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J. Biol. Chem., Vol. 281, Issue 15, 10098-10104, April 14, 2006

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Regulation of FOXC1 Stability and Transcriptional Activity by an Epidermal Growth Factor-activated Mitogen-activated Protein Kinase Signaling Cascade^*

Fred B. Berry¹, Farideh Mirzayans, and Michael A. Walter

From the Departments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

Mutations in the FOXC1 transcription factor gene result in Axenfeld Rieger malformations, a disorder that affects the anterior segment of the eye, the teeth, and craniofacial structures. Individuals with this disorder possess an elevated risk for developing glaucoma. Previous work in our laboratory has indicated that FOXC1 transcriptional activity may be regulated by phosphorylation. We report here that FOXC1 is a short-lived protein (t<30 min), and serine 272 is a critical residue in maintaining proper stability of FOXC1. Furthermore, we have demonstrated that activation of the ERK1/2 mitogen-activated protein kinase through epidermal growth factor stimulation is required for maximal FOXC1 transcriptional activation and stability. Finally, we have demonstrated that FOXC1 is targeted to the ubiquitin 26 S proteasomal degradation pathway and that amino acid residues 367–553, which include the C-terminal transactivation domain of FOXC1, are essential for ubiquitin incorporation and proteolysis. These results indicate that FOXC1 protein levels and activity are tightly regulated by post-translational modifications.

Received for publication, December 21, 2005 , and in revised form, February 9, 2006.

^* This work was supported by grants from the Canadian Institutes for Health Research (to M. A. W.). 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.

¹ To whom correspondence should be addressed: Dept. of Ophthalmology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. Tel.: 780-492-3028; Fax: 780-492-6934; E-mail: fberry{at}ualberta.ca.

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