title: Nucleolin inhibits Fas ligand binding and suppresses Fas-mediated apoptosis in vivo via a surface nucleolin-Fas complex.
abstract: Resistance to Fas-mediated apoptosis is associated with poor cancer outcomes and chemoresistance. To elucidate potential mechanisms of defective Fas signaling, we screened primary lymphoma cell extracts for Fas-associated proteins that would have the potential to regulate Fas signaling. An activation-resistant Fas complex selectively included nucleolin. We confirmed the presence of nucleolin-Fas complexes in B-cell lymphoma cells and primary tissues, and the absence of such complexes in B-lymphocytes from healthy donors. RNA-binding domain 4 and the glycine/arginine-rich domain of nucleolin were essential for its association with Fas. Nucleolin colocalized with Fas on the surface of B-cell lymphoma cells. Nucleolin knockdown sensitized BJAB cells to Fas ligand (FasL)-induced and Fas agonistic antibody-induced apoptosis through enhanced binding, suggesting that nucleolin blocks the FasL-Fas interaction. Mice transfected with nucleolin were protected from the lethal effects of agonistic anti-mouse Fas antibody (Jo2) and had lower rates of hepatocyte apoptosis, compared with vector and a non-Fas-binding mutant of nucleolin. Our results show that cell surface nucleolin binds Fas, inhibits ligand binding, and thus prevents induction of Fas-mediated apoptosis in B-cell lymphomas and may serve as a new therapeutic target.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Jillian F
authors.initials: JF
authors.lastname: Wise
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Berkova
authors.forename: Rohit
authors.initials: R
authors.lastname: Mathur
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhu
authors.forename: Frank K
authors.initials: FK
authors.lastname: Braun
authors.forename: Rong-Hua
authors.initials: RH
authors.lastname: Tao
authors.forename: Anita L
authors.initials: AL
authors.lastname: Sabichi
authors.forename: Xue
authors.initials: X
authors.lastname: Ao
authors.forename: Hoyoung
authors.initials: H
authors.lastname: Maeng
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000097796:Nucleolin
chemical_list: D053222:Fas Ligand Protein; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000097796:Nucleolin