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Submitted on February 27, 2006
Accepted on September 19, 2006
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Molecular Endocrinology Group, Department of Clinical Sciences, University of Las Palmas de Gran Canaria - Spain.; Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, Oregon 97239-3098, USA.; Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Norway
* To whom correspondence should be addressed. E-mail: Amilcar.Flores{at}ki.se.
The growth hormone (GH)-activated signal transducer and activator of transcription 5b (STAT5b) is an essential regulator of somatic growth. The transcriptional response to STAT5b in liver is poorly understood. We have combined microarray-based expression profiling and phylogenetic analysis of gene regulatory regions to study the interplay between STAT5b and GH in the regulation of hepatic gene expression. The acute transcriptional response to GH in vivo after a single pulse of GH was studied in the liver of hypophysectomized rats in the presence of either constitutively active (CA) or a dominant-negative (DN) STAT5b delivered by adenoviral gene transfer. Genes showing differential expression in these two situations were analyzed for the presence of STAT5b binding sites in promoter and intronic regions that are phylogenetically conserved between rats and humans. Using this approach, we showed that most rapid transcriptional effects of GH in the liver are not results of direct actions of STAT5b. In addition, we identified novel STAT5b cis regulatory elements in genes such as Frizzled-4, epithelial membrane protein-1 and the suppressor of cytokine signaling 2 (SOCS2). Detailed analysis of SOCS2 promoter demonstrated its direct transcriptional regulation by STAT5b upon GH stimulation. A novel response element was identified within the first intron of the human SOCS2 gene composed of an E-box followed by tandem STAT5b binding sites, both of which are required for full GH responsiveness. In summary, we demonstrate the power of combining transcript profiling with phylogenetic sequence analysis to define novel regulatory paradigms.
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