Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells

Jeffrey W. Streb, Xiaochun Long, Ting Hein Lee, Qiang Sun, Chad M. Kitchen, Mary A. Georger, Orazio J. Slivano, William S. Blaner, Daniel W. Carr, Irwin H. Gelman, Joseph M. Miano

Research output: Contribution to journalArticle

Abstract

Retinoids are used clinically to treat a number of hyper-proliferative disorders and have been shown in experimental animals to attenuate vascular occlusive diseases, presumably through nuclear receptors bound to retinoic acid response elements (RARE) located in target genes. Here, we show that natural or synthetic retinoids rapidly induce mRNA and protein expression of a specific isoform of A-Kinase Anchoring Protein 12 (AKAP12β) in cultured smooth muscle cells (SMC) as well as the intact vessel wall. Expression kinetics and actinomycin D studies indicate Akap12β is a retinoid-induced, immediate-early gene. Akap12β promoter analyses reveal a conserved RARE mildly induced with atRA in a region that exhibits hyper-acetylation. Immunofluorescence microscopy and protein kinase A (PKA) regulatory subunit overlay assays in SMC suggest a physical association between AKAP12β and PKA following retinoid treatment. Consistent with its designation as a tumor suppressor, inducible expression of AKAP12β attenuates SMC growth in vitro. Further, immunohistochemistry studies establish marked decreases in AKAP12 expression in experimentally-injured vessels of mice as well as atheromatous lesions in humans. Collectively, these results demonstrate a novel role for retinoids in the induction of an AKAP tumor suppressor that blocks vascular SMC growth thus providing new molecular insight into how retiniods may exert their anti-proliferative effects in the injured vessel wall.

Original languageEnglish (US)
Article numbere18538
JournalPloS one
Volume6
Issue number4
DOIs
StatePublished - Apr 11 2011
Externally publishedYes

Fingerprint

tumor suppressor genes
retinoids
Retinoids
Tumor Suppressor Genes
Vascular Smooth Muscle
blood vessels
smooth muscle
myocytes
Smooth Muscle Myocytes
Muscle
Tumors
Genes
protein kinases
Protein Kinases
Cells
Phosphotransferases
cAMP-dependent protein kinase
response elements
retinoic acid
Cell growth

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Streb, J. W., Long, X., Lee, T. H., Sun, Q., Kitchen, C. M., Georger, M. A., ... Miano, J. M. (2011). Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells. PloS one, 6(4), [e18538]. https://doi.org/10.1371/journal.pone.0018538

Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells. / Streb, Jeffrey W.; Long, Xiaochun; Lee, Ting Hein; Sun, Qiang; Kitchen, Chad M.; Georger, Mary A.; Slivano, Orazio J.; Blaner, William S.; Carr, Daniel W.; Gelman, Irwin H.; Miano, Joseph M.

In: PloS one, Vol. 6, No. 4, e18538, 11.04.2011.

Research output: Contribution to journalArticle

Streb, JW, Long, X, Lee, TH, Sun, Q, Kitchen, CM, Georger, MA, Slivano, OJ, Blaner, WS, Carr, DW, Gelman, IH & Miano, JM 2011, 'Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells', PloS one, vol. 6, no. 4, e18538. https://doi.org/10.1371/journal.pone.0018538
Streb, Jeffrey W. ; Long, Xiaochun ; Lee, Ting Hein ; Sun, Qiang ; Kitchen, Chad M. ; Georger, Mary A. ; Slivano, Orazio J. ; Blaner, William S. ; Carr, Daniel W. ; Gelman, Irwin H. ; Miano, Joseph M. / Retinoid-induced expression and activity of an immediate early tumor suppressor gene in vascular smooth muscle cells. In: PloS one. 2011 ; Vol. 6, No. 4.
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