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J Biol Chem, Vol. 275, Issue 19, 14743-14751, May 12, 2000

beta -Cell Differentiation Factor Nkx6.1 Contains Distinct DNA Binding Interference and Transcriptional Repression Domains*

Raghavendra G. MirmiraDagger §, Hirotaka WatadaDagger ||, and Michael S. GermanDagger §**

From the Dagger  Hormone Research Institute and § Department of Medicine, University of California, San Francisco, California 94143

beta -Cell differentiation factor Nkx6.1 is a homeodomain protein expressed in developing and mature beta -cells in the pancreatic islets of Langerhans. To understand how it contributes to beta -cell development and function, we characterized its DNA binding and transactivation properties. A single copy of the homeodomain of Nkx6.1 binds to a strictly conserved 8-base pair DNA consensus sequence, TTAATTAC; even minor variations to this consensus reduce DNA binding affinity significantly. Full-length Nkx6.1, however, has markedly reduced DNA binding affinity due to an acidic domain at the carboxyl end of the molecule that functions as a mobile binding interference domain capable of interrupting the interaction between DNA and DNA binding domains of the helix-turn-helix type. When expressed in fibroblast cell lines, Nkx6.1 represses transcription through isolated Nkx6.1 binding sites; in beta -cell lines, Nkx6.1 specifically represses the intact insulin promoter through TAAT-containing sequences. In Gal4 one-hybrid fusion studies, transcriptional repression maps to a discreet region within the amino terminus. Our findings suggest a model in which Nkx6.1, regulated by interactions through its carboxyl terminus, directs the repression of specific genes in developing and mature beta -cells.

* This work was supported in part by Grant DK21344 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Receipient of Research Career Award K08 from the National Institutes of Health.

|| Receipient of a Juvenile Diabetes Foundation international postdoctoral fellowship.

** To whom correspondence should be addressed: Hormone Research Inst., University of California, 513 Parnassus Ave., San Francisco, CA 94143-0534. Tel.: 415-476-9262; Fax: 415-731-3612; E-mail: mgerman@ biochem.ucsf.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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