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Molecular Pharmacology

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Research ArticleArticle

Genetic Profiling of α1-Adrenergic Receptor Subtypes by Oligonucleotide Microarrays: Coupling to Interleukin-6 Secretion but Differences in STAT3 Phosphorylation and gp-130

Pedro J. Gonzalez-Cabrera, Robert J. Gaivin, June Yun, Sean A. Ross, Robert S. Papay, Dan F. McCune, Boyd R. Rorabaugh and Dianne M. Perez
Molecular Pharmacology May 2003, 63 (5) 1104-1116; DOI: https://doi.org/10.1124/mol.63.5.1104
Pedro J. Gonzalez-Cabrera
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Robert J. Gaivin
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June Yun
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Sean A. Ross
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Robert S. Papay
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Dan F. McCune
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Boyd R. Rorabaugh
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Dianne M. Perez
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Abstract

α1-Adrenoceptor subtypes (α1A-, α1B-, α1D-) are known to couple to similar signaling pathways, although differences among the subtypes do exist. As a more sensitive assay, we used oligonucleotide microarrays to identify gene expression changes in Rat-1 fibroblasts stably expressing each individual subtype. We report the gene expressions that change by at least a factor of 2 or more. Gene expression profiles significantly changed equally among all three subtypes, despite the unequal efficacy of the inositol phosphate response. Gene expressions were clustered into cytokines/growth factors, transcription factors, enzymes, and extracellular matrix proteins. There were also a number of individual subtype-specific changes in gene expression, suggesting a link to independent pathways. In addition, all three α1-AR subtypes robustly stimulated the transcription of the prohypertrophic cytokine interleukin (IL)-6, but differentially altered members of the IL-6 signaling pathway (gp-130 and STAT3). This was confirmed by measurement of secreted IL-6, activated STAT3, and gp-130 levels. Activation of STAT3 Tyr705 phosphorylation by the α1-ARs was not through IL-6 activation but was synergistic with IL-6, suggesting direct effects. Interestingly, α1B-AR stimulation caused the dimerization-dependent phosphorylation of Tyr705 on STAT3 but did not activate the transcriptional-dependent phosphorylation of Ser727. The α1B-AR also constitutively down-regulated the protein levels of gp-130. These results suggest that the α1B-AR has differential effects on the phosphorylation status of the STAT3 pathway and may not be as prohypertrophic as the other two subtypes.

Footnotes

  • ↵1 Present address: GlaxoSmithKline Inc., 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709.

  • This work was funded by R01-HL61438 (to D.M.P.), a local American Heart Association fellowship to (to S.A.R. and P.J.G.-C.), an NRSA (to D.F.M.), and a T32-HL07914 training grant in Vascular Cell Biology (to B.R. and J.Y.).

  • Abbreviations:
    AR
    adrenergic receptor
    GPCR
    G protein-coupled receptor
    IL
    interleukin
    IP
    inositol phosphate
    MAPK
    mitogen-activated protein kinase
    STAT
    signal transducer and activator of transcription
    125I-BE-2254
    2-[β-(4-hydroxy-3-[125I]iodophenyl)ethylaminomethyl]tetralone
    DMEM
    Dulbecco's modified essential medium
    PBS
    phosphate-buffered saline
    CCF
    Cleveland Clinic Foundation
    PM
    perfectly matched
    MM
    mismatched
    ELISA
    enzyme-linked immunosorbent assay
    JAK
    Janus tyrosine kinase
    LIF
    leukemia inhibitory factor
    VEGF
    vascular endothelial growth factor
    gp
    glycoprotein
    • Received August 29, 2002.
    • Accepted February 4, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (5)
Molecular Pharmacology
Vol. 63, Issue 5
1 May 2003
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Research ArticleArticle

Genetic Profiling of α1-Adrenergic Receptor Subtypes by Oligonucleotide Microarrays: Coupling to Interleukin-6 Secretion but Differences in STAT3 Phosphorylation and gp-130

Pedro J. Gonzalez-Cabrera, Robert J. Gaivin, June Yun, Sean A. Ross, Robert S. Papay, Dan F. McCune, Boyd R. Rorabaugh and Dianne M. Perez
Molecular Pharmacology May 1, 2003, 63 (5) 1104-1116; DOI: https://doi.org/10.1124/mol.63.5.1104

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Research ArticleArticle

Genetic Profiling of α1-Adrenergic Receptor Subtypes by Oligonucleotide Microarrays: Coupling to Interleukin-6 Secretion but Differences in STAT3 Phosphorylation and gp-130

Pedro J. Gonzalez-Cabrera, Robert J. Gaivin, June Yun, Sean A. Ross, Robert S. Papay, Dan F. McCune, Boyd R. Rorabaugh and Dianne M. Perez
Molecular Pharmacology May 1, 2003, 63 (5) 1104-1116; DOI: https://doi.org/10.1124/mol.63.5.1104
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