title: Differential STAT3 signaling in the heart: Impact of concurrent signals and oxidative stress.
abstract: Multiple lines of evidence suggest that the transcription factor STAT3 is linked to a protective and reparative response in the heart. Thus, increasing duration or intensity of STAT3 activation ought to minimize damage and improve heart function under conditions of stress. Two recent studies using genetic mouse models, however, report findings that appear to refute this proposition. Unfortunately, studies often approach the question of the role of STAT3 in the heart from the perspective that all STAT3 signaling is equivalent, particularly when it comes to signaling by IL-6 type cytokines, which share the gp130 signaling protein. Moreover, STAT3 activation is typically equated with phosphorylation of a critical tyrosine residue. Yet, STAT3 transcriptional behavior is subject to modulation by serine phosphorylation, acetylation, and redox status of the cell. Unphosphorylated STAT3 is implicated in gene induction as well. Thus, how STAT3 is activated and also what other signaling events are occurring at the same time is likely to impact on the outcome ultimately linked to STAT3. Notably STAT3 may serve as a scaffold protein allowing it to interact with other singling pathways. In this context, canonical gp130 cytokine signaling may function to integrate STAT3 signaling with a protective PI3K/AKT signaling network via mutual involvement of JAK tyrosine kinases. Differences in the extent of integration may occur between those cytokines that signal through gp130 homodimers and those through heterodimers of gp130 with a receptor α chain. Signal integration may have importance not only for deciding the particular gene profile linked to STAT3, but for the newly described mitochondrial stabilization role of STAT3 as well. In addition, disruption of integrated gp130-related STAT3 signaling may occur under conditions of oxidative stress, which negatively impacts on JAK catalytic activity. For these reasons, understanding the importance of STAT3 signaling to heart function requires a greater appreciation of the plasticity of this transcription factor in the context in which it is investigated.
authors.affiliation: Department of Pharmacology and Toxicology; School of Medicine; and the Center for Excellence in Cardiovascular-Renal Research; The University of Mississippi Medical Center; Jackson, MS USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Zgheib
authors.forename: Fouad A
authors.initials: FA
authors.lastname: Zouein
authors.forename: Mazen
authors.initials: M
authors.lastname: Kurdi
authors.forename: George W
authors.initials: GW
authors.lastname: Booz
keywords: JAK1; JAK2; cardiac protection; gene expression; intracellular signaling; oxidative stress; preconditioning; redox; signal transduction
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