| First Author | Tao RH | Year | 2011 |
| Journal | Blood | Volume | 118 |
| Issue | 11 | Pages | 3107-18 |
| PubMed ID | 21803845 | Mgi Jnum | J:184109 |
| Mgi Id | MGI:5320263 | Doi | 10.1182/blood-2011-04-349670 |
| Citation | Tao RH, et al. (2011) PMLRARalpha binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo. Blood 118(11):3107-18 |
| abstractText | 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 alpha (PMLRARalpha). We found PMLRARalpha interaction with Fas in acute promyelocytic leukemia (APL)-derived cells and APL primary cells, and PML-Fas complexes in normal tissues. Binding of PMLRARalpha to Fas was mapped to the B-box domain of PML moiety and death domain of Fas. PMLRARalpha blockage of Fas apoptosis was demonstrated in U937/PR9 cells, human APL cells and transgenic mouse APL cells, in which PMLRARalpha recruited c-FLIP(L/S) and excluded procaspase 8 from Fas death signaling complex. PMLRARalpha expression in mice protected the mice against a lethal dose of agonistic anti-Fas antibody (P < .001) and the protected tissues contained Fas-PMLRARalpha-cFLIP complexes. Taken together, PMLRARalpha 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. |
