Biochemistry and Pharmacology - Research Publications

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Subject: cytokine × Subject: signal transducer and activator of transcription 3 (STAT3) × Subject: nucleocytoplasmic trafficking × Subject: interleukin-6 (IL-6) × Start date: 2012 × End date: 2012 ×

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    Selective STAT3-alpha or -beta expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes
    Ng, IHW ; Ng, DCH ; Jans, DA ; Bogoyevitch, MA (PORTLAND PRESS LTD, 2012-10-01)
    Phosphorylation of STAT3 (signal transducer and activator of transcription 3) is critical for its nuclear import and transcriptional activity. Although a shorter STAT3β spliceform was initially described as a negative regulator of STAT3α, gene knockout studies have revealed that both forms play critical roles. We have expressed STAT3α and STAT3β at comparable levels to facilitate a direct comparison of their functional effects, and have shown their different cytokine-stimulated kinetics of phosphorylation and nuclear translocation. Notably, the sustained nuclear translocation and phosphorylation of STAT3β following cytokine exposure contrasted with a transient nuclear translocation and phosphorylation of STAT3α. Importantly, co-expression of the spliceforms revealed that STAT3β enhanced and prolonged the phosphorylation and nuclear retention of STAT3α, but a STAT3β R609L mutant, with a disrupted SH2 (Src homology 2) domain, was not tyrosine phosphorylated following cytokine stimulation and could not cross-regulate STAT3α. The physiological importance of prolonged phosphorylation and nuclear retention was indicated by transcriptome profiling of STAT3(-/-) cells expressing either STAT3α or STAT3β, revealing the complexity of genes that are up- and down-regulated by the STAT3 spliceforms, including a distinct set of STAT3β-specific genes regulated under basal conditions and after cytokine stimulation. These results highlight STAT3β as a significant transcriptional regulator in its own right, with additional actions to cross-regulate STAT3α phosphorylation and nuclear retention after cytokine stimulation.
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    Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes
    Ng, Ivan H. W. ; Ng, Dominic C. H. ; Jans, David A. ; Bogoyevitch, Marie A. (Portland Press, 2012)