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J. Biol. Chem., Vol. 280, Issue 10, 8994-9004, March 11, 2005
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From the
Department of Medicine, ¶Abramson Family Cancer Research Institute, ||Institute for Medicine and Engineering, and **Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Notch signaling is essential for vascular patterning and response of the vasculature to injury and growth factor stimulation. Despite these findings, the molecular basis of Notch signaling in the vasculature is poorly understood. Here we report that activation of Notch signaling mediated through members of the HRT family of basic helix-loop-helix transcription factors represses smooth muscle cell (SMC) differentiation and expression of genes encoding smooth muscle cell contractile markers. Activation of Notch receptors by Jagged1 or forced expression of the constitutively active Notch1 intracellular domain in C3H10T1/2 fibroblasts inhibited myocardin-dependent transcription of SMC-restricted genes and activity of multiple SMC-restricted transcriptional regulatory elements. Consistent with these findings, forced expression of HRT2 inhibited myocardin-induced expression of SMC-restricted genes and activity of SMC-restricted transcriptional regulatory elements. Moreover, forced expression of HRT2 repressed transcription of multiple SMC-restricted transcriptional regulatory elements in A10 SMCs. The repressive function of HRT2 was not mediated via the capacity of HRT2 to bind SMC CArG elements or by disruption of myocardin-SRF protein complexes. Structure-function analyses of HRT2 indicated that repression required the basic DNA binding domain and additional C-terminal sequence. Taken together, these results demonstrate that Notch signaling represses myocardin-dependent SMC transcription. These data are consistent with a model wherein Notch signaling represses SMC differentiation and maintenance of the contractile SMC phenotype.
Received for publication, November 26, 2004 , and in revised form, December 30, 2004.
* This work was supported in part by National Institutes of Health (NIH) Grants RO1 HL56915 and PO1 HL075380 (to M. S. P.). 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.
Supported by NIH Grant T32 HL0783.
Supported by NIH Grant PO1 CA93615.
To whom correspondence should be addressed: Dept. of Medicine, University of Pennsylvania, 9123 Founders Pavilion, 3400 Spruce St., Philadelphia, PA 19104. Tel.: 215-662-3140; Fax: 215-349-8017; E-mail: Michael.parmacek{at}uphs.upenn.edu.
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