![]() ![]() Ablation and overexpression experiments suggest an important role of PML in the regulation of cell growth, hematopoietic cell differentiation, tumorigenesis, apoptosis, and RA signaling ( 44, 63). ![]() RING finger proteins are implicated in transcriptional regulation, and some members of the RING family are associated directly with chromatin ( 53). PML belongs to a family of proteins characterized by the presence of a RING finger domain ( 8). These findings indicate that abnormalities in transcriptional repression by the oncogenic fusion proteins may be involved in leukemogenesis. This differential degree of dissociation of corepressors induced by atRA correlates with the ability of histone deacetylase inhibitors and atRA to induce terminal differentiation of these two subtypes of APL cells. Pharmacological concentrations of all- trans-RA (atRA) induce dissociation of the corepressors from PML-RARα, but not PLZF-RARα, due to the presence of an additional, RA-insensitive corepressor-interacting surface on PLZF. Both fusion proteins form homodimers that bind to RA response elements and interact with the nuclear receptor corepressors SMRT (silencing mediator for retinoid and thyroid hormone action) and N-CoR (nuclear receptor corepressor), which in turn recruit a histone deacetylase complex ( 1, 27, 40, 46). Recent studies have focused on analyzing the functional properties of PML-RARα and PLZF-RARα ( 20, 22, 25, 40) in order to understand the molecular basis of leukemogenesis. ![]() Transgenic mice that overexpress PML-RARα or PLZF-RARα developed an APL-like phenotype ( 9, 21, 26), suggesting that these fusion proteins are directly involved in APL pathogenesis. This translocation creates an oncogenic fusion protein, PML-RARα, which contains both the DNA-binding domain (DBD) and ligand-binding domains of RARα and the N terminus of PML. The t(15 17) translocation between PML and RARα accounts for nearly all APL cases. These data suggest that Daxx is a novel nuclear protein bearing transcriptional repressor activity that may be regulated by interaction with PML.Īcute promyelocytic leukemia (APL) arises as a result of chromosomal translocation involving the retinoic acid (RA) receptor α ( RARα) gene on chromosome 17 fused with either the promyelocytic leukemia gene ( PML) on chromosome 15, the promyelocytic leukemia zinc finger gene ( PLZF) on chromosome 11, the nucleophosmin/B23 ( NPM) gene on chromosome 5, or the nuclear mitotic apparatus gene ( NuMA) on chromosome 11 ( 30, 39). Consistently, Daxx is found at condensed chromatin in cells that lack PML. In addition, SUMO-1 modification of PML is required for sequestration of Daxx to the PODs and for efficient inhibition of Daxx-mediated transcriptional repression. PML, but not its oncogenic fusion PML-RARα, inhibits the repressor function of Daxx. Reporter gene assay shows that Daxx drastically represses basal transcription, likely by recruiting histone deacetylases. Biochemical and immunofluorescence analyses reveal that Daxx is a nuclear protein that interacts and colocalizes with PML in the PODs. We isolated the Fas-binding protein Daxx as a PML-interacting protein in a yeast two-hybrid screen. In addition to localizing diffusely throughout the nucleoplasm, PML mainly resides in discrete nuclear structures known as PML oncogenic domains (PODs), which are disrupted in APL and spinocellular ataxia cells. PML fuses with retinoic acid receptor α (RARα) in the t(15 17) translocation that causes acute promyelocytic leukemia (APL). ![]()
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