title: GATA-6 and NF-κB activate CPI-17 gene transcription and regulate Ca2+ sensitization of smooth muscle contraction.
abstract: Protein 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 Ca(2+) 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.
authors.affiliation: Division of Urology, University of Pennsylvania, Glenolden, Pennsylvania, USA.
authors.forename: Ettickan
authors.initials: E
authors.lastname: Boopathi
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hypolite
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Zderic
authors.forename: Cristiano Mendes
authors.initials: CM
authors.lastname: Gomes
authors.forename: Bruce
authors.initials: B
authors.lastname: Malkowicz
authors.forename: Hsiou-Chi
authors.initials: HC
authors.lastname: Liou
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Wein
authors.forename: Samuel
authors.initials: S
authors.lastname: Chacko
mesh_terms: D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D017124:Conserved Sequence; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D006984:Hypertrophy / Q000235:genetics / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000235:genetics*; D009130:Muscle, Smooth / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015854:Up-Regulation; D001743:Urinary Bladder / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D001748:Urinary Bladder Neck Obstruction / Q000235:genetics / Q000473:pathology
chemical_list: D050993:GATA6 Transcription Factor; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; C107507:PPP1R14A protein, human; D010750:Phosphoproteins; C491520:Ppp1r14a protein, mouse; D010749:Phosphoprotein Phosphatases; D002118:Calcium