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GATA-6 and NF-κB activate CPI-17 gene transcription and regulate Ca2+ sensitization of smooth muscle contraction

Ettickan Boopathi1, Joseph A Hypolite, Stephen A Zderic

  • 1Division of Urology, University of Pennsylvania, Glenolden, Pennsylvania, USA.

Molecular and Cellular Biology
|January 1, 2013
PubMed

Insights

GATA-6 and nuclear factor kappa B (NF-κB) control the expression of CPI-17, a key protein in smooth muscle contraction. Aberrant GATA-6 and NF-κB activity disrupts smooth muscle function, particularly in bladder conditions like benign prostatic hyperplasia.

Area of Science:

  • Physiology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein kinase C (PKC)-potentiated inhibitory protein of 17 kDa (CPI-17) regulates smooth muscle contractility by inhibiting myosin light chain phosphatase.
  • Altered CPI-17 levels impact myosin light chain phosphorylation and Ca(2+) sensitivity in smooth muscle.

Purpose of the Study:

  • To characterize the CPI-17 promoter and identify key transcription factors regulating its expression.
  • To investigate the roles of GATA-6 and nuclear factor kappa B (NF-κB) in CPI-17 regulation and smooth muscle function.

Main Methods:

  • Promoter analysis to identify transcription factor binding sites.
  • In vitro studies using cultured human and mouse bladder smooth muscle (BSM) cells.
  • Gene silencing and knockout mouse models (NF-κB KO).
  • Assessment of BSM contractility and force maintenance.

Main Results:

  • GATA-6 and NF-κB were identified as binding sites on the CPI-17 promoter.
  • Both factors additively upregulated CPI-17 expression in BSM cells.
  • GATA-6 silencing decreased CPI-17 expression; NF-κB KO mice showed reduced BSM force maintenance.
  • Overexpression of GATA-6 and NF-κB correlated with CPI-17 overexpression in BPH-induced bladder hypertrophy and a mouse model of bladder outlet obstruction.

Conclusions:

  • GATA-6 and NF-κB are critical regulators of CPI-17 transcription in smooth muscle.
  • Aberrant GATA-6 and NF-κB expression disrupts CPI-17 levels and smooth muscle contractile function.
  • These findings offer insights into smooth muscle remodeling and lower urinary tract symptoms in BPH.

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