S100A6 Regulates Endothelial Cell Cycle Progression by Attenuating Antiproliferative Signal Transducers and Activators of Transcription 1 Signaling

Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1854-67. doi: 10.1161/ATVBAHA.115.306415. Epub 2016 Jul 7.


Objective: S100A6, a member of the S100 protein family, has been described as relevant for cell cycle entry and progression in endothelial cells. The molecular mechanism conferring S100A6's proliferative actions, however, remained elusive.

Approach and results: Originating from the clinically relevant observation of enhanced S100A6 protein expression in proliferating endothelial cells in remodeling coronary and carotid arteries, our study unveiled S100A6 as a suppressor of antiproliferative signal transducers and activators of transcription 1 signaling. Discovery of the molecular liaison was enabled by combining gene expression time series analysis with bioinformatic pathway modeling in S100A6-silenced human endothelial cells stimulated with vascular endothelial growth factor A. This unbiased approach led to successful identification and experimental validation of interferon-inducible transmembrane protein 1 and protein inhibitors of activated signal transducers and activators of transcription as key components of the link between S100A6 and signal transducers and activators of transcription 1.

Conclusions: Given the important role of coordinated endothelial cell cycle activity for integrity and reconstitution of the inner lining of arterial blood vessels in health and disease, signal transducers and activators of transcription 1 suppression by S100A6 may represent a promising therapeutic target to facilitate reendothelialization in damaged vessels.

Keywords: S100A6 protein, human; STAT1 transcription factor; cell cycle; endothelium; protein inhibitors of activated STAT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle* / drug effects
  • Cell Proliferation* / drug effects
  • Cells, Cultured
  • Computational Biology
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Gene Expression Profiling / methods
  • Gene Regulatory Networks
  • Gene Silencing
  • Humans
  • Male
  • Protein Inhibitors of Activated STAT / genetics
  • Protein Inhibitors of Activated STAT / metabolism
  • RNA Interference
  • Rats, Sprague-Dawley
  • Re-Epithelialization
  • S100 Calcium Binding Protein A6
  • S100 Proteins / genetics
  • S100 Proteins / metabolism*
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction
  • Small Ubiquitin-Related Modifier Proteins / genetics
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Sus scrofa
  • Time Factors
  • Transcriptome
  • Transfection
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular System Injuries / genetics
  • Vascular System Injuries / metabolism
  • Vascular System Injuries / pathology


  • Antigens, Differentiation
  • Cell Cycle Proteins
  • PIAS1 protein, human
  • Protein Inhibitors of Activated STAT
  • S100 Calcium Binding Protein A6
  • S100 Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • leu-13 antigen
  • S100A6 protein, human