Activation of Stat3 in endothelial cells following hypoxia-reoxygenation is mediated by Rac1 and protein Kinase C.

Abstract

Stat3 is an important transcription factor that regulates both proinflammatory and anit-apoptotic pathways in the heart. This study examined the mechanisms of activation of Stat3 in human endothelial cells following hypoxia/reoxygenation (H/R). By expression of constitutively active Rac1 mutant protein, and by RNA silencing of Rac1, we found that Stat3 forms a multiprotein complex with Rac1 and PKC in an H/R-dependent manner, which at least in part, appears to regulate Stat3 S727 phosphorylation. Selective inhibition of PKC with calphostin C produces a marked suppression of Stat3 S727 phosphorylation. The association of Stat3 with Rax1 occurs predominantly at the cell membrane, but also inside the nucleus, and occurs through the binding of the coiled-coil domain of Stat3 to the 54 NH(2)-terminal residues of Rac1. Transfection with a peptide comprising the NH(2)-terminal 17 amino acid residues of Rac1-dependent signaling pathways resulting in physical association between Rac1 and Stat3 and the formation of a novel multiprotein complex with PKC.

• Authors: Subhendra N Mattagajasingh, Xiao Ping Yang, Kaikobad Irani, Ilwola Mattagajasingh, Lewis C Becker
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1823 Issue 5 Pg. 997-1006 (May 2012) ISSN: 0006-3002 [Print] Netherlands
• PMID: 22791907 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Peptides
• RNA, Small Interfering
• Reactive Oxygen Species
• STAT3 Transcription Factor
• STAT3 protein, human
• Phosphoserine
• Phosphotyrosine
• protein kinase C zeta
• Protein Kinase C
• rac1 GTP-Binding Protein
• Oxygen
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Cell Hypoxia (drug effects)
• Cell Membrane (drug effects, enzymology)
• Cell Nucleus (drug effects, enzymology)
• Gene Knockdown Techniques
• Human Umbilical Vein Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• Oxygen (pharmacology)
• Peptides (chemistry, metabolism)
• Phosphorylation (drug effects)
• Phosphoserine (metabolism)
• Phosphotyrosine (metabolism)
• Protein Binding (drug effects)
• Protein Kinase C (metabolism)
• Protein Structure, Tertiary
• Protein Transport (drug effects)
• RNA, Small Interfering (metabolism)
• Reactive Oxygen Species (metabolism)
• STAT3 Transcription Factor (chemistry, metabolism)
• Transfection
• rac1 GTP-Binding Protein (chemistry, metabolism)