an activating antibody to Fas/CD95. Comprehensive analysis, encompassing global RNA or protein expression profiling performed by microarray experiments and pulsed stable isotope labeling with amino acids in cell culture (pSILAC), led to the discovery of the antiapoptotic protein Fas apoptosis inhibitory molecule (FAIM) as immediate miR-133b target. Moreover, miR-133b impaired the expression of the detoxifying protein glutathione-S-transferase pi (GSTP1). Expression of miR-133b in tumor specimens of prostate cancer patients was significantly downregulated in 75% of the cases, when compared with matched healthy tissue. Furthermore, introduction of synthetic miR-133b into an ex-vivo model of prostate cancer resulted in impaired proliferation and cellular metabolic activity. PC3 cells were also sensitized to apoptotic stimuli after transfection with miR-133b similar to HeLa cells. These data reveal the ability of a single miR to influence major apoptosis pathways, suggesting an essential role for this molecule during cellular transformation, tumorigenesis and tissue homeostasis.
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Patron
authors.forename: Annika
authors.initials: A
authors.lastname: Fendler
authors.forename: Matthias
authors.initials: M
authors.lastname: Bild
authors.forename: Ulrike
authors.initials: U
authors.lastname: Jung
authors.forename: Henrik
authors.initials: H
authors.lastname: Müller
authors.forename: Magnus Ø
authors.initials: MØ
authors.lastname: Arntzen
authors.forename: Chloe
authors.initials: C
authors.lastname: Piso
authors.forename: Carsten
authors.initials: C
authors.lastname: Stephan
authors.forename: Bernd
authors.initials: B
authors.lastname: Thiede
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Schreiber
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D053218:Receptors, Death Domain / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; C421307:FAIM protein, human; D035683:MicroRNAs; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D005982:Glutathione Transferase