Abstract
The promyelocytic leukemia (PML) protein is a tumor suppressor that is disrupted by the chromosomal translocation t(15;17), a consistent cytogenetic feature of acute promyelocytic leukemia. A role of PML in multiple pathways of apoptosis was conclusively demonstrated using PML(-/-) animal and cell culture models. In a previous study, we found that PML sensitizes tumor necrosis factor-induced apoptosis in tumor necrosis factor (TNF)-resistant U2OS cells. This finding helped to explain the mechanism of PML-induced apoptosis. The zinc finger protein A20 is a target gene of NF kappa B inducible by TNF alpha, and it is a potent inhibitor of TNF-induced apoptosis. In the this study, we demonstrated that PML is a transcriptional repressor of the A20 promoter and that PML represses A20 expression induced by TNF alpha. We showed that PML inhibits A20 transactivation through the NF kappa B site by interfering with its binding to the promoter. We also showed that stable overexpression of A20 inhibits apoptosis and caspase activation induced by PML/TNF alpha. The results of this study suggest that A20 is a downstream target of PML-induced apoptosis and supports a role of A20 in modulating cell death induced by PML/TNF alpha in TNF-resistant cells.
Highlights
The disruption of the promyelocytic leukemia (PML)1 gene by the t(15;17) chromosomal translocation is believed to play an important role in the pathogenesis of acute promyelocytic leukemia (APL) [1]
PML Inhibits Upregulation of A20 Induced by tumor necrosis factor (TNF)␣—Our preliminary study showed that PML significantly sensitized TNF-induced apoptosis in the TNF-resistant cell line U2O
To understand the effects of PML on the TNF-induced apoptotic pathway, we investigated the effect of PML on the expression of A20 in the osteosarcoma cell line U2OS
Summary
The disruption of the promyelocytic leukemia (PML)1 gene by the t(15;17) chromosomal translocation is believed to play an important role in the pathogenesis of acute promyelocytic leukemia (APL) [1]. The zinc finger protein A20 is a target gene of NFB inducible by TNF␣, and it is a potent inhibitor of TNF-induced apoptosis. We demonstrated that PML is a transcriptional repressor of the A20 promoter and that PML represses A20 expression induced by TNF␣.
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