Interaction of promyelocytic leukemia/p53 affects signal transducer and activator of transcription-3 activity in response to oncostatin M

Abstract

Promyelocytic leukemia (PML) gene, through alternative splicing of its Cterminal region, generates several PML isoforms that interact with specific partners and perform distinct functions. The PML protein is a tumor suppressor that plays an important role by interacting with various proteins. Herein, we investigated the effect of the PML isoforms on oncostatin M (OSM)-induced signal transducer and activator of transcription-3 (STAT-3) transcriptional activity. PML influenced OSMinduced STAT-3 activity in a cell type-specific manner, which was dependent on the p53 status of the cells but regardless of PML isoform. Interestingly, overexpression of PML exerted opposite effects on OSM-induced STAT-3 activity in p53 wild-type and mutant cells. Specifically, overexpression of PML in the cell lines bearing wild-type p53 (NIH3T3 and U87-MG cells) decreased OSM-induced STAT-3 transcriptional activity, whereas overexpression of PML increased OSM-induced STAT-3 transcriptional activity in mutant p53-bearing cell lines (HEK293T and U251-MG cells). When wild-type p53 cells were co-transfected with PML-IV and R273H-p53 mutant, OSM-mediated STAT-3 transcriptional activity was significantly enhanced, compared to that of cells which were transfected with PML-IV alone; however, when cells bearing mutant p53 were co-transfected with PML-IV and wild-type p53, OSM-induced STAT-3 transcriptional activity was significantly decreased, compared to that of transfected cells with PML-IV alone. In conclusion, PML acts together with wild-type or mutant p53 and influences OSM-mediated STAT-3 activity in a negative or positive manner, resulting in the aberrant activation of STAT-3 in cancer cells bearing mutant p53 probably might occur through the interaction of mutant p53 with PML.

Regulating the p53 Tumor Suppressor Network at PML Biomolecular Condensates

“…Although it has been shown that a p53 nonsense mutant can still localize to PML NBs [ 135 ], raising the possibility that other p53 mutants, including the more common p53 missense mutations, also localize to PML NBs, the functional consequences remain largely unexplored. PML has been found to be important for cell proliferation, p53 transactivation [ 136 ], and STAT3 signaling in cancer cells harboring missense p53 mutations [ 137 ]. The interaction of mutant p53 with STAT3 has been shown to increase JAK2/STAT3 signaling, promoting cancer cell proliferation and tumorigenesis [ 138 ].…”