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Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions

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Abstract

The promyelocytic leukemia protein PML is a tumor and growth suppressor and plays an important role in a multiple pathways of apoptosis and regulation of cell cycle progression. Our previous studies and others also documented a role of PML in transcriptional regulation through its association with transcription coactivator CBP and transcription corepressor HDAC. Here, we showed that PML is a potent transcriptional repressor of Nur77, an orphan receptor and a member of the steroid receptor superfamily of proteins. We found that PML represses Nur77-mediated transactivation through a physical and functional interaction between the two proteins. PML interacts with Nur-77 in vitro in a GST-pull down assay and in vivo by coimmunoprecipitation assay. PML/Nur77 colocalized in vivo in a double immunofluorescent staining and confocal microscopic analysis. Our study further showed that the coiled–coil domain of PML interacts with the DNA-binding domain of Nur77 (amino acids 267–332). Electrophoretic mobility shift assay demonstrated that PML interferes with Nur77 DNA binding in a dose-dependent manner. This study indicates that PML interacts with the DNA-binding domain of Nur77 and represses transcription by preventing it from binding to the target promoter. This study supports a role of PML/Nur77 interaction in regulating cell growth and apoptosis.

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Acknowledgements

DNA sequencing facility and Confocal microscopic analysis were supported by a research grant CA-16627 from the National Cancer Institute. This study was supported by a grant from the National Institute of Health CA-55577 to KS Chang.

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  1. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, TX, USA

    Wen-Shu Wu, Zhi-Xiang Xu, Ruixiang Ran, Feng Meng & Kun-Sang Chang

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  1. Wen-Shu Wu
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  2. Zhi-Xiang Xu
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Correspondence to Kun-Sang Chang.

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Wu, WS., Xu, ZX., Ran, R. et al. Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions. Oncogene 21, 3925–3933 (2002). https://doi.org/10.1038/sj.onc.1205491

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