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PMID:20864106

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Citation

Tsoyi, K, Jang, HJ, Nizamutdinova, IT, Park, K, Kim, YM, Kim, HJ, Seo, HG, Lee, JH and Chang, KC (2010) PTEN differentially regulates expressions of ICAM-1 and VCAM-1 through PI3K/Akt/GSK-3β/GATA-6 signaling pathways in TNF-α-activated human endothelial cells. Atherosclerosis 213:115-21

Abstract

Phosphotase and tensin homolog deleted on chromosome 10 (PTEN) is a potent negative regulator of PI3K/Akt pathway. Here, we tried to elucidate the role of PTEN in the regulation of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1, induced by TNF-α in human endothelial cells (ECs). Transfection with PTEN overexpressing vector resulted in the significant decrease in phosphorylation of Akt in TNF-α-treated ECs. PTEN strongly inhibited VCAM-1 but not ICAM-1, however this inhibitory effect was reversed by co-transfection with constitutively active-Akt (CA-Akt-HA) in TNF-α-stimulated ECs. Additionally, silencing of PTEN with specific siRNA showed significant increase of phosphor-Akt compared with TNF-α alone treated ECs. siPTEN significantly upregulated VCAM-1 but was indifferent to ICAM-1 in TNF-α-treated cells. Further, chromatin immunoprecipitation (ChIP) assay showed that PTEN targets GATA-6 but not IRF-1 binding to VCAM-1 promoter. In addition, GATA-6 is associated with glycogen synthesis kinase-3beta (GSK-3β) which is in turn regulated by PTEN-dependent Akt activity. Finally, PTEN significantly prevented monocyte adhesion to TNF-α-induced ECs probably through VCAM-1 regulation. It is concluded that PTEN selectively inhibits expression of VCAM-1 but not ICAM-1 through modulation of PI3K/Akt/GSK-3β/GATA-6 signaling cascade in TNF-α-treated ECs.

Links

PubMed Online version:10.1016/j.atherosclerosis.2010.07.061

Keywords

Cells, Cultured; GATA6 Transcription Factor/metabolism; Gene Expression Regulation; Glycogen Synthase Kinase 3/metabolism; Humans; Intercellular Adhesion Molecule-1/metabolism; PTEN Phosphohydrolase/metabolism; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt/metabolism; RNA, Small Interfering/metabolism; Signal Transduction; Tumor Necrosis Factor-alpha/metabolism; Vascular Cell Adhesion Molecule-1/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:GSK3B

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92908

F

Seeded From UniProt

complete

HUMAN:GATA6

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49841

F

Seeded From UniProt

complete

HUMAN:GSK3B

enables

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92908

F

Seeded From UniProt

complete


See also

References

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