Requirement of the co-repressor homeodomain-interacting protein kinase 2 for ski-mediated inhibition of bone morphogenetic protein-induced transcriptional activation.

Multiple co-repressors such as N-CoR/SMRT, mSin3, and the c-ski proto-oncogene product (c-Ski) mediate the transcriptional repression induced by Mad and the thyroid hormone receptor by recruiting the histone deacetylase complex. c-Ski also binds directly to Smad proteins, which are transcriptional activators in the transforming growth factor-beta (TGF-beta)/bone morphogenetic protein (BMP) ...
signaling pathways, and inhibits TGF-beta/BMP-induced transcriptional activation. However, it remains unknown whether other co-repressor(s) are also involved with Ski in the negative regulation of the TGF-beta/BMP signaling pathways. Here, we report that the co-repressor homeodomain-interacting protein kinase 2 (HIPK2) directly binds to both c-Ski and Smad1. HIPK2 efficiently inhibited Smad1/4-induced transcription from the Smad site-containing promoter. A dominant negative form of HIPK2, in which the ATP binding motif in the kinase domain and the putative phosphorylation sites were mutated, enhanced Smad1/4-dependent transcription and the BMP-induced expression of alkaline phosphatase. Furthermore, the c-Ski-induced inhibition of the Smad1/4-dependent transcription was suppressed by a dominant negative form of HIPK2. The HIPK2 co-repressor activity may be regulated by an uncharacterized HIPK2 kinase. These results indicate that HIPK2, together with c-Ski, plays an important role in the negative regulation of BMP-induced transcriptional activation.
Mesh Terms:
Adenosine Triphosphate, Alkaline Phosphatase, Amino Acid Motifs, Amino Acid Sequence, Bone Morphogenetic Proteins, Carrier Proteins, Cell Division, Cell Line, DNA-Binding Proteins, Gene Expression Regulation, Enzymologic, Genes, Dominant, Glutathione Transferase, Histone Deacetylases, Humans, Luciferases, Microscopy, Fluorescence, Models, Genetic, Molecular Sequence Data, Phosphorylation, Plasmids, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Signal Transduction, Smad Proteins, Smad1 Protein, Trans-Activators, Transcription, Genetic, Transcriptional Activation, Transfection
J. Biol. Chem.
Date: Oct. 03, 2003
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