title: PMLRARα binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo.
abstract: Defective Fas signaling leads to resistance to various anticancer therapies. Presence of potential inhibitors of Fas which could block Fas signaling can explain cancer cells resistance to apoptosis. We identified promyelocytic leukemia protein (PML) as a Fas-interacting protein using mass spectrometry analysis. The function of PML is blocked by its dominant-negative form PML-retinoic acid receptor α (PMLRARα). We found PMLRARα interaction with Fas in acute promyelocytic leukemia (APL)-derived cells and APL primary cells, and PML-Fas complexes in normal tissues. Binding of PMLRARα to Fas was mapped to the B-box domain of PML moiety and death domain of Fas. PMLRARα blockage of Fas apoptosis was demonstrated in U937/PR9 cells, human APL cells and transgenic mouse APL cells, in which PMLRARα recruited c-FLIP(L/S) and excluded procaspase 8 from Fas death signaling complex. PMLRARα expression in mice protected the mice against a lethal dose of agonistic anti-Fas antibody (P < .001) and the protected tissues contained Fas-PMLRARα-cFLIP complexes. Taken together, PMLRARα binds to Fas and blocks Fas-mediated apoptosis in APL by forming an apoptotic inhibitory complex with c-FLIP. The presence of PML-Fas complexes across different tissues implicates that PML functions in apoptosis regulation and tumor suppression are mediated by direct interaction with Fas.
authors.affiliation: Departments of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rong-Hua
authors.initials: RH
authors.lastname: Tao
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Berkova
authors.forename: Jillian F
authors.initials: JF
authors.lastname: Wise
authors.forename: Abdol-Hossein
authors.initials: AH
authors.lastname: Rezaeian
authors.forename: Urszula
authors.initials: U
authors.lastname: Daniluk
authors.forename: Xue
authors.initials: X
authors.lastname: Ao
authors.forename: David H
authors.initials: DH
authors.lastname: Hawke
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D020298:U937 Cells; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C491901:FAS protein, human; D015514:Oncogene Proteins, Fusion; D019014:fas Receptor; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein