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Am J Physiol Cell Physiol 293: C1093-C1102, 2007. First published July 11, 2007; doi:10.1152/ajpcell.00225.2007
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MUSCLE CELL BIOLOGY AND CELL MOTILITY

GATA-6 mediates human bladder smooth muscle differentiation: involvement of a novel enhancer element in regulating {alpha}-smooth muscle actin gene expression

Akihiro Kanematsu, Aruna Ramachandran, and Rosalyn M. Adam

Urological Diseases Research Center, Children's Hospital Boston, and Department of Surgery, Harvard Medical School, Boston, Massachusetts

Submitted 31 May 2007 ; accepted in final form 8 July 2007

Hollow organs exposed to pathological stimuli undergo phenotypic modulation characterized by altered expression of smooth muscle contractile proteins and loss of normal function. The molecular mechanisms that regulate smooth muscle differentiation, especially in organs other than the vasculature, are poorly understood. In this study, we describe a role for the GATA-6 transcription factor in regulation of human bladder smooth muscle differentiation. Knockdown of endogenous GATA-6 in primary human bladder smooth muscle cells (pBSMC) led to decreased mRNA levels of the differentiation markers {alpha}-smooth muscle actin ({alpha}-SMA), calponin, and smooth muscle myosin heavy chain. Similar effects were obtained following downregulation of GATA-6 by forskolin-induced elevation of intracellular cAMP levels. Forskolin treatment of pBSMC abolished recruitment of GATA-6 to the {alpha}-SMA promoter in vivo and reduced activity of human {alpha}-SMA promoter-directed gene expression by >60%. This inhibitory effect was rescued by enforced expression of wild-type GATA-6 but not by a zinc-finger-deleted mutant, GATA-6-{Delta}ZF, which lacks DNA-binding ability. In silico analysis of a region of the human {alpha}-SMA promoter, described previously as a transcriptional enhancer, identified a putative GATA-binding site at position –919/–913. Point mutation of this site in SMA-Luc abrogated GATA-6-induced activation of promoter activity. Together, these results provide the first evidence for a functional role for GATA-6 in regulation of bladder smooth muscle differentiation. In addition, these findings demonstrate that GATA-6 regulates human {alpha}-SMA expression via a novel regulatory cis element in the {alpha}-SMA promoter-enhancer.

hollow organs; contractile proteins; dedifferentiation; adenosine 3',5'-cyclic monophosphate


Address for reprint requests and other correspondence: R. M. Adam, Urological Diseases Research Center, John F. Enders Research Laboratories, Rm. 1077, 300 Longwood Ave., Boston, MA 02115 (e-mail: rosalyn.adam{at}childrens.harvard.edu)






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