Pax-6 and Cdx-2/3 Interact to Activate Glucagon Gene Expression on the G sub(1) Control Element
The promoter element G sub(1) critical for alpha -cell-specific expression of the glucagon gene contains two AT-rich sequences important for transcriptional activity. Pax-6, a paired homeodomain protein previously shown to be required for normal alpha -cell development and to interact with the enhan...
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Veröffentlicht in: | The Journal of biological chemistry 1999-02, Vol.274 (7), p.4124-4132 |
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Sprache: | eng |
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Zusammenfassung: | The promoter element G sub(1) critical for alpha -cell-specific expression of the glucagon gene contains two AT-rich sequences important for transcriptional activity. Pax-6, a paired homeodomain protein previously shown to be required for normal alpha -cell development and to interact with the enhancer element G sub(3) of the glucagon gene, binds as a monomer to the distal AT-rich site of G sub(1). However, although the paired domain of Pax-6 is sufficient for interaction with the G sub(3) element the paired domain and the homeodomain are required for high affinity binding to G sub(1). In addition to monomer formation, Pax-6 interacts with Cdx-2/3, a caudal-related homeodomain protein binding to the proximal AT- rich site, to form a heterodimer on G sub(1). Both proteins are capable of directly interacting in the absence of DNA. In BHK-21 cells, Pax-6 activates glucagon gene transcription both through G sub(3) and G sub(1), and heterodimerization with Cdx-2/3 on G sub(1) leads to more than additive transcriptional activation. In glucagon- producing cells, both G sub(1) and G sub(3) are critical for basal transcription and the Pax-6 and Cdx-2/3 binding sites are required for activation. We conclude that Pax-6 is not only critical for alpha - cell development but also for glucagon gene transcription by its independent interaction with the two DNA control elements, G sub(1) and G sub(3). |
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ISSN: | 0021-9258 |