GATA-6 and NF-κB Activate CPI-17 Gene Transcription and Regulate Ca2+Sensitization of Smooth Muscle Contraction

Author:

Boopathi Ettickan1,Hypolite Joseph A.1,Zderic Stephen A.2,Gomes Cristiano Mendes3,Malkowicz Bruce1,Liou Hsiou-Chi4,Wein Alan J.1,Chacko Samuel15

Affiliation:

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

2. Department of Urology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

3. Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil

4. Division of Immunology, Department of Medicine, Weill Medical College of Cornell University, New York, New York, USA

5. Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Abstract

ABSTRACTProtein kinase C (PKC)-potentiated inhibitory protein of 17 kDa (CPI-17) inhibits myosin light chain phosphatase, altering the levels of myosin light chain phosphorylation and Ca2+sensitivity in smooth muscle. In this study, we characterized the CPI-17 promoter and identified binding sites for GATA-6 and nuclear factor kappa B (NF-κB). GATA-6 and NF-κB upregulated CPI-17 expression in cultured human and mouse bladder smooth muscle (BSM) cells in an additive manner. CPI-17 expression was decreased upon GATA-6 silencing in cultured BSM cells and in BSM from NF-κB knockout (KO) mice. Moreover, force maintenance by BSM strips from KO mice was decreased compared with the force maintenance of BSM strips from wild-type mice. GATA-6 and NF-κB overexpression was associated with CPI-17 overexpression in BSM from men with benign prostatic hyperplasia (BPH)-induced bladder hypertrophy and in a mouse model of bladder outlet obstruction. Thus, aberrant expression of NF-κB and GATA-6 deregulates CPI-17 expression and the contractile function of smooth muscle. Our data provide insight into how GATA-6 and NF-κB mediate CPI-17 transcription, PKC-mediated signaling, and BSM remodeling associated with lower urinary tract symptoms in patients with BPH.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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