Homeoprotein DLX-1 Interacts with Smad4 and Blocks a Signaling Pathway from Activin A in Hematopoietic Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-12, Vol.100 (26), p.15577-15582
• Main Authors: Chiba, Shigeru, Takeshita, Kenichi, Imai, Yoichi, Kumano, Keiki, Kurokawa, Mineo, Masuda, Shigeo, Shimizu, Kiyoshi, Nakamura, Shuji, Ruddle, Frank H., Hirai, Hisamaru
• Format: Article
• Language: English
• Subjects: activin A; Activins - metabolism; Biological Sciences; Blood; Cell lines; Cellular biology; Complementary DNA; distal-less gene; DLX-1 protein; DNA, Complementary; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Library; Hematopoietic Stem Cells - physiology; Homeobox genes; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Inhibin-beta Subunits - metabolism; Leukemia; Leukemia, Erythroblastic, Acute; Lymphocytes; Messenger RNA; Molecular Sequence Data; NIH 3T3 cells; Plasmids; Proteins; Signal Transduction - physiology; Smad4 Protein; Trans-Activators - genetics; Trans-Activators - metabolism; Transactivation; Transcription Factors; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2536757100

In the transforming growth factor β (TGF-β) superfamily, activin A, TGF-β1, and bone morphogenic protein 4 (BMP-4) have various effects on hematopoiesis, including early mesodermo-hematogenesis. After these cytokines bind to their respective receptor, a regulatory Smad is phosphorylated and becomes associated with Smad4, the common Smad, and the resulting complex translocates to the nucleus to regulate transcription. DLX1 is the product of a member of the distal-less homeobox gene family, which is known to have important roles in embryogenesis, particularly in craniofacial development, and in GABAergic neurogenesis. DLX1 has been reported to be temporally and spatially coexpressed with BMP-4 during embryogenesis in selected contexts. We report here that, in addition to the previously reported regions/cells, DLX1 is expressed in hematopoietic cells in a lineage-dependent manner and that DLX1 interacts with Smad4 through its homeodomain. We show that it blocks multiple signals from TGF-β superfamily cytokines such as activin A, TGF-β1, and BMP-4, including differentiation of a hematopoietic cell line by activin A. Taken together, these data suggest that DLX1 may function as a regulator of multiple signals from TGF-β superfamily members in broad biological contexts during blood production.