TAILIEUCHUNG - Báo cáo khoa học: An autoinhibitory effect of the homothorax domain of Meis2

Myeloid ecotropic insertion site (Meis)2 is a homeodomain protein contain-ing a conserved homothorax (Hth) domain that is present in all Meis and Prep family proteins and in theDrosophilaHth protein. The Hth domain mediates interaction with Pbx homeodomain proteins, allowing for efficient DNA binding. | An autoinhibitory effect of the homothorax domain of Meis2 Cathy Hyman-Walsh Glen A. Bjerke and David Wotton Department of Biochemistry and Molecular Genetics and Center for CellSignaling University of Virginia Charlottesville VA USA Keywords homeodomain Meis Pbx repression transcription Correspondence D. Wotton Center for Cell Signaling University of Virginia Box 800577 HSC Charlottesville VA 22908 USA Fax 1 434 924 1236 Tel 1 434 243 6752 E-mail dw2p@ Received 16 December 2009 revised 24 March 2010 accepted 30 March 2010 doi Myeloid ecotropic insertion site Meis 2 is a homeodomain protein containing a conserved homothorax Hth domain that is present in all Meis and Prep family proteins and in the Drosophila Hth protein. The Hth domain mediates interaction with Pbx homeodomain proteins allowing for efficient DNA binding. Here we show that like Meis1 Meis2 has a strong C-termi-nal transcriptional activation domain which is required for full activation of transcription by homeodomain protein complexes composed of Meis2 and Pbx1. We also show that the activity of the activation domain is inhibited by the Hth domain and that this autoinhibition can be partially relieved by the interaction of Pbx1 with the Hth domain of Meis2. Targeting of the Hth domain to DNA suggests that it is not a portable transacting repression domain. However the Hth domain can inhibit a linked activation domain and this inhibition is not limited to the Meis2 activation domain. Database searching reveals that the splice variant which is found in several vertebrate species disrupts the Hth domain by removing 17 codons from the 5 -end of exon 6. We show that the equivalent deletion in Meis2 derepresses the C-terminal activation domain and weakens interaction with Pbx1. This work suggests that the transcriptional activity of all members of the Meis Prep Hth protein family is subject to autoinhibition by their Hth domains and that the .

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