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J. Biol. Chem., Vol. 280, Issue 27, 25854-25863, July 8, 2005

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Regulation of Smooth Muscle-specific Gene Expression by Homeodomain Proteins, Hoxa10 and Hoxb8^*

Omar El-Mounayri, Jason W. Triplett, Charles W. Yates, and B. Paul Herring

From the Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202

Smooth muscle cells arise from different populations of precursor cells during embryonic development. The mechanisms that specify the smooth muscle cell phenotype in each of these populations of cells are largely unknown. In many tissues and organs, homeodomain transcription factors play a key role in directing cell specification. However, little is known about how these proteins regulate smooth muscle differentiation. Using degenerate reverse transcription-PCR coupled to cDNA library screening we identified two homeodomain proteins, Hoxa10 and Hoxb8, which are expressed in adult mouse smooth muscle tissues. All three of the previously described transcripts of the Hoxa10 gene, Hoxa10-1, Hoxa10-2, and Hoxa10-3, were identified. Hoxa10-1 directly activated the smooth muscle-specific telokin promoter but did not activate the SM22, smooth muscle -actin, or smooth muscle myosin heavy chain promoters. Small interfering RNA-mediated knock-down of Hoxa10-1 demonstrated that Hoxa10-1 is required for high levels of telokin expression in smooth muscle cells from uterus and colon. On the other hand, Hoxb8 inhibited the activity of the telokin, SM22, and smooth muscle -actin promoters. Cotransfection of Hoxa10-1 together with Hoxa10-2 or Hoxb8 suggested that Hoxa10-2 and Hoxb8 act as competitive inhibitors of Hoxa10-1. Results from gel mobility shift assays demonstrated that Hoxa10-1, Hoxa10-2, and Hoxb8 bind directly to multiple sites in the telokin promoter. Mutational analysis of telokin promoter reporter genes demonstrated that the three homeodomain protein binding sites located between -80 and -75, +2 and +6, and +14 and +17 were required for maximal promoter activation by Hoxa10-1 and maximal inhibition by Hoxb8. Together these data demonstrate that the genes encoding smooth muscle-restricted proteins are direct transcriptional targets of clustered homeodomain proteins and that different homeodomain proteins have distinct effects on the promoters of these genes.

Received for publication, January 27, 2005 , and in revised form, April 28, 2005.

^* This work was supported by National Institutes of Health Grants HL58571, DK61130, and DK65644 (to B. P. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202. Tel.: 317-278-1785; Fax: 317-274-3318; E-mail: pherring{at}iupui.edu.

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