Regulation of NF-κB by PML and PML-RARα

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Ahmed, Abrar
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University College Cork
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The transcription factor NF-κB is the master regulator of the immune response but also acts broadly to regulate gene expression that influences cell survival, proliferation and differentiation. Post-translational modification of NF-κB, phosphorylation in particular, is essential for the transactivation activity of NF-κB. Promyelocytic Leukemia (PML) is a nuclear protein that forms nuclear bodies (PML NBs), sub-nuclear structures that are associated with transcriptionally active genomic regions that have been implicated in multiple processes such as apoptosis, senescence and anti-viral responses. A significant proportion of PML protein is not bound by NBs and there is limited literature to separate the function of diffused PML and PML NBs. Chromosomal translocations leading to the expression of a PML-retinoic acid receptor-α (PML/RARα) fusion protein are causative for acute promyelocytic leukemia (APL). We demonstrate that sumoylation of PML and PML NBs isinvovled in NF-κB- induced transcriptional responses and is required for phosphorylation of NF-κB p65. This is the first study to separate the function of diffused PML and PML NBs. Additionally, our analysis of available transcriptional profiles of all-trans retinoic acid treated APL cells identifies a NF-κB transcriptional programme suppressed by PML/RARα. We further demonstrate that PML/RARα inhibits NF-κB phosphorylation and transcriptional activity. Our findings establish an important role for PML in promoting NF-κB transcriptional activity which may contribute to APL initiation and maintenance. Together, our findings demonstrate a critical role for PML in supporting NF-κB post-translational modification and transcriptional activity and identify a PML/RARα suppressed NF-κB transcriptional programme which may be relevant to the pathogenesis of APL.
NF-κB , PML , PML , PML-RARα , p65
Ahmed, A. 2014. Regulation of NF-κB by PML and PML-RARα. PhD Thesis, University College Cork.